Potentiation of antiseizure and neuroprotective efficacy of standard nerve agent treatment by addition of tariquidar Neurotoxicology (IF 3.076) Pub Date : 2018-08-18 Gideon F. Meerhoff, Stefanie M. Vester, Peter Hesseling, Steven D. Klaassen, Alex S. Cornelissen, Paul J. Lucassen, Marloes J.A. Joosen
Organophosphate (OP) induced seizures are commonly treated with anticholinergics, oximes and anticonvulsants. Inhibition of P-glycoprotein (PgP) enhanced the efficacy of nerve agent treatment in soman exposed rats. In the present study, the promising effects of the PgP inhibitor tariquidar were investigated in more detail in rats s.c. exposed to 150 µg/kg soman. Treatment with HI-6 and atropine sulfate (125 and 3 mg/kg i.m respectively) was administered 1 minute after exposure. Diazepam (0.5 mg/kg i.m.) and/or tariquidar (7.5 mg/kg i.v.) were included either at 1 minute or 40 minutes following onset of seizures. Animals that received tariquidar, in addition to HI-6 and atropine, at 1 min, displayed a rapid normalization of EEG activity and cessation of seizure-associated behaviour. This improvement by addition of tariquidar was even more substantial in animals that also received diazepam, either immediately or delayed. Animals exhibiting lower intensity seizures displayed less severe neuropathology (neuronal loss, microglia activation and astrogliosis), primarily in the piriform cortex, and to a lesser extent amygdala and entorhinal cortex. The present findings suggest that the interaction of tariquidar with atropine may be the decisive factor for enhanced treatment efficacy, given that atropine was previously found to be a PgP substrate. A more thorough understanding of the interactions of nerve agent antidotes, in particular the actions of central anticholinergics with benzodiazepines, could contribute to a future optimization of treatment combinations, particularly those aimed at later stage medical interventions.
Maternal Marginal Iodine Deficiency Delays Cerebellar Bergmann Glial Cell Development in Rat Offspring: Involvement of Notch Signaling Pathway Neurotoxicology (IF 3.076) Pub Date : 2018-08-16 Ye Yu, Yuan Wang, Yi Wang, Jing Dong, Hui Min, Jie Chen
During early pregnancy, iodine deficiency (ID) is linked to adverse effects on child motor and psychomotor function. Maternal marginal ID has become a common public health problem. It is unclear whether marginal ID influences the development of the cerebellum or its underlying mechanisms. Thus, the purpose of this study was to determine the effects of marginal ID on the development of cerebellar Bergmann glial cells (BGs) and investigate the activation of the Notch signaling pathway, which is crucial for the development and morphology of BGs. We treated Wistar rats with an ID diet (iodine content 60 ± 1.5 ng/g) supplemented with deionized water containing different concentrations of potassium iodide (KI) (183, 117, and 0 μg/L for the control, marginal ID, and severe ID groups, respectively) during pregnancy and lactation. We explored the morphology of the BGs by Golgi-Cox staining and immunofluorescence and investigated the Notch signaling pathway using western blot. Our results showed that the marginal ID and severe ID groups had decreased cerebellar BG fiber lengths (P < 0.05 and 0.01, respectively) and numbers (P < 0.01 for both) on postnatal day (PN) 7, PN14, and PN21 compared to the control group. Moreover, the data showed that severe ID significantly reduced Dll1, Notch1, RBP-Jκ, and BLBP protein levels at all three time points. Marginal ID slightly reduced the expression of Notch1 on PN7 (P < 0.05) and PN21 (P < 0.01), RBP-Jκ on PN14 (P < 0.01) and PN21 (P < 0.05), and BLBP on PN7 (P < 0.05). There was no significant difference in Dll1 protein levels between the marginal ID and control groups at any time point. Our study suggests that marginal ID leads to mild damage to BG morphogenesis in the cerebellum. The abnormal regulation of the Notch signaling pathway may be involved in the damage to BGs.
Intravenous anesthetic-induced calcium dysregulation and neurotoxic shift with age during development in primary cultured neurons Neurotoxicology (IF 3.076) Pub Date : 2018-08-11 Satoshi Shibuta, Tomotaka Morita, Jun Kosaka
Anesthetic-induced neurotoxicity in the developing brain is a concern. This neurotoxicity is closely related to anesthetic exposure time, dose, and developmental stages. Using calcium imaging and morphological examinations in vitro, we sought to determine whether intravenous anesthetic-induced direct neurotoxicity varies according to different stages of the days in vitro (DIV) of neurons in primary culture. Cortical neurons from E17 Wistar rats were prepared. On DIV 3, 7, and 13, cells were exposed to the intravenous anesthetics thiopental sodium (TPS), midazolam (MDZ), or propofol (PPF), to investigate direct neurotoxicity using morphological experiments. Furthermore, using calcium imaging, the anesthetic-induced intracellular calcium concentration ([Ca2+]i) elevation was monitored in cells on DIV 4, 8, and 13. All anesthetics elicited significant [Ca2+]i increases on DIV 4. While TPS (100 µM) and MDZ (10 µM) did not alter neuronal death, PPF (10 µM and 100 µM) decreased the survival ratio (SR) significantly. On DIV 8, TPS and MDZ did not elicit [Ca2+]i elevation or SR decrease, while PPF still induced [Ca2+]i elevation (both at 10 µM and 100 μM) and significant SR decrease at 100 μM (0.76 ± 0.03; P < 0.05), but not at 10 μM (0.91 ± 0.03). Such anesthetic-induced [Ca2+]i elevation and SR decrease were not observed on DIV 13―14 for any of the anesthetic drugs. Our study indicates that more caution may be exercised when using PPF compared to TPS or MDZ during development.
Intermittent low-level lead exposure provokes anxiety, hypertension, autonomic dysfunction and neuroinflammation Neurotoxicology (IF 3.076) Pub Date : 2018-08-08 Liana Shvachiy, Vera Geraldes, Ângela Amaro-Leal, Isabel Rocha
Background Exposures to lead (Pb) during developmental phases can alter the normal course of development, with lifelong health consequences. Permanent Pb exposure leads to behavioral changes, cognitive impairment, sympathoexcitation, tachycardia, hypertension and autonomic dysfunction. However, the effects of an intermittent lead exposure are not yet studied. This pattern of exposure has been recently increasing due to migrations, implementation of school exchange programs and/or residential changes. Objective To determine and compare lead effects on mammal’s behavior and physiology, using a rat model of intermittent and permanent Pb exposures. Methods Fetuses were intermittently (PbI) or permanently (PbP) exposed to water containing lead acetate (0.2% w/v) throughout life until adulthood (28 weeks of age). A control group (CTL) without any exposure to lead was also used. Anxiety was assessed by elevated plus maze (EPM) and locomotor activity and exploration by open field test (OFT). Blood pressure (BP), electrocardiogram (ECG), heart rate (HR), respiratory frequency (RF), sympathetic and parasympathetic activity and baro- and chemoreceptor reflex profiles were evaluated. Immunohistochemistry protocol for the assessment of neuroinflammation, neuronal loss (NeuN), gliosis and synaptic alterations (Iba-1, GFAP, Syn), were performed at the hippocampus. One-way ANOVA with Tukey’s multiple comparison between means were used (significance p < 0.05) for statistical analysis. Results The intermittent lead exposure produced a significant increase in diastolic and mean BP values, concomitant with a tendency to sympathetic overactivity (estimated by increased low-frequency power) and without significant changes in systolic BP, HR and RF. A chemoreceptor hypersensitivity and a baroreflex impairment were also observed, however, less pronounced when compared to the permanent exposure. Regarding behavioral changes, both lead exposure profiles showed an anxiety-like behavior without changes in locomotor and exploratory activity. Increase in GFAP and Iba-1 positive cells, without changes in NeuN positive cells were found in both exposed groups. Syn staining suffered a significant decrease in PbI group and a significant increase in PbP group. Conclusion This study is the first to show that developmental Pb exposure since fetal period can cause lasting impairments in physiological parameters. The intermittent lead exposure causes adverse health effects, i.e, hypertension, increased respiratory frequency and chemoreflex sensitivity, baroreflex impairment, anxiety, decreased synaptic activity, neuroinflammation and reactive gliosis, in some ways similar to a permanent exposure, however some are lower-grade, due to the shorter duration of exposure. This study brings new insights on the environmental factors that influence autonomic and cardiovascular systems during development, which can help in creating public policy strategies to prevent and control the adverse effects of Pb toxicity.
Mode of action of piperovatine, an insecticidal piperamide isolated from Piper piscatorum (Piperaceae), against voltage-gated sodium channels Neurotoxicology (IF 3.076) Pub Date : 2018-08-08 Tatsuya Suzuki, Seiji Yamato
Involvement of the p38 MAPK signaling pathway in overexpression of matrix metalloproteinase-9 during the course of brain edema in 1,2-dichloroethane-intoxicated mice Neurotoxicology (IF 3.076) Pub Date : 2018-08-03 Xiaoxia Jin, Yingjun Liao, Xiaoqiong Tan, Jingjing Guo, Gaoyang Wang, Fenghong Zhao, Yaping Jin
Accumulated data have revealed that subacute poisoning of 1,2-dichloroethane (1,2-DCE), an industrial solvent used in some countries can cause encephalopathy, in which brain edema is the main pathological change. However, the underlying mechanisms are unclear. In the present study, we hypothesized that the p38 MAPK (p38) signaling pathway could be activated in 1,2-DCE-intoxicated mice, which in turn stimulates transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), and then enhances the expression of proinflammatory factors, including matrix metalloproteinase-9 (MMP-9), finally leading to blood-brain barrier (BBB) disruption and brain edema formation. Our results revealed that brain water content and BBB permeability increased significantly in the intoxicated mice. Meanwhile, the levels of phosphorylated p38 (p-p38) and inhibitory κBα (p-IκB), as well as the expression levels of MMP-9, c-jun, c-fos, and p65, also increased markedly in the brains of intoxicated mice. Conversely, the protein levels of ZO-1, occludin and claudin-5 in these mice decreased markedly, but their JAM-1 protein levels increased dramatically. Our results revealed that p-p38 levels in the brains of intoxicated mice were suppressed by pretreatment with a p38 inhibitor. In response to suppressed p-p38 levels, the brain water contents and DNA binding activities of NF-κB and AP-1, as well as the expression levels of MMP-9, c-jun, c-fos, p65, p-IκB and JAM-1, decreased, whereas the protein levels of ZO-1, occludin and claudin-5 increased markedly. Taken together, our findings indicated that the p38 signaling pathway might be activated and involved in the course of brain edema in 1,2-DCE-intoxicated mice.
Assessing mercury intoxication in isolated/remote populations: increased S100B mRNA in blood in exposed riverine inhabitants of the Amazon Neurotoxicology (IF 3.076) Pub Date : 2018-08-01 Gabriela de Paula Fonseca Arrifano, Rosa Del Carmen Rodriguez Martin-Doimeadios, María Jiménez-Moreno, Marcus Augusto-Oliveira, José Rogério Souza-Monteiro, Ricardo Paraense, Camila Rodrigues Machado, Marcelo Farina, Barbarella Macchi, José Luiz Martins do Nascimento, Maria Elena Crespo-Lopez
Uranium exposure of human dopaminergic cells results in low cytotoxicity, accumulation within sub-cytoplasmic regions, and down regulation of MAO-B Neurotoxicology (IF 3.076) Pub Date : 2018-08-01 Asuncion Carmona, Véronique Malard, Emilie Avazeri, Stéphane Roudeau, Francesco Porcaro, Eduardo Paredes, Claude Vidaud, Carole Bresson, Richard Ortega
Natural uranium is an ubiquitous element present in the environment and human exposure to low levels of uranium is unavoidable. Although the main target of acute uranium toxicity is the kidney, some concerns have been recently raised about neurological effects of chronic exposure to low levels of uranium. Only very few studies have addressed the molecular mechanisms of uranium neurotoxicity, indicating that the cholinergic and dopaminergic systems could be altered. The main objective of this study was to investigate the mechanisms of natural uranium toxicity, after 7-day continuous exposure, on terminally differentiated human SH-SY5Y cells exhibiting a dopaminergic phenotype. Cell viability was first assessed showing that uranium cytotoxicity only occurred at high exposure concentrations (> 125 µM), far from the expected values for uranium in the blood even after occupational exposure. SH-SY5Y differentiated cells were then continuously exposed to 1, 10, 125 or 250 µM of natural uranium for 7 days and uranium quantitative subcellular distribution was investigated by means of micro-PIXE (Particle Induced X-ray Emission). The subcellular element imaging revealed that uranium was located in defined perinuclear regions of the cytoplasm, suggesting its accumulation in organelles. Uranium was not detected in the nucleus of the differentiated cells. Quantitative analysis evidenced a very low intracellular uranium content at non-cytotoxic levels of exposure (1 and 10 µM). At higher levels of exposure (125 and 250 µM), when cytotoxic effects begin, a larger and disproportional intracellular accumulation of uranium was observed. Finally the expression of dopamine-related genes was quantified using real time qRT-PCR. The expression of monoamine oxidase B (MAO-B) gene was statistically significantly decreased after exposure to uranium while other dopamine-related genes were not modified. The down regulation of MAO-B was confirmed at the protein level. This original result suggests that the inhibition of dopamine catabolism, but also of other MAO-B substrates, could constitute selective effects of uranium neurotoxicity.
Neurotransmitter amines and antioxidant agents in neuronal protection against methylmercury-induced cytotoxicity in primary cultures of mice cortical neurons Neurotoxicology (IF 3.076) Pub Date : 2018-07-31 Nair Olguín, Marie-Lena Müller, Eduard Rodríguez-Farré, Cristina Suñol
Methylmercury (MeHg) is an environmental toxicant with detrimental effects on the developing brain and adult nervous system. The main mechanisms identified include oxidative stress, changes in intracellular calcium, mitochondrial changes, inhibition of glutamate uptake, of protein synthesis and disruption of microtubules. However, little is known about mechanisms of protection against MeHg neurotoxicity. We found that resveratrol (10µM) and ascorbic acid (200µM) protected MeHg-induced cell death in primary cultures of cortical neurons. In this work, we aimed at finding additional targets that may be related to MeHg mode of action in cell toxicity with special emphasis in cell protection. We wonder whether neurotransmitters may affect the MeHg effects on neuronal death. Our findings show that neurons exposed to low MeHg concentrations exhibit less mortality if co-exposed to 10µM dopamine (DA). However, DA metabolites, HVA (homovanillic acid) and DOPAC (3,4-dihydroxyphenylacetic acid) are not responsible for such protection. Furthermore, both DA D1 and D2 receptors agonists showed a protective effect against MeHg toxicity. It is striking though that DA receptor antagonists SKF83566 (10µM) and haloperidol (10µM) did not inhibit DA protection against MeHg. In addition, the protective effect of 10µM DA against MeHg-induced toxicity was not affected by additional organochlorine pollutants exposure. Our results also demonstrate that cells exposed to MeHg in presence of 100µM acetylcholine (ACh), show an increase in cell mortality at the “threshold value” of 100 nM MeHg. Finally, norepinephrine (10µM) and serotonin (20µM) also had an effect on cell protection. Altogether, we propose to further investigate the additional mechanisms that may be playing an important role in MeHg-induced cytotoxicity.
Effects of Environmental Pollutants on Calcium Release and Uptake by Rat Cortical Microsomes Neurotoxicology (IF 3.076) Pub Date : 2018-07-26 Hanna M. Dusza, Peter H. Cenijn, Jorke H. Kamstra, Remco H.S. Westerink, Pim E.G. Leonards, Timo Hamers
Dysregulation of neuronal intracellular Ca2+ homeostasis can play a crucial role in many neurotoxic effects, including impaired brain development and behavioral dysfunctions. This study examined 40 suspected neurotoxicants from different chemical classes for their capacity to alter Ca2+ release and uptake from rat cortical microsomes. First, ten suspected neurotoxicants have been tested using a well-established cuvette-based Ca2+ flux assay. Five out of ten compounds (TOCP, endosulfan, PCB-95, chlorpyrifos and BDE-49) showed a significant, concentration-dependent alteration of Ca2+ release and uptake in adult rat cortical microsomes. The original cuvette assay was downscaled and customized to a fast, higher throughput microplate method and the 40 suspected neurotoxicants were screened for their effects on intracellular Ca2+homeostasis. In decreasing order of potency, the 15 test compounds that showed the strongest alteration of Ca2+ levels in adult rat microsomes were TOCP, endosulfan, BDE-49, 6-OH-BDE-47, PCB-95, permethrin, alpha-cypermethrin, chlorpyrifos, bioallethrin, cypermethrin, RDP, DEHP, DBP, BDE-47, and PFOS. Results from co-exposure experiments with selective inhibitors suggested that for some compounds Ca2+ releasing effects could be attributed to RyR activation (PFOS, DBP, and DEHP) or to SERCA inhibition (a potential novel mechanism of action for all four tested pyrethroid insecticides). The effects of the two most potent compounds, endosulfan and TOCP, were not blocked by any of the inhibitors tested, indicating other possible mechanism of action. For all other potent test compounds, a combined effect on RyR, IP3R, and/or SERCA has been observed. PFOS and 6-OH-BDE-47 caused increased Ca2+ release from adult but not from neonatal rat brain microsomes, indicating age-dependent difference in susceptibility to these test compounds. The current study suggests that the neurotoxic potential of compounds belonging to different chemical classes could partly be attributed to the effects on intracellular Ca2+ release and uptake. Although further validation is required, the downscaled method developed in this study presents technical advance that could be used for the future screening of suspected intracellular Ca2+ disruptors.
Evaluating the Broad-Spectrum Efficacy of the Acetylcholinesterase Oximes Reactivators MMB4 DMS, HLö-7 DMS, and 2-PAM Cl Against Phorate Oxon, Sarin, and VX in the Hartley Guinea Pig Neurotoxicology (IF 3.076) Pub Date : 2018-07-26 Christina M. Wilhelm, Thomas H. Snider, Michael C. Babin, Gennady E. Platoff, David A. Jett, David T. Yeung
Organophosphorus (OP) compounds, including pesticides and chemical warfare nerve agents (CWNA), are threats to the general population as possible weapons of terrorism or by accidental exposure whether through inadvertent release from manufacturing facilities or during transport. To mitigate the toxicities posed by these threats, a therapeutic regimen that is quick-acting and efficacious against a broad spectrum of OPs is highly desired. The work described herein sought to assess the protective ratio (PR), median effective doses (ED50), and therapeutic index (TI = oxime 24-hr LD50/oxime ED50) of MMB4 DMS, HLö-7 DMS, and 2-PAM Cl against the OPs sarin (GB), VX, and phorate-oxon (PHO). All OPs are representative of the broader classes of G and V chemical warfare nerve agents and persistent pesticides. MMB4 DMS and HLö-7 DMS were previously identified as comparative efficacy leads warranting further evaluations. 2-PAM Cl is the U.S. FDA-approved standard-of-care oxime therapy for OP intoxication. Briefly, PRs were determined in male guinea pigs by varying the subcutaneously (SC) delivered OP dose followed then by therapy with fixed levels of the oxime and atropine (0.4 mg/kg; administered intramuscularly [IM]). ED50s were determined using a similar approach except the OP dose was held constant at twice the median lethal dose (2 x LD50) while the oxime treatment levels were varied. The ED50 information was then used to calculate the TI for each OP/oxime combination. Both MMB4 DMS and HLö-7 DMS provided significant protection, i.e., higher PR against GB, VX, and PHO when compared to atropine controls, but significance was not readily demonstrated across the board when compared against 2-PAM Cl. The ED50 values of MMB4 DMS was consistently lower than that of the other oximes against all three OPs. Furthermore, based on those ED50s, the TI trend of the various oximes against both GB and VX was MMB4 DMS > HLö-7 DMS > 2-PAM Cl, while against PHO, MMB4 DMS > 2-PAM Cl > HLö-7 DMS.
Chronic near lifetime toluene exposure in rodents does not replicate solvent abuse leukoencephalopathy in humans Neurotoxicology (IF 3.076) Pub Date : 2018-07-26 Marc A. Ranson, Marc R. Del Bigio
Toluene is an organic solvent used in industry and as a substance of abuse. The latter situation may be associated with a leukoencephalopathy characterized by white matter atrophy, multifocal myelin loss, and macrophages that contain birefringent granular inclusions. To determine if rodents can develop the same white matter damage, we studied archived rodent brain samples from three near-lifetime toluene carcinogenicity experiments. Rats and mice were exposed to toluene via an inhalation chamber at 1200 ppm for 6.5 hours daily, 5 days per week, for 103 weeks. Rats were exposed to toluene via oral gavage of 800 mg/kg, 4 days per week, for 104 weeks. In gavage-exposed brains, immunohistochemical staining was used to detect reactive astroglial and microglial changes, neuron populations, and cytochrome P450 upregulation. None of the white matter changes reported in human toluene abuse were identified in the rat or mouse brains. In a blinded analysis, a mild widespread increase in reactive microglia was detected in female rats that received toluene by gavage at 800 mg/kg. However, no significant differences were detected in neurons or astrocytes. Potential reasons for the absence of changes are discussed. We conclude that rodent studies designed to study carcinogenicity of toluene might not adequately model abuse exposure.
Isoliquiritigenin attenuates glutamate-induced mitochondrial fission via calcineurin-mediated Drp1 dephosphorylation in HT22 hippocampal neuron cells Neurotoxicology (IF 3.076) Pub Date : 2018-07-23 Dong Gil Lee, Ju-Sik Min, Hyun-Shik Lee, Dong-Seok Lee
Numerous studies suggest that glutamate toxicity is a major contributor to neuronal dysfunction and death in several neurodegenerative diseases. In our previous study, isoliquiritigenin (ISL) isolated from Glycyrrhiza uralensis showed neuroprotective effects against neuronal cell death mediated by intracellular reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential. However, the mechanisms by which ISL protects against glutamate-induced oxidative stress are unknown. In the present study, we focused on the cellular and molecular mechanisms underlying the inhibition of ROS production and induction of mitochondrial dysfunction by ISL in glutamate-stimulated HT22 mouse hippocampal neuron cells. The results revealed that ISL inhibited glutamate-induced mitochondrial ROS production and decline of glutathione levels and ATP generation in HT22 cells. Interestingly, we discovered that ISL prevents glutamate-induced mitochondrial fission by inhibiting the dephosphorylation of Drp1 at the serine 637 residue, which is a regulatory factor of mitochondrial dynamics, and both a S637D mutation of Drp1, which resulted in a phosphorylation-mimetic form of Drp1 at Ser637, and mitochondria-targeted antioxidant Mito-TEMPO inhibited glutamate-induced mitochondrial fission. Furthermore, ISL also prevented the increase of intracellular calcium accompanied by activation of calcineurin, which is a key regulator of dephosphorylation of Drp1 (Ser637), in glutamate-treated HT22 cells. Taken together, our results demonstrated that ISL protects against glutamate-induced mitochondrial fission by inhibiting the increase of mitochondrial ROS and intracellular calcium, which are accompanied by dephosphorylation of Drp1 (Ser637), and consequently attenuates glutamate-induced neuronal cell death. Therefore, these findings suggest that ISL exhibits the potential for protection against glutamate toxicity. These results may contribute to the development of new drugs and novel strategies for the treatment of neurodegenerative disorders related to glutamate toxicity.
Critical developmental periods for effects of low-level tobacco smoke exposure on behavioral performance Neurotoxicology (IF 3.076) Pub Date : 2018-07-20 Marty Cauley, Brandon J. Hall, Yael Abreu-Villaça, Shaqif Junaid, Hannah White, Abtin Kiany, Theodore A. Slotkin, Edward D. Levin
Tobacco exposure during development leads to neurobehavioral dysfunction in children, even when exposure is limited to secondhand smoke. We have previously shown in rats that developmental exposure to tobacco smoke extract (TSE), at levels mimicking secondhand smoke, starting preconception and extending throughout gestation, evoked subsequent locomotor hyperactivity and cognitive impairment. These effects were greater than those caused by equivalent exposures to nicotine alone, implying that other agents in tobacco smoke contributed to the adverse behavioral effects. In the present study, we examined the critical developmental windows of vulnerability for these effects, restricting TSE administration (0.2 mg/kg/day nicotine equivalent, or DMSO vehicle, delivered by subcutaneously-implanted pumps) to three distinct 10 day periods: the 10 days preceding mating, the first 10 days of gestation (early gestation), or the second 10 days of gestation (late gestation). The principal behavioral effects revealed a critical developmental window of vulnerability, as well as sex selectivity. Late gestational TSE exposure significantly increased errors in the initial training on the radial-arm maze in female offspring, whereas no effects were seen in males exposed during late gestation, or with either sex in the other exposure windows. In attentional testing with the visual signal detection test, male offspring exposed to TSE during early or late gestation showed hypervigilance during low-motivating conditions. These results demonstrate that gestational TSE exposure causes persistent behavioral effects that are dependent on the developmental window in which exposure occurs. The fact that effects were seen at TSE levels modeling secondhand smoke, emphasizes the need for decreasing involuntary tobacco smoke exposure, particularly during pregnancy.
System-specific neurodegeneration following glucotoxicity in the C. elegans model Neurotoxicology (IF 3.076) Pub Date : 2018-07-20 Adi Pinkas, Michael Lawes, Michael Aschner
Hyperglycemia-related neuropathy leads to the onset and exacerbation of several pathologies. The C. elegans model has been used to study this phenomenon and its underlying mechanisms using a broad evaluation for neurodegeneration. Here, we report a system-specific susceptibility for glucotoxicity, namely the dopaminergic, glutamatergic and cholinergic system. Under high-glucose conditions, these systems (and not the serotonergic or GABAergic) were impaired, as observed by evaluating the fluorescent signal in GFP-tagged worm strains. The significance and implications of unequal susceptibility for glucotoxicity in the nervous system is discussed.
Oxaliplatin treatment impairs extension of sensory neuron neurites in vitro through miR-204 overexpression Neurotoxicology (IF 3.076) Pub Date : 2018-07-18 María José López-González, Anaïs Soula, Marc Landry, Alexandre Favereaux
Oxaliplatin is a platinum-based drug used in the treatment of gastric cancers. Oxaliplatin treatment induces sensory neuropathy characterized by cold hypersensibility in the acute phase and sensory impairment when the neuropathy becomes chronic. In order to determine the effect of oxaliplatin on sensory neurons, we used an in vitro model in which oxaliplatin treatment reduced arborization of dorsal root ganglia neurons in a dose-dependent manner. Moreover, we characterized the role of microRNAs in oxaliplatin induced-neuropathy. In particular, we focused on microRNAs that control the expression of axon guidance molecules, and therefore, regulate neurite arborization. As a result, we highlighted the upregulation of miR-204, a microRNA that controls the expression of PlexinA2, a semaphorin receptor involved in neurite guidance. Interaction of miR-204 and Plexin A2 was confirmed by luciferase assay. In addition, overexpression of miR-204 in dorsal root ganglia neuron cultures reduced length and extension of neurites and also reduced Plexin A2 labelling without increasing apoptosis rate. On the other hand, sequestration of miR-204 by a specific microRNA sponge increases neurite length and PlexinA2 expression. Taken together, our data indicate that oxaliplatin impairs sensory neurons arborization through up-regulation of miR-204 that decreases PlexinA2 expression and neurite length.
Neuroprotective effects of cordycepin inhibit Aβ-induced apoptosis in hippocampal neurons Neurotoxicology (IF 3.076) Pub Date : 2018-07-18 Hao Song, Li-Ping Huang, Yuping Li, Chao Liu, Songhua Wang, Wei Meng, Shanshan Wei, Xin-Ping Liu, Yanchun Gong, Li-Hua Yao
In Alzheimer’s disease (AD), β-amyloid (Aβ) protein toxicity increases the formation of reactive oxygen species (ROS) and intracellular calcium levels, resulting in neuronal dysfunction, neurodegenerative disorders, and cell death. Cordycepin is a derivative of the nucleoside adenosine; also, it is speculated to exert neuroprotective effects against Aβ-induced oxidative toxicity in hippocampal neurons. In the present study, the fluorescence detection method and whole-cell patch-clamp recordings were used to study the neuroprotective effects against Aβ-induced toxicity in the primary hippocampal cultured neurons. The results revealed that Aβ25–35 toxicity causes increased cellular ROS production and abnormal calcium homeostasis in hippocampal neurons. Moreover, Aβ25–35-induced cytotoxicity led to a series of downstream events, including the activation of acetylcholinesterase, increased p-Tau expression, and increased apoptosis. Cordycepin inhibits ROS production, elevated levels of Ca2+ induced by Aβ25–35, and the activation of acetylcholinesterase; all these are involved in oxidative-induced apoptosis. In addition, it decreases the increased p-Tau expression that plays a key role in the initiation of the AD. Results showed that the anti-apoptotic effects of cordycepin are partially dependent on the activation of adenosine A1 receptor, whereas an antagonist selectively attenuated the neuroprotective effects of cordycepin. Collectively, these results suggest that cordycepin could be a potential future therapeutic agent for neuronal disorders, such as AD.
Biosafety assessment of conducting nanostructured materials by using co-cultures of neurons and astrocytes Neurotoxicology (IF 3.076) Pub Date : 2018-07-18 Mathieu P. Lichtenstein, Nina M. Carretero, Estela Pérez, Marta Pulido-Salgado, Javier Moral-Vico, Carme Solà, Nieves Casañ-Pastor, Cristina Suñol
Neural electrode implants are made mostly of noble materials. We have synthesized a nanostructured material combining the good electrochemical properties of iridium oxide (IrOx) and carbon-nanotubes (CNT) and the properties of poly(3,4-ethylenedioxythiophene) (PEDOT). IrOx-CNT-PEDOT charge storage capacity was lower than that of IrOx and IrOx-CNT, but higher than that of other PEDOT-containing hybrids and Pt. Cyclic voltammetry, SEM, XPS and micro-Raman spectroscopy suggest that PEDOT encapsulates IrOx and CNT. In our search for a cell culture platform that could optimize modelling the in vivo environment, we determined cell viability, neuron and astrocyte functionality and the response of astrocytes to an inflammatory insult by using primary cultures of neurons, of astrocytes and co-cultures of both. The materials tested (based on IrOx, CNT and PEDOT, as well as Pt as a reference) allowed adhesion and proliferation of astrocytes and full compatibility for neurons grown in co-cultures. Functionality assays show that uptake of glutamate in neuron-astrocyte co-culture was significantly higher than the sum of the uptake in astrocytes and neurons. In co-cultures on IrOx, IrOx-CNT and IrOx-CNT-PEDOT, glutamate was released by a depolarizing stimulus and induced a significant increase in intracellular calcium, supporting the expression of functional NMDA/glutamate receptors. LPS-induced inflammatory response in astrocytes showed a decreased response in NOS2 and COX2 mRNA expression for IrOx-CNT-PEDOT. Results indicate that neuron-astrocyte co-cultures are a reliable model for assessing the biocompatibility and safety of nanostructured materials, evidencing also that hybrid IrOx-CNT-PEDOT nanocomposite materials may offer larger resistance to inflammatory insults.
Outcomes of developmental exposure to total particulate matter from cigarette smoke in zebrafish (Danio rerio) Neurotoxicology (IF 3.076) Pub Date : 2018-07-17 Andrey Massarsky, Nishad Jayasundara, Lilah Glazer, Edward D. Levin, G.L. Prasad, Richard T. Di Giulio
The effects of prenatal exposure to cigarette smoke remain a subject of major interest, especially as it relates to neural development and adverse behavioral outcomes. Several studies have investigated the developmental toxicity of cigarette smoke components in a zebrafish model, showing that developmental exposure to total particulate matter (TPM; particulate phase of cigarette smoke) leads to adverse physiological aberrations and locomotor hyperactivity. Thus, the current study examines whether developmental TPM exposure of zebrafish embryos/larvae (F0) leads to physiological and behavioral alterations, and whether adverse effects are observed in adult fish and the next generation (F1; i.e. F0 offspring). We also examine whether behavioral effects are associated with changes in neural development, stress response, neurotransmitters, and bioenergetics. We demonstrate that TPM exposure during F0 development increased the incidence of deformities in F0 larvae, but F1 larvae did not exhibit any deformities. TPM exposure also resulted in swimming hyperactivity in F0 larvae and several behavioral changes were noted in F0 fish when they grew into adulthood. These behavioral changes were generally not associated with changes in markers of neural development in larvae, stress response in F0 adults, and concentration of neurotransmitters (acetylcholine, dopamine, and serotonin) in F0 adult brain. There were also no changes in F0 or F1 embryonic oxygen consumption rate (OCR; marker of bioenergetics and mitochondrial health); however the OCR in the brain of F0 males was reduced with TPM. We conclude that developmental exposure to TPM affects larval physiology and induces hyperactive swimming behavior, but these effects do not persist in F1 larvae. Moreover, developmental TPM exposure leads to long-lasting sex-specific behavioral outcomes in the F0 adult fish.
Reduced Regional Volumes Associated with Total Psychopathy Scores in an Adult Population with Childhood Lead Exposure Neurotoxicology (IF 3.076) Pub Date : 2018-04-07 Travis J. Beckwith, Kim N. Dietrich, John P. Wright, Mekibib Altaye, Kim M. Cecil
Childhood lead exposure has been correlated to acts of delinquency and criminal behavior; however, little research has been conducted to examine its potential long term influence on behavioral factors such as personality, specifically psychopathic personality. Neuroimaging studies have demonstrated that the effects of childhood lead exposure persist into adulthood, with structural abnormalities found in gray and white matter regions involved in behavioral decision making. The current study examined whether measurements of adult psychopathy were associated with neuroanatomical differences in structural brain volumes for a longitudinal cohort with measured childhood lead exposure. We hypothesized that increased total psychopathy scores and increased blood lead levels would be inversely associated with volumetric measures of gray and white matter brain structures responsible for executive and emotional processing. Analyses did not display a direct effect between total psychopathy score and gray matter volume; however, reduced white matter volume in the cerebellum and brain stem in relation to increased total psychopathy scores was observed. An interaction between sex and total psychopathy score was also detected. Females displayed increased gray matter volume in the frontal, temporal, parietal, and occipital lobes associated with increased total psychopathy score, but did not display any white matter volume differences. Males displayed reductions in frontal gray and white matter brain volume, as well as decreased cerebellar white matter volume. Additionally, reduced gray and white matter volume was associated with increased blood lead levels in the frontal lobes; reduced white matter volume was also observed in the parietal and temporal lobes. Females demonstrated gray and white matter volume loss associated with increased PbB78 values in the right temporal lobe, as well as reduced gray matter volume in the frontal lobe. Males displayed reduced gray matter volumes associated with increased PbB78 values in the frontal and parietal lobes; white matter volume loss was observed in the frontal and temporal lobes. Comparison of the two primary models revealed a volumetric decrease in the white matter of the left prefrontal cortex associated with increased total psychopathy scores and increased blood lead concentration in males. The results of this study suggested that increased psychopathy scores in this cohort may be attributable to the neuroanatomical abnormalities observed and that childhood lead exposure may be influential to these outcomes.
Forebrain glutamate uptake and behavioral parameters are altered in adult zebrafish after the induction of Status Epilepticus by kainic acid Neurotoxicology (IF 3.076) Pub Date : 2018-04-19 Ben Hur Marins Mussulini, Adriana Fernanda Kuckartz Vizuete, Marcos Braga, Luana Moro, Suelen Baggio, Emerson Santos, Gabriela Lazzarotto, Kamila Cagliari Zenki, Letícia Pettenuzzo, João Batista Texeira da Rocha, Diogo Losch de Oliveira, Maria Elisa Calcagnotto, José Angelo Silveira Zuanazzi, Javier Santos Burgos, Eduardo Pacheco Rico
The development of new antiepileptic drugs is a high-risk/high-cost research field, which is made even riskier if the behavioral epileptic seizure profile is the unique approach on which the development is based. In order to increase the effectiveness of the screening conducted in the zebrafish model of status epilepticus (SE), the evaluation of neurochemical markers of SE would be of great relevance. Epilepsy is associated with changes in the glutamatergic system, and glutamate uptake is one of the critical parameters of this process. Therefore, we evaluated the levels of glutamate uptake in the zebrafish brain and analyzed its correlation with the progression of behavioral changes in zebrafish at different times after the administration of kainic acid (5 mg/kg). The results showed that the zebrafish suffered with lethargy while swimming for up to 72 h after SE, had reduced levels of GFAP cells 12 h after SE, reduced levels of S100B up to 72 h after SE, and reduced levels of glutamate uptake in the forebrain between 3 h and 12 h after SE. The forebrain region of adult zebrafish after SE present similar changes to the neurochemical limbic alterations that are seen in rodent models of SE. This study demonstrated that there is a time window in which to use the KA zebrafish model of SE to explore some of the known neurochemical alterations that have been observed in rodent models of epilepsy and epileptic human patients.
Comparative proteomics reveals the neurotoxicity mechanism of ER stressors tunicamycin and dithiothreitol Neurotoxicology (IF 3.076) Pub Date : 2018-07-10 Bingyu Ren, Yujuan Wang, Heng Wang, Yingying Wu, Jiayi Li, Jing Tian
Severity or duration of endoplasmic reticulum (ER) stress leads to two different cellular events: cell survival and apoptosis. Drug-induced ER stress or neurotoxicity has been observed as one of the main side effects. However, how ER stress affects cellular signaling cascades leading to neuronal damage is still not well understood. In this study, the toxicological mechanisms of two typical ER stress inducers, tunicamycin (Tm) and dithiothreitol (DTT), were investigated by cell viability, unfolded protein response, apoptosis and proteomic responses in mouse neuro-2a cells. A large portion of differentially expressed proteins (DEPs) that participate in protein synthesis and folding were identified in the Tm treated group, indicating adaptive cellular responses like the unfolded protein response were activated, which was not the case in the DTT treated group. Interestingly, KEGG pathway analysis and validation experiments revealed that proteins involved in proteasomal degradation were down-regulated by both inducers, while proteins involved in ubiquitination were up-regulated by Tm and down-regulated by DTT. A protein responsible for delivering ubiquitinated proteins to the proteasome, the UV excision repair protein RAD23 homolog A (HR23 A), was discovered as a DEP altered by both Tm and DTT. This protein was down-regulated in the Tm treated group and up-regulated in the DTT treated group, which explained the differences we observed in the ubquintination and proteasomal degradation pathways. Autophagy was activated in the Tm treated group, suggesting that it may serve as a compensatory effect to proteasomal degradation. Our work provides new insights into the neurotoxicity generated by various ER stress inducers and the underlying mechanisms.
Diffusion kurtosis imaging as a neuroimaging biomarker in patients with carbon monoxide intoxication Neurotoxicology (IF 3.076) Pub Date : 2018-07-11 Jun-Jun Lee, Wen-Neng Chang, Jung-Lung Hsu, Chi-Wei Huang, Ya-Ting Chang, Shih-Wei Hsu, Shu-Hua Huang, Chen-Chang Lee, Chia-Yi Lien, Chiung-Chih Chang
Attempting suicide by burning charcoal can lead to carbon monoxide (CO) intoxication and cognitive deficits. Changes in white matter (WM) quantified by diffusion tensor imaging (DTI)-derived parameters have been validated to reflect cognitive test scores. As diffusion kurtosis imaging (DKI) measures biological microstructures using non-Gaussian diffusivity, we assessed the added-information of DKI with neuropsychological test scores as the major outcome measure. A total of 45 patients were enrolled and compared with 30 age-matched controls. The patients were stratified into acute or chronic phase according to the intervals of intoxication and assessments. WM status was assessed using tract-based spatial statistics for DKI and DTI topographies, and the sensitivity/specificity of either model was tested using area under the curve (AUC) analysis. To evaluate their clinical significance, values of DKI- and DTI-derived parameters were extracted from seven regions of interest (ROI) and correlated with neuropsychiatric scores. The kurtosis parameters were lower in the patients than in the controls but none of the parameters provided differentiations between the acute or chronic phase. Kurtosis fractional anisotropy (KFA) had a higher AUC than fractional anisotropy while the other 3 DTI parameters had higher AUC than the corresponding DKI ones. In clinical correlations, KFA value of right posterior WM correlated with visual memory (r = 0.326, p = 0.029), and KFA values of bilateral posterior WM correlated with the digit forward score (right: r = 0.302, p = 0.043; left: r = 0.314, p = 0.036). Although DTI was more sensitive in reflecting disease status, KFA may be more sensitive and specific than fractional anisotropy in cognitive test score predictions.
Molecular mechanisms of neuroprotective effect of adjuvant therapy with phenytoin in pentylenetetrazole-induced seizures: impact on Sirt1/NRF2 signaling pathways Neurotoxicology (IF 3.076) Pub Date : 2018-07-11 Marwa M. Nagib, Mariane G. Tadros, Hadwa Ali Abd Al-khalek, Rania M. Rahmo, Nagwa Ali Sabri, Amani E. Khalifa, Somaia I. Masoud
Current anticonvulsant therapies are principally aimed at suppressing neuronal hyperexcitability to prevent or control the incidence of seizures. However, the role of oxidative stress processes in seizures led to the proposition that antioxidant compounds may be considered as promising candidates for limiting the progression of epilepsy. Accordingly, the aim of this study is to determine if coenzyme Q10 (CoQ10) and alpha-tocopherol (α-Toc) have a neuroprotective effect in rats against the observed oxidative stress and inflammation during seizures induced by pentylenetetrazole (PTZ) in rats, and to study their interactions with the conventional antiseizure drug phenytoin (PHT), either alone or in combination. Overall, the data revealed that α-Toc and CoQ10 supplementation can ameliorate PTZ-induced seizures and recommended that nuclear factor erythroid 2–related factor 2 (NRF2) and silencing information regulator 1 (Sirt1) signaling pathways may exemplify strategic molecular targets for seizure therapies. The results of the present study provide novel mechanistic insights regarding the protective effects of antioxidants and suggest an efficient therapeutic strategy to attenuate seizures. Additionally, concurrent supplementation of CoQ10 and α-Toc may be more effective than either antioxidant alone in decreasing inflammation and oxidative stress in both cortical and hippocampal tissues. Also, CoQ10 and α-Toc effectively reverse the PHT-mediated alterations in the brain antioxidant status when compared to PHT only.
Latent consequences of early-life lead (Pb) exposure and the future: Addressing the Pb Crisis Neurotoxicology (IF 3.076) Pub Date : 2018-07-05 Bryan Maloney, Baindu L. Bayon, Nasser H. Zawia, Debomoy K. Lahiri
Background. The lead (Pb) exposure crisis in Flint, Michigan has passed from well-publicized to a footnote, while its biological and social impact will linger for a lifetime. Interest in the “water crisis” has dropped to pre-event levels, which is neither appropriate nor safe. Flint’s exposure was severe, but it was not unique. Problematic Pb levels have also been found in schools and daycares in 42 states in the USA. The enormity of Pb exposure via municipal water systems requires multiple responses. Herein, we focus on addressing a possible answer to long-term sequelae of Pb exposure. We propose “4R’s” (remediation, renovation, reallocation, and research) against the Pb crisis that goes beyond a short-term fix. Remediation for affected individuals must continue to provide clean water and deal with both short and long-term effects of Pb exposure. Renovation of current water delivery systems, at both system-wide and individual site levels, is necessary. Reallocation of resources is needed to ensure these two responses occur and to get communities ready for potential sequelae of Pb exposure. Finally, properly focused research can track exposed individuals and illuminate latent (presumably epigenetic) results of Pb exposure and inform further resource reallocation.Conclusion. Motivation to act by not only the general public but also by scientific and medical leaders must be maintained beyond initial news cycle spikes and an annual follow-up story. Environmental impact of Pb contamination of drinking water goes beyond one exposure incident in an impoverished and forgotten Michigan city. Population effects must be addressed long-term and nationwide.
Association between environmental exposure to pesticides and epilepsy Neurotoxicology (IF 3.076) Pub Date : 2018-07-06 Mar Requena, Tesifón Parrón, Angela Navarro, Jessica García, María Isabel Ventura, Antonio F. Hernández, Raquel Alarcón
There is increasing evidence of an association between long-term environmental exposure to pesticides and neurodegenerative disorders; however, the relationship with epilepsy has not been addressed thus far. This study was aimed at determining the prevalence and risk of developing epilepsy among people from South-East Spain living in areas of high vs. low exposure to pesticides based on agronomic data. The study population consisted of 4007 subjects with a diagnosis of epilepsy and 580,077 control subjects adjusted for age, sex and geographical area. Data were collected from hospital records of the Spanish health care system (basic minimum dataset) between the years 1998 and 2010. The prevalence of epilepsy was significantly higher in areas of greater pesticide use relative to areas of lesser use. Overall, an increased risk of epilepsy was observed in the population living in areas of high vs. low use of pesticides (OR: 1.65; p < 0.001). Although this study was exploratory in nature, the results suggest that environmental exposure to pesticides might increase the risk of having epilepsy.
EFFECT OF WEDELOLACTONE AND GALLIC ACID ON QUINOLINIC ACID-INDUCED NEUROTOXICITY AND IMPAIRED MOTOR FUNCTION: SIGNIFICANCE TO SPORADIC AMYOTROPHIC LATERAL SCLEROSIS Neurotoxicology (IF 3.076) Pub Date : 2018-07-04 S Maya, Prakash T, Divakar Goli
Quinolinic acid (QUIN) is a well-known neuroactive metabolite of tryptophan degradation pathway or kynurenine pathway. The QUIN is involved in the development of several toxic cascades which leads to the neuronal degeneration processes. The QUIN-induced toxicity is also responsible for the impairment of the motor function and motor learning ability. This study seeks to investigate the several mechanisms which are involved in the intrastriatal administration of QUIN-induced neurodegeneration and the neuroprotective effects of wedelolactone (WL) and gallic acid (GA) over QUIN-induced toxicity. The Wistar rats were used for the study and conducted behavioral model to evaluate the effects of WL (100 & 200 mg/kg) and GA (100 & 200 mg/kg) on impaired motor function and motor learning ability. We also assessed the effects of WL and GA on the antioxidant profile, cytotoxicity, apoptosis, excitotoxicity, inflammatory cascades, and on growth factors which helps in neurogenesis. The compounds effectively improved the motor function, motor learning memory in the rats. Similarly, enhanced the activity of Glutathione peroxidase, SOD, catalase, and declined the lipid peroxidation and nitrite production in the brain. The treatment with WL and GA lowered the activities of LDH, m-calpain, and caspase-3. The reports strongly support that both compounds are useful in the prevention of glutamate excitotoxicity induced by QUIN. The NAA, IGF-1, and VEGF levels in the brain were improved after treatment with WL and GA. The neuroprotective effects of WL and GA further proved through the anti-inflammatory effects. The compounds significantly down-regulated the expression of TNF-α, IL-6, and IL-β in the brain. Immunohistochemical analysis shows that the WL and GA reduced the expression of NF-κB. The histopathological studies for cerebellum, hippocampus, striatum, and spinal cord confirms the toxic effects of QUIN and neuroprotective effects of WL and GA. The results suggest that WL and GA could ameliorate the toxic events triggered by QUIN and might be effective in the prevention and progression of several cascades which lead to the development of sALS.
Clioquinol increases the expression of interleukin-8 by down-regulating GATA-2 and GATA-3 Neurotoxicology (IF 3.076) Pub Date : 2018-06-30 Masato Katsuyama, Masakazu Ibi, Kazumi Iwata, Misaki Matsumoto, Chihiro Yabe-Nishimura
Clioquinol was used in the mid-1900s as an amebicide to treat indigestion and diarrhea. However, it was withdrawn from the market in Japan because it was linked to subacute myelo-optic neuropathy (SMON). The pathogenesis of SMON has not yet been elucidated in detail. As reported previously, we performed a global analysis on human neuroblastoma cells using DNA chips. The global analysis and quantitative PCR demonstrated that the mRNA level of interleukin-8 (IL-8) was significantly increased when SH-SY5Y neuroblastoma cells were treated with clioquinol. An enzyme-linked immunosorbent assay also demonstrated that clioquinol induced the secretion of IL-8 into culture media. Promoter analyses on SH-SY5Y cells revealed that a region responsive to clioquinol exists between –152 and –144 of the human IL-8 gene, which contains a consensus GATA-binding site sequence. The introduction of mutations at this site or the activator protein (AP)-1 site sequence at –126/–120 significantly reduced clioquinol-induced transcriptional activation. Among the GATA transcription factors expressed in SH-SY5Y cells, GATA-2 and GATA-3 protein levels were significantly decreased by the addition of clioquinol. Electrophoresis mobility shift assays using a probe corresponding to –159/–113 of the human IL-8 gene revealed two major shifted bands, one of which was increased and the other was decreased by clioquinol. The introduction of mutations showed that the former corresponded to binding to the AP-1 site, and the latter to binding to the GATA site. Supershift analyses revealed that the binding of c-Jun and c-Fos was increased, whereas that of GATA-3 was decreased by clioquinol. Genome editing against GATA-2 or GATA-3, not GATA-4 significantly enhanced clioquinol-induced IL-8 mRNA expression. On the other hand, the stable expression of GATA-2 or GATA-3 attenuated clioquinol-induced IL-8 mRNA expression and IL-8 secretion. These results suggest that the clioquinol-induced suppression of GATA-2 and GATA-3 expression mediates the up-regulation of IL-8.
The protective effects of sumatriptan on vincristine - induced peripheral neuropathy in a rat model Neurotoxicology (IF 3.076) Pub Date : 2018-06-26 Mina Khalilzadeh, Ghodratollah Panahi, Amir Rashidian, Mohammad Reza Hadian, Alireza Abdollahi, Khashayar Afshari, Saeed Shakiba, Abbas Norouzi-Javidan, Nastaran Rahimi, Majid Momeny, Ahmad Reza Dehpour
Clinical use of vincristine (VCR), an effective chemotherapeutic agent, has been limited due to its peripheral neuropathy toxicity. Sumatriptan, which is an anti-migraine agent is a specific agonist for 5-hydroxytryptamine 1B, 1D (5HT1B, 1D) receptors. Several studies have shown that sumatriptan exerts anti-inflammatory and immunomodulatory properties. This study aimed to investigate the effects of sumatriptan on VCR-induced peripheral neuropathy in a rat model. Male Wistar rats were intraperitoneally injected with VCR and normal saline four times per week for 2 weeks. In the treatment group, sumatriptan (1 mg/kg) was administered intraperitoneally 30 min prior to VCR injection every day. Mortality rate, weight variations and histopathological changes were monitored. Hot plate, tail flick and motor nerve conduction velocity (MNCV) tests were used to evaluate sensory and motor neuropathy. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and caspase-3 in the dorsal ganglion root were assessed by quantitative reverse transcription-PCR (qRT-PCR). Moreover, the protein levels of p65 nuclear factor kappa B (NF-<kappa > B) and phospho-p65 NF-<kappa > B were examined by Western blot analysis. Co-administration of sumatriptan with VCR significantly reversed alterations in the hot plate, tail flick threshold and sciatic MNCV induced by VCR and also prevented mixed sensory-motor neuropathy, as indicated by better general conditions, behavioral and electrophysiological results. In addition, sumatriptan improved the body weight loss caused by VCR. The mRNA levels of TNF-α, IL-1β and caspase-3 were significantly diminished in the treatment group. These findings were confirmed by histopathological analysis. In conclusion, this study demonstrated that sumatriptan significantly attenuated VCR-induced neuropathy and could be considered as a neuroprotective agent to prevent the VCR-induced neuropathy.
Methamphetamine toxicity-induced calcineurin activation, nuclear translocation of nuclear factor of activated T-cells and elevation of cyclooxygenase 2 levels are averted by calpastatin overexpression in neuroblastoma SH-SY5Y cells Neurotoxicology (IF 3.076) Pub Date : 2018-06-23 Jirapa Chetsawang, Sutisa Nudmamud-Thanoi, Ruchee Phonchai, Zuroida Abubakar, Piyarat Govitrapong, Banthit Chetsawang
Methamphetamine (METH) is an addictive stimulant drug that has many negative consequences, including toxic effects to the brain. Recently, the induction of inflammatory processes has been identified as a potential contributing factor to induce neuronal cell degeneration. It has been demonstrated that the expression of inflammatory agents, such as cyclooxygenase 2 (COX-2), depends on the activation of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT). Moreover, the excessive elevation in cytosolic Ca2+ levels activates the cell death process, including calpain activation in neurons, which was diminished by the overexpression of the calpain inhibitor protein, calpastatin. However, it is unclear whether calpain mediates CaN-NFAT activation in the neurotoxic process. In the present study, we observed that the toxic high dose of METH-treated neuroblastoma SH-SY5Y cells significantly decreased cell viability but increased apoptotic cell death, the active cleaved form of calcineurin, the nuclear translocation of NFAT, and COX-2 levels. Nevertheless, these toxic effects were diminished in METH-treated calpastatin-overexpressing SH-SY5Y cells. These findings might emphasize the role of calpastatin against METH-induced toxicity by a mechanism related to calpain-dependent CaN-NFAT activation-induced COX-2 expression.
Combined exposure to carbon disulfide and low-frequency noise reversibly affects vestibular function Neurotoxicology (IF 3.076) Pub Date : 2018-06-19 Monique Chalansonnet, Maria Carreres-Pons, Thomas Venet, Aurélie Thomas, Lise Merlen, Carole Seidel, Frédéric Cosnier, Hervé Nunge, Benoît Pouyatos, Jordi Llorens, Pierre Campo
Chronic occupational exposure to carbon disulfide (CS2) has debilitating motor and sensory effects in humans, which can increase the risk of falls. Although no mention of vestibulotoxic effects is contained in the literature, epidemiological and experimental data suggest that CS2 could cause low-frequency hearing loss when associated with noise exposure. Low-frequency noise might also perturb the peripheral balance receptor through an as-yet unclear mechanism. Here, we studied how exposure to a low-frequency noise combined with 250-ppm CS2 affected balance in rats. Vestibular function was tested based on post-rotary nystagmus recorded by a video-oculography system. These measurements were completed by behavioral tests and analysis of the cerebellum to measure expression levels for gene expression associated with neurotoxicity. Assays were performed prior to and following a 4-week exposure, and again after a 4-week recovery period. Functional measurements were completed by histological analyses of the peripheral organs.Nystagmus was unaltered by exposure to noise alone, while CS2 alone caused a moderate 19% decrease of the saccade number. In contrast, coexposure to 250-ppm CS2 and low-frequency noise decreased both saccade number and duration by 33% and 34%, respectively. After four weeks, recovery was only partial but measures were not significantly different from pre-exposure values. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis of cerebellar tissue revealed a slight but significant modification in expression levels for two genes linked to neurotoxicity in CS2-exposed animals. However, neither histopathological changes to the peripheral receptor nor behavioral differences were observed. Based on all these results, we propose that the effects of CS2 were due to reversible neurochemical disturbance of the efferent pathways managing post-rotatory nystagmus. Because the nervous structures involving the vestibular function appear particularly sensitive to CS2, post-rotary nystagmus could be used as an early, non-invasive measurement to diagnose CS2 intoxication as part of an occupational conservation program.
The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice Neurotoxicology (IF 3.076) Pub Date : 2018-06-21 Chiung-Mei Chen, Wan-Ling Chen, Chen-Ting Hung, Te-Hsien Lin, Chih-Ying Chao, Chih-Hsin Lin, Yih-Ru Wu, Kuo-Hsuan Chang, Ching-Fa Yao, Guey-Jen Lee-Chen, Ming-Tsan Su, Hsiu Mei Hsieh-Li
Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On cells with inducible SCA17 TBP/Q79-GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment.
Aldehyde Dehydrogenase 2 in the spotlight: the link between mitochondria and neurodegeneration Neurotoxicology (IF 3.076) Pub Date : 2018-06-21 Romina Deza-Ponzio, Macarena Lorena Herrera, María José Bellini, Miriam Beatriz Virgolini, Claudia Beatriz Hereñú
Growing body of evidence suggests that mitochondrial dysfunctions and resultant oxidative stress are likely responsible for many neurodegenerative diseases, including Alzheimer´s disease (AD) and Parkinson´s disease (PD). Aldehyde dehydrogenase (ALDH) superfamily plays a crucial role in several biological processes including development and detoxification pathways in the organism. In particular, ALDH2 is crucial in the oxidative metabolism of toxic aldehydes in the brain, such as catecholaminergic metabolites (DOPAL and DOPEGAL) and the principal product of lipid peroxidation process 4-HNE. This review aims to deepen the current knowledge regarding to ALDH2 function and its relation with brain-damaging processes that increase the risk to develop neurodegenerative disorders. We focused on relevant literature of what is currently known at molecular and cellular levels in experimental models of these pathologies. The understanding of ALDH2 contributions could be a potential target in new therapeutic approaches for PD and AD due to its crucial role in mitochondrial normal function maintenance that protects against neurotoxicity.
Excess amounts of 3-iodo-L-tyrosine induce Parkinson-like features in experimental approaches of Parkinsonism Neurotoxicology (IF 3.076) Pub Date : 2018-06-06 Emilio Fernández-Espejo, Cristian Bis-Humbert
3-iodo-L-tyrosine might play a role in Parkinson’s disease since this molecule is able, at high concentration, to inhibit tyrosine-hydroxylase activity, the rate-limiting enzyme in dopamine biosynthesis. The possible Parkinson-like effects of 3-iodo-L-tyrosine were tested on three experimental approaches in mice: cultured substantia nigra neurons, the enteric nervous system of the jejunum after intra-peritoneal infusions, and the nigrostriatal system following unilateral intrabrain injections. 3-iodo-L-tyrosine, a physiological molecule, was used at concentrations higher than its serum levels in humans. Parkinson-like signs were evaluated through abnormal aggregation of α-synuclein and tyrosine-hydroxylase, loss of tyrosine-hydroxylase-expressing and striatum-projecting neurons and fibers, reduced tyrosine-hydroxylase density, and Parkinson-like motor and non-motor deficits. The retrograde tracer FluoroGold was used in the brain model. The findings revealed that excess amounts of 3-iodo-L-tyrosine induce Parkinson-like effects in the three experimental approaches. Thus, culture neurons of substantia nigra show, after 3-iodo-L-tyrosine exposure, intracytoplasmic inclusions that express α-synuclein and tyrosine-hydroxylase. Intra-peritoneal infusions of 3-iodo-L-tyrosine cause, in the long-term, α-synuclein aggregation, thicker α-synuclein-positive fibers, and loss of tyrosine-hydroxylase-positive cells and fibers in intramural plexuses and ganglia of the jejunum. Infusion of 3-iodo-L-tyrosine into the left dorsal striata of mice damages the nigrostriatal system, as revealed through lower striatal tyrosine-hydroxylase density, reduced number of tyrosine-hydroxylase-expressing and striatum-projecting neurons in the left substantia nigra, as well as the emergence of Parkinson-like behavioral deficits such as akinesia, bradykinesia, motor disbalance, and locomotion directional bias. In conclusion, excess amounts of 3-iodo-L-tyrosine induce Parkinson-like features in cellular, enteric and brain approaches of Parkinsonism in mice.
Effects of inhaled particulate matter on the central nervous system in mice Neurotoxicology (IF 3.076) Pub Date : 2018-06-04 So Young Kim, Jin Ki Kim, Byeong-Gon Kim, An-Soo Jang, Seung Ha Oh, Jun Ho Lee, Myung-Whan Seo, Moo Kyun Park
Little is known regarding the adverse effects of chronic particulate matter (PM) inhalation on the central nervous system (CNS). The present study aimed to examine how PM exposure impacts on oxidative stress and inflammatory processes, as well as the expression of interneurons and perineuronal nets (PNNs) in the CNS. BALB/c mice (6-week-old females, n = 32) were exposed to 1 to 5 μm size diesel-extracted particles (DEPs) (100 µg/m3, 5 d/week, 5 h/day) and categorized into the following four groups: 1) 4-week DEP (n = 8); 2) 4-week control (n = 8), 3) 8-week DEP (n = 8); and 4) 8-week control (n = 8). The olfactory bulb, prefrontal cortex, temporal cortex, striatum, and cerebellum were harvested from the animals in each group. The expression of antioxidants (heme oxygenase 1 [HO-1] and superoxide dismutase 2 [SOD-2]), and markers of the unfolded protein response (X-box binding protein [XBP]-1S), inflammation (tumor necrosis factor-alpha [TNF-α]), and proliferation (neurotrophin-3 and brain-derived neurotrophic factor [BDNF]) were measured using reverse transcription polymerase chain reaction (PCR) and Western blotting. The expression levels of HO-1, SOD-2, XBP-1S, TNF-α, neurotrophin-3, and BDNF were compared among groups using the Mann–Whitney U test. The temporal cortex was immunostained for parvalbumin (PV) and Wisteria floribunda agglutinin (WFA). The numbers of PV- and WFA-positive cells were counted using a confocal microscope and analyzed with the Mann–Whitney U test. HO-1 expression was elevated in the prefrontal cortex, temporal cortex, striatum, and cerebellum of mice in the 8-week DEP group compared with the control group. Expression of SOD-2 and XBP-1S was elevated in the prefrontal cortex and striatum of the 8-week DEP group compared with the control group. TNF-α expression was elevated in the prefrontal cortex, temporal cortex, striatum, and cerebellum in the 4- and 8-week DEP groups compared with the control group. Neurotrophin-3 expression was decreased in the olfactory bulb and striatum of the 8-week DEP group compared with the control group. WFA density was increased in the 8-week DEP group compared with the control group. The PV and PV + WFA densities were decreased in the 4-week DEP group compared with the control group. Chronic DEP inhalation activated oxidative stress and inflammation in multiple brain regions. Chronic DEP inhalation increased PNNs and decreased the number of interneurons, which may contribute to PM exposure-related CNS dysfunction.
Reducing occupational lead exposures: Strengthened standards for a healthy workforce Neurotoxicology (IF 3.076) Pub Date : 2017-11-08 Rachel M. Shaffer, Steven G. Gilbert
Outdated federal and state occupational lead standards leave workers and their families vulnerable to the adverse effects of lead. Standards should be updated to reflect the best available scientific and medical evidence, which documents harm to multiple organ systems even at low levels of exposure. This commentary will review the inadequacies of existing policies, highlight susceptible populations, and briefly summarize state revision efforts to date. Federal policies must be strengthened to protect all workers and their families from this well-documented hazard.
Association between prenatal exposure to organochlorine pesticides and the mental and psychomotor development of infants at ages 6 and 18 months: The Hokkaido Study on Environment and Children’s Health Neurotoxicology (IF 3.076) Pub Date : 2017-12-02 Keiko Yamazaki, Atsuko Araki, Sonomi Nakajima, Chihiro Miyashita, Tamiko Ikeno, Sachiko Itoh, Machiko Minatoya, Sumitaka Kobayashi, Futoshi Mizutani, Yoichi Chisaki, Reiko Kishi
Organochlorine pesticides (OCPs) are environmental contaminants that persist in the environment and bioaccumulate through the food chain in humans and animals. Although previous studies have shown an association between prenatal OCP exposure and subsequent neurodevelopment, the levels of OCPs included in these studies were inconsistent. A hospital-based prospective birth cohort study was conducted to examine the associations between prenatal exposure to relatively low levels of OCPs and neurodevelopment in infants at 6 (n = 164) and 18 (n = 115) months of age. Blood samples were analyzed using gas chromatography/mass spectrometry techniques to quantify 29 OCPs. The Bayley Scales of Infant Development 2nd edition (BSID-II) was used to assess the Mental and Psychomotor Developmental Index. After controlling for confounders, we found an inverse association between prenatal exposure to cis-heptachlor epoxide and the Mental Developmental Index at 18 months of age. Furthermore, infants born to mothers with prenatal concentrations of cis-heptachlor epoxide in the highest quartile had Mental Developmental Index scores −9.8 (95% confidence interval: −16.4, −3.1) lower than that recorded for infants born to mothers with concentrations of cis-heptachlor epoxide in the first quartile (p for trend <0.01). These results support the hypothesis that prenatal exposure to OCPs, especially cis-heptachlor epoxide, may have an adverse effect on the neurodevelopment of infants at specific ages, even at low levels.
Can we predict intermediate syndrome? A review Neurotoxicology (IF 3.076) Pub Date : 2017-12-05 Chanika Alahakoon, Tharaka Lagath Dassanayake, Indika Bandara Gawarammana, Vajira Senaka Weerasinghe
Introduction Ingestion of organophosphorus insecticides (OPI) is a common method of deliberate self harm in the developing world. Deaths mainly follow as a result of the respiratory failure associated with both cholinergic crisis and the intermediate syndrome. Even though death can be prevented by early mechanical ventilation of these patients, limited studies are available regarding the prediction of intermediate syndrome and subsequent respiratory failure. Objective To systematically review articles that are published with regard to possible prediction of intermediate syndrome using clinical, biochemical and electrophysiological parameters. Methods A systematic review on literature published in English language was done in the PubMed database without a date limitation. Two sets of search terms were used. The first set consisted of MeSH Terms “organophosphates”, “organophosphate poisoning”, “op poisoning” “organophosphate insecticide poisoning” and “organophosphorus”. The second set included the MeSH Terms “Intermediate syndrome”, “proximal muscle weakness”, “cranial nerve palsies”, “respiratory depression” and “neck muscle weakness”. Articles containing at least one word from each set were reviewed. Results At least one MeSH term from each set was incorporated in 179 articles. Of these, 69 were rejected as they were not related to organophosphate poisoning or intermediate syndrome. Prediction of IMS Clinical prediction is mostly based on ICU scoring systems. Biochemical markers such as reduced levels of serum and erythrocyte acetylcholine esterase have been studied many times. Both clinical and biochemical markers show a modest relationship in predicting IMS. Single fibre electromyography show promising results as it directly assesses neuromuscular junction. Conclusion The intermediate syndrome which follows organophosphate poisoning still remains a significant problem with its high morbidity. Clinical and biochemical markers show modest results in predicting IMS. Neurophysiological markers such as single fibre EMG should be studied further as they measure activity of affected nicotinic receptors directly.
LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells Neurotoxicology (IF 3.076) Pub Date : 2017-12-05 Yuan Chen, Ya-jun Lian, Yun-qing Ma, Chuan-jie Wu, Ya-ke Zheng, Nan-chang Xie
Numerous long non-coding RNAs (lncRNAs) have been identified as aberrantly expressed in Parkinson’s disease (PD). However, limited knowledge is available concerning the roles of dysregulated lncRNAs and the underlying molecular regulatory mechanism in the pathological process of PD. In this study, we found that lncRNA small nucleolar RNA host gene 1 (SNHG1) and seven in absentia homolog 1 (SIAH1) were upregulated, but microRNA-15b-5p (miR-15b-5p) was downregulated in SH-SY5Y cells pretreated with MPP+, as well as in MPTP-induced mouse model of PD. Overexpression of SIAH1 enhanced cellular toxicity of α-synuclein in SH-SY5Y cells, as indicated by the reduction of cell viability and elevation of LDH release. The percentage of α-synuclein aggregate-positive cells and the number of α-synuclein aggregates per cell were increased in SH-SY5Y cells transfected with pcDNA-SIAH1, while decreased after transfection with short interfering RNA specific for SIAH1 (si-SIAH1). Bioinformatics and luciferase reporter assay revealed that SIAH1 was a direct target of miR-15b-5p. We also found that SNHG1 could directly bind to miR-15-5p and repress miR-15-5p expression. Upregulation of miR-15b-5p alleviated α-synuclein aggregation and apoptosis by targeting SIAH1 in SH-SY5Y cells overexpressing α-synuclein. Overexpression of SNHG1 enhanced, whereas SNHG1 knockdown inhibited α-synuclein aggregation and α-synuclein-induced apoptosis. Moreover, the neuroprotective effect of si-SNHG1 was abrogated by downregulation of miR-15b-5p. In summary, our data suggest that SNHG1, as a pathogenic factor, promotes α-synuclein aggregation and toxicity by targeting the miR-15b-5p/SIAH1 axis, contributing to a better understanding of the mechanisms of Lewy body formation and loss of dopaminergic neurons in PD.
HEK-293 secretome attenuates kainic acid neurotoxicity through insulin like growth factor-phosphatidylinositol-3-kinases pathway and by temporal regulation of antioxidant defense machineries Neurotoxicology (IF 3.076) Pub Date : 2017-12-06 Chaitra Venugopal, Y.S.Harish Chandra Prasad, K. Shobha, Venkata Bharatkumar Pinnelli, Anandh Dhanushkodi
A major impediment in the success of cell therapy for neurodegenerative diseases is the poor survival of grafted cells in the in vivo milieu, predominantly due to accumulated reactive oxygen species, thus prompting the search for suitable alternatives. Accumulating evidence suggests that the therapeutic potential of transplanted cells is partially attributed to the secretome released by them into the extracellular milieu. Studies that investigated the neuroprotective potential of the secretome attributes to the mere presence of growth factors without addressing other underlying cellular/molecular changes that occur upon post-secretome intervention like re-establishing the host cell’s free radical scavenging machineries. In the present study, we investigated the neuroprotective effects of human embryonic kidney (HEK-293) cell line derived secretome (HEK-S) in an in vitro model of kainic acid (KA) induced neurodegeneration and explored the possible neuroprotective mechanism(s) of HEK-S. Murine hippocampal cells were exposed to toxic doses of KA (200 μM) for 6 hours (H) or 24H to induce excitotoxicity. Kainic acid exposed hippocampal cells were then treated with HEK-S either simultaneously or 6 h post-KA exposure. Our results revealed that HEK-S confers significant neuroprotection in early/later stages of neurodegeneration through insulin like growth factor (IGF) – phosphatidylinositol-3-kinases (PI3 K) pathway, efficiently restoring the host’s free radical scavenging mechanisms at molecular-cellular-biochemical levels and also by modulating kainate receptor subunit expressions in host neurons.
Developmental exposure to low level ambient ultrafine particle air pollution and cognitive dysfunction Neurotoxicology (IF 3.076) Pub Date : 2017-12-13 D.A. Cory-Slechta, J.L. Allen, K. Conrad, E. Marvin, M. Sobolewski
Developmental exposures to ambient ultrafine particles (UFPs) can produce multiple neuropathological and neurochemical changes that might contribute to persistent alterations in cognitive-type functions. The objective of the current study was to test the hypothesis that developmental UFP exposure produced impairments in learning, memory and impulsive-like behaviors and to determine whether these were selective and thus independent of deficits in other behavioral domains such as motor activity or motivation. Performance on measures of learning (repeated learning), memory (novel object recognition, NOR), impulsive-like behavior (differential reinforcement of low rate (DRL), schedule of reward and delay of reward (DOR)), motor activity (locomotor behavior) and motivation (progressive ratio schedule) were examined in adult mice that had been exposed to concentrated (10–20x) ambient ultrafine particles (CAPS) averaging approximately 45 ug/m3 particle mass concentrations from postnatal day (PND) 4–7 and 10–13 for 4 h/day. Given the number of behavioral tests, animals were tested in different groups. Results showed male-specific alterations in learning and memory functions (repeated learning, NOR and DRL) specifically during transitions in reinforcement contingencies (changes in rules governing behavior) that did not appear to be related to alterations in locomotor function or motivation. Females did not exhibit cognitive-like deficits at these exposure concentrations, but displayed behaviors consistent with altered motivation, including increases in response rates during repeated learning, significantly increased latencies to respond on the delay of reward paradigm, and reductions in the progressive ratio break point. Consistent with our prior findings, male-specific learning and memory-related deficits were seen and occurred even at relatively low level developmental UFP exposures, while females show alterations in motivational behaviors but not final performance. These findings add to the evidence suggesting the need to regulate UFP levels.
The brains of bats foraging at wastewater treatment works accumulate arsenic, and have low non-enzymatic antioxidant capacities Neurotoxicology (IF 3.076) Pub Date : 2017-12-14 Kate Hill, M. Corrie Schoeman, Dalene Vosloo
Increasing rates of urbanisation cause ubiquitous infrastructures that remove anthropogenic contaminants – particularly Wastewater Treatment Works (WWTWs) – to become stressed, and hence pollute surrounding water systems. Neoromicia nana bats are suitable models to study the effects of pollution in these environments because they exploit abundant pollutant-tolerant chironomid midges that breed at WWTWs, and consequently accumulate metals such as iron, copper and zinc in their livers and kidneys. If these metals persist in their circulatory systems, and cross the blood brain barrier (BBB) they can have adverse effects on critical functions such as flight and echolocation. The aim of this study was to investigate the potential neurological effects on N. nana foraging at WWTWs versus bats at reference sites in Durban, South Africa. Our objectives were to 1) compare trace metal levels in brain and hair samples (as a proxy for circulating metals) between N. nana foraging at WWTWs and reference sites to determine if excess metals pass through the BBB via the circulatory system; and 2) compare biomarkers of neuron function (acetylcholinesterase activity), protection (antioxidant capacity), DNA integrity (DNA fragmentation), lipid integrity (lipid peroxidation) and cell viability (caspase-3 activity) between N. nana foraging at WWTW and reference sites. We found a significantly higher concentration of arsenic in hair (p < 0.05) and brain tissue (p < 0.1) of WWTW bats compared to bats at reference sites. By contrast, acetylcholinesterase activity did not differ in bats among sites and there was no evidence of significant differences in lipid peroxidation, compromised DNA integrity or apoptosis in the brains between WWTW bats and reference site bats. However, total antioxidant capacity was significantly lower in brains of WWTW bats than bats at reference sites suggesting that antioxidant protection may be compromised. Long-term exposure to environmental pollutants at WWTWs may therefore affect cellular processes and protection mechanisms in brains of N. nana bats. It may also affect other mechanisms and functions in the brain such as mitochondrial efficiency and other neurotransmitters but that remains to be tested.
Occupational exposure to extremely low frequency magnetic fields and risk of Alzheimer disease: A systematic review and meta-analysis Neurotoxicology (IF 3.076) Pub Date : 2017-12-24 Hamed Jalilian, Saeed Hosseini Teshnizi, Martin Röösli, Masoud Neghab
Introduction Occupational exposure to extremely low frequency magnetic fields (ELF-MF) occurs in many occupations such as welders, electric utility workers, train drivers and sewing machine operators. There is some evidence suggesting ELF-MF exposure to be a risk factor for Alzheimer’s disease (AD). The current study aims at systematically reviewing the literature and conducting a meta-analysis to evaluate the risk of AD amongst workers exposed to ELF-MF. Methods Bibliographic databases were searched including PubMed, EMBASE, Cochrane Library, and Web of Science in November 2017. Risk of bias was assessed in the all included studies. Pooled estimates were obtained using random-effects meta-analysis. In addition, sources of heterogeneity between studies and publication bias were explored. Results In total, 20 articles met the inclusion criteria. The pooled results suggest an increased risk of AD (RR: 1.63; 95% CI: 1.35, 1.96). Higher risk estimates were obtained from case-control studies (OR: 1.80; 95% CI: 1.40, 2.32) than from cohort studies (RR: 1.42; 95% CI: 1.08, 1.87). A moderate to high heterogeneity (I2 = 61.0%) and indication for publication bias (Egger test: p < 0.001) were found. Conclusion The results suggested that occupational exposure to ELF-MF might increase the risk of AD. However, this suggestion should be interpreted with caution given the moderate to high heterogeneity and indication for publication bias.
Environmental manganese exposure and associations with memory, executive functions, and hyperactivity in Brazilian children Neurotoxicology (IF 3.076) Pub Date : 2018-02-09 Chrissie Ferreira de Carvalho, Youssef Oulhote, Marina Martorelli, Carla Oliveira de Carvalho, José Antônio Menezes-Filho, Nayara Argollo, Neander Abreu
Manganese (Mn) is an essential element, however high levels of Mn have been associated with lower neuropsychological performance and behavioral problems in children. We investigated the associations between hair Mn concentrations and neuropsychological and behavioral performances among children with long-term exposure to airborne Mn aged between 7 and 12 years. Neuropsychological performance included tests of: verbal memory, inhibitory control, cognitive flexibility, verbal fluency, and motor function. We used the Conners Abbreviated Rating Scale for teachers to assess students’ behaviors of hyperactivity. Hair manganese (MnH) concentrations in children and exposure to airborne manganese from a ferro-manganese alloy plant were analyzed and correlated with tests scores. Multivariable linear models adjusting for potential confounders showed that elevated levels of MnH were associated with lower performance in verbal memory, as measured by the free recall after interference (β = – 1.8; 95% CI: – 3.4, – 0.2), which indicates susceptibility to interference, and Delayed Effect (β = –2.0; 95% CI: –3.7, – 0.2), representing a loss of information over time. Additionally, we found patterns of effect modification by sex in three subtests measuring verbal memory: the free recall after interference score, Interference Effect, and Delayed Effect (all at p < 0.10). Overall, the results suggest that long-term airborne Mn exposure may be associated with lower performance in verbal memory, and hyperactivity behaviors.
Acute exposure to zinc oxide nanoparticles critically disrupts operation of the respiratory neural network in neonatal rat Neurotoxicology (IF 3.076) Pub Date : 2018-05-31 Angelo Nicolosi, Laura Cardoit, Pierrick Pasquereau, Christèle Jaillet, Muriel Thoby-Brisson, Laurent Juvin, Didier Morin
Due to their extremely small size that gives them unique physicochemical properties, nanoparticles (NPs) are used in the production of everyday materials. However, NPs can accumulate in body organs and could cause various diseases. Moreover, NPs that cross biological membranes such as the blood-brain barrier can aggregate in the brain and potentially produce neuronal damage. Although studies have reported the effects of diverse NPs on the bioelectrical properties of individual neurons, their potential influences on the operation of whole neuronal networks have not been documented. Here, we aimed to evaluate the effects of an acute exposure to zinc oxide (ZnO) NPs on the central neural networks responsible for mammalian respiratory rhythm generation. Using an isolated ex vivo brainstem-spinal cord preparation from neonatal rat in which the circuitry for the central respiratory command remained intact, we show that ZnO NPs accelerate, then profoundly disrupt respiratory-related activity produced by the pre-Bötzinger complex (preBötC) responsible for inspiratory rhythm generation. Consequently, a sudden and definitive cessation of respiratory-related activity occurs in ZnO NPs-exposed preparations. Part of these effects is related to zinc ions released from NPs. Using brainstem slice preparations containing the preBötC network, whole-cell patch-clamp recordings revealed that ZnO NPs depolarize preBötC inspiratory neurons and affect their bioelectrical properties by reducing the amplitude of action potentials, thereby leading to a depression of intra-network activity and the ultimate termination of respiratory rhythmogenesis. These findings support the conclusion that ZnO NPs may have deleterious effects on the central respiratory centers of newborn mammals.
AMELIORATIVE EFFECT OF CARVACROL AGAINST PROPICONAZOLE-INDUCED NEUROBEHAVIORAL TOXICITY IN RATS Neurotoxicology (IF 3.076) Pub Date : 2018-05-28 Peter A. Noshy, Mohamed A. Elhady, Abdel Azeim A. Khalaf, Mervat M. Kamel, Eman I. Hassanen
Propiconazole (PCZ) is a triazole fungicide extensively used in agriculture. Carvacrol (CAR) is a naturally occurring phenolic monoterpene which has various biological and pharmacological effects. The present study was designed to investigate the neurobehavioral toxic effects of PCZ in albino rats and to evaluate the ameliorative role of CAR against such toxic effects. Sixty adult male rats were used in this investigation; they were randomly and equally divided into 4 groups: control group, PCZ group, CAR group and PCZ + CAR group. PCZ (75 mg/kg) and/or CAR (50 mg/kg) were administered daily by oral gavage for 8 weeks. Behavioral investigation clearly demonstrated the negative impact of PCZ on psychological, motor and cognitive brain functions. Exposure to PCZ also adversely affected the measured oxidative stress and lipid peroxidation parameters in brain tissue. A significant decrease in activity of acetylcholinesterase enzyme in neural tissue was also observed in PCZ-exposed rats. Histopathological examination of the cerebrum, cerebellum, and hippocampus showed various histopathological lesions after exposure to PCZ which were confirmed by immunohistochemical examination. On the other hand, co-administration of CAR ameliorated most of the undesirable effects of PCZ.
Children’s Contrast Sensitivity Function in Relation to Organophosphate Insecticide Prenatal Exposure in the Mother-Child PELAGIE Cohort Neurotoxicology (IF 3.076) Pub Date : 2018-05-24 Chloé Cartier, Charline Warembourg, Christine Monfort, Florence Rouget, Gwendolina Limon, Gaël Durand, Sylvaine Cordier, Dave Saint-Amour, Cécile Chevrier
Human exposure to organophosphate pesticides (OP) is widespread. Several studies suggest that OP prenatal exposure alters the development of cognitive and behavioural functions in children, but the effects of OP prenatal exposure on child sensory functions are largely unknown. The aim of the study was to evaluate the association between OP prenatal exposure and visual processing in school-aged children from the mother-child PELAGIE cohort (France). OP biomarkers of exposure were measured in maternal urine samples at the beginning of pregnancy. The Functional Acuity Contrast Test (FACT) was used to assess visual contrast sensitivity in 180 children at 6 years of age. Linear regression models were performed on all children, and separately for boys and girls, taking into account various potential confounders, including maternal education and breastfeeding. No associations were observed in the whole sample, while maternal OP urinary metabolite levels were associated with a decrease of FACT scores in boys. These findings indicate that OP prenatal exposure might impair visual processing later in life in boys only.
Valproic acid attenuates manganese-induced reduction in expression of GLT-1 and GLAST with concomitant changes in murine dopaminergic neurotoxicity Neurotoxicology (IF 3.076) Pub Date : 2018-05-18 James Johnson Jr., Edward Pajarillo, Pratap Karki, Judong Kim, Deok-Soo Son, Michael Aschner, Eunsook Lee
Exposure to elevated levels of manganese (Mn) causes manganism, a neurological disorder with similar characteristics to those of Parkinson’s disease (PD). Valproic acid (VPA), an antiepileptic, is known to inhibit histone deacetylases and exert neuroprotective effects in many experimental models of neurological disorders. In the present study, we investigated if VPA attenuated Mn-induced dopaminergic neurotoxicity and the possible mechanisms involved in VPA’s neuroprotection, focusing on modulation of astrocytic glutamate transporters (glutamate aspartate transporter, GLAST and glutamate transporter 1, GLT-1) and histone acetylation in H4 astrocyte culture and mouse models. The results showed that VPA increased promoter activity, mRNA/protein levels of GLAST/GLT-1 and glutamate uptake, and reversed Mn-reduced GLAST/GLT-1 in in vitro astrocyte cultures. VPA also attenuated Mn-induced reduction of GLAST and GLT-1 mRNA/protein levels in midbrain and striatal regions of the mouse brain when VPA (200 mg/kg, i.p., daily, 21 d) was administered 30 min prior to Mn exposure (30 mg/kg, intranasal instillation, daily, 21 d). Importantly, VPA attenuated Mn-induced dopaminergic neuronal damage by reversing Mn-induced decrease of tyrosine hydroxylase (TH) mRNA/protein levels in the nigrostriatal regions. VPA also reversed Mn-induced reduction of histone acetylation in astrocytes as well as mouse brain tissue. Taken together, VPA exerts attenuation against Mn-induced decrease of astrocytic glutamate transporters parallel with reversing Mn-induced dopaminergic neurotoxicity and Mn-reduced histone acetylation. Our findings suggest that VPA could serve as a potential neuroprotectant against Mn neurotoxicity as well as other neurodegenerative diseases associated with excitotoxicity and impaired astrocytic glutamate transporters.
PI3K/Akt/GSK3β induced CREB activation ameliorates arsenic mediated alterations in NMDA receptors and associated signaling in rat hippocampus: Neuroprotective role of curcumin Neurotoxicology (IF 3.076) Pub Date : 2018-04-30 Pranay Srivastava, Yogesh K. Dhuriya, Vivek Kumar, Akriti Srivastava, Richa Gupta, Rajendra K. Shukla, Rajesh S. Yadav, Hari N. Dwivedi, Aditya B. Pant, Vinay K. Khanna
Protective efficacy of curcumin in arsenic induced NMDA receptor dysfunctions and PI3 K/Akt/ GSK3β signalling in hippocampus has been investigated in vivo and in vitro. Exposure to sodium arsenite (in vivo - 20 mg/kg, body weight p.o. for 28 days; in vitro - 10 µM for 24 hrs) and curcumin (in vivo - 100 mg/kg body weight p.o. for 28 days; in vitro – 20 µM for 24 hrs) was carried out alone or simultaneously. Treatment with curcumin ameliorated sodium arsenite induced alterations in the levels of NMDA receptors, its receptor subunits and synaptic proteins - pCaMKIIα, PSD-95 and SynGAP both in vivo and in vitro. Decreased levels of BDNF, pAkt, pERK1/2, pGSK3β and pCREB on sodium arsenite exposure were also protected by curcumin. Curcumin was found to decrease sodium arsenite induced changes in hippocampus by modulating PI3 K/Akt/GSK3β neuronal survival pathway, known to regulate various cellular events. Treatment of hippocampal cultures with pharmacological inhibitors for ERK1/2, GSK3β and Akt individually inhibited levels of CREB and proteins associated with PI3 K/Akt/GSK3β pathway. Simultaneous treatment with curcumin was found to improve sodium arsenite induced learning and memory deficits in rats assessed by water maze and Y-maze. The results provide evidence that curcumin exercises its neuroprotective effect involving PI3 K/Akt pathway which may affect NMDA receptors and downstream signalling through TrKβ and BDNF in arsenic induced cognitive deficits in hippocampus.
Opportunities and challenges for using the zebrafish to study neuronal connectivity as an endpoint of developmental neurotoxicity Neurotoxicology (IF 3.076) Pub Date : 2018-04-25 Galen W. Miller, Vidya Chandrasekaran, Bianca Yaghoobi, Pamela J. Lein
Chemical exposures have been implicated as environmental risk factors that interact with genetic susceptibilities to influence individual risk for complex neurodevelopmental disorders, including autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder and intellectual disabilities. Altered patterns of neuronal connectivity represent a convergent mechanism of pathogenesis for these and other neurodevelopmental disorders, and growing evidence suggests that chemicals can interfere with specific signaling pathways that regulate the development of neuronal connections. There is, therefore, a growing interest in developing screening platforms to identify chemicals that alter neuronal connectivity. Cell-cell, cell-matrix interactions and systemic influences are known to be important in defining neuronal connectivity in the developing brain, thus, a systems-based model offers significant advantages over cell-based models for screening chemicals for effects on neuronal connectivity. The embryonic zebrafish represents a vertebrate model amenable to higher throughput chemical screening that has proven useful in characterizing conserved mechanisms of neurodevelopment. Moreover, the zebrafish is readily amenable to gene editing to integrate genetic susceptibilities. Although use of the zebrafish model in toxicity testing has increased in recent years, the diverse tools available for imaging structural differences in the developing zebrafish brain have not been widely applied to studies of the influence of gene by environment interactions on neuronal connectivity in the developing zebrafish brain. Here, we discuss tools available for imaging of neuronal connectivity in the developing zebrafish, review what has been published in this regard, and suggest a path forward for applying this information to developmental neurotoxicity testing.
Quinolinic Acid and glutamatergic neurodegeneration in Caenorhabditis elegans Neurotoxicology (IF 3.076) Pub Date : 2018-04-24 Tássia Limana da, Silveira, Daniele Coradine Zamberlan, Leticia Priscilla Arantes, Marina Lopes Machado, Thayanara Cruz da, Silva, Daniela de Freitas Câmara, Abel Santamaría, Michael Aschner, Felix Alexandre Antunes Soares
Quinolinic acid (QUIN) is an endogenous neurotoxin that acts as an N-methyl-D-aspartate receptor (NMDAR) agonist generating a toxic cascade, which can lead to neurodegeneration. The action of QUIN in Caenorhabditis elegans and the neurotoxins that allow the study of glutamatergic system disorders have not been carefully addressed. The effects of QUIN on toxicological and behavioral parameters in VM487 and VC2623 transgenic, as well as wild-type (WT) animals were performed to evaluate whether QUIN could be used as a neurotoxin in C. elegans. QUIN reduced survival of WT worms in a dose-dependent manner. A sublethal dose of QUIN (20 mM) increased reactive oxygen species (ROS) levels in an nmr-1/NMDAR-dependent manner, activated the DAF-16/FOXO transcription factor, and increased expression of the antioxidant enzymes, superoxide dismutase-3, glutathione S-transferase-4, and heat shock protein-16.2. QUIN did not change motor behavioral parameters, but altered the sensory behavior in N2 and VM487 worms. Notably, the effect of QUIN on the sensory behavioral parameters might occur, at least in part, secondary to increased ROS. However, the touch response behavior indicates a mechanism of action that is independent of ROS generation. In addition, non-lethal doses of QUIN triggered neurodegeneration in glutamatergic neurons. Our findings indicate that C. elegans might be useful as a model for studies of QUIN as a glutamatergic neurotoxin in rodent models.
Ag-NPs induce apoptosis, mitochondrial damages and MT3/OSGIN2 expression changes in an in vitro model of human dental-pulp-stem-cells-derived neurons Neurotoxicology (IF 3.076) Pub Date : 2018-04-23 Gabriele Bonaventura, Valentina La Cognata, Rosario Iemmolo, Massimo Zimbone, Annalinda Contino, Giuseppe Maccarrone, Bruno Failla, Maria Luisa Barcellona, Luisa Conforti Francesca, Velia D’Agata, Sebastiano Cavallaro
Silver nanoparticles (Ag-NPs) are one of the most popular nanotechnologies because of their unique antibacterial and antifungal properties. Given their increasing use in a wide range of commercial, biomedical and food products, exposure to Ag-NPs is now a reality in people’s lives. However, there is a serious lack of information regarding their potential toxic effects in the central nervous system. In this study, we investigated the biocompatibility of “homemade” Ag-NPs in an in vitro model of human neurons derived from dental pulp mesenchymal stem cells. Our results showed that acute exposure to Ag-NPs cause cytotoxicity, by triggering cell apoptosis, damaging neuronal connections, affecting the mitochondrial activity and changing the mRNA expression level of MT3 and OSGIN2, two genes involved in heavy metals metabolism and cellular growth during oxidative stress conditions. Further studies are needed to understand the molecular mechanisms and the physiological consequences underlying Ag-NPs exposure.
Moderate Perinatal Thyroid Hormone Insufficiency Alters Visual System Function in Adult Rats ☆ Neurotoxicology (IF 3.076) Pub Date : 2018-04-21 William K. Boyes, Laura Degn, Barbara Jane George, Mary E. Gilbert
Thyroid hormone (TH) is critical for many aspects of neurodevelopment and can be disrupted by a variety of environmental contaminants. Sensory systems, including audition and vision are vulnerable to TH insufficiencies, but little data are available on visual system development at less than severe levels of TH deprivation. The goal of the current experiments was to explore dose-response relations between graded levels of TH insufficiency during development and the visual function of adult offspring. Pregnant Long Evans rats received 0 or 3 ppm (Experiment 1), or 0, 1, 2, or 3 ppm (Experiment 2) of propylthiouracil (PTU), an inhibitor of thyroid hormone synthesis, in drinking water from gestation day (GD) 6 to postnatal day (PN) 21. Treatment with PTU caused dose-related reductions of serum T4, with recovery on termination of exposure, and euthyroidism by the time of visual function testing. Tests of retinal (electroretinograms; ERGs) and visual cortex (visual evoked potentials; VEPs) function were assessed in adult offspring. Dark-adapted ERG a-waves, reflecting rod photoreceptors, were increased in amplitude by PTU. Light-adapted green flicker ERGs, reflecting M-cone photoreceptors, were reduced by PTU exposure. UV-flicker ERGs, reflection S-cones, were not altered. Pattern-elicited VEPs were significantly reduced by 2 and 3 ppm PTU across a range of stimulus contrast values. The slope of VEP amplitude-log contrast functions was reduced by PTU, suggesting impaired visual contrast gain. Visual contrast gain primarily reflects function of visual cortex, and is responsible for adjusting sensitivity of perceptual mechanisms in response to changing visual scenes. The results indicate that moderate levels of pre-and post-natal TH insufficiency led to alterations in visual function of adult rats, including both retinal and visual cortex sites of dysfunction.
Forebrain glutamate uptake and behavioral parameters are altered in adult zebrafish after the induction of Status Epilepticus by kainic acid Neurotoxicology (IF 3.076) Pub Date : 2018-04-19 Ben Hur Marins Mussulini, Adriana Fernanda Kuckartz Vizuete, Marcos Braga, Luana Moro, Suelen Baggio, Emerson Santos, Gabriela Lazzarotto, Kamila Cagliari Zenki, Letícia Pettenuzzo, João Batista Texeira Rocha, Diogo Losch de Oliveira, Maria Elisa Calcagnotto, José Angelo Silveira Zuanazzi, Javier Santos Burgos, Eduardo Pacheco Rico
The development of new antiepileptic drugs is a high-risk/high-cost research field, which is made even riskier if the behavioral epileptic seizure profile is the unique approach on which the development is based. In order to increase the effectiveness of the screening conducted in the zebrafish model of status epilepticus (SE), the evaluation of neurochemical markers of SE would be of great relevance. Epilepsy is associated with changes in the glutamatergic system, and glutamate uptake is one of the critical parameters of this process. In this study therefore, we evaluated the levels of glutamate uptake in the zebrafish brain and analyzed its correlation with the progression of behavioral changes in zebrafish at different times after the administration of kainic acid 5 mg/kg). The results showed that the zebrafish suffered with lethargy while swimming for up to 72 h after SE, had reduced levels of GFAP cells 12 h after SE, reduced levels of S100B up to 72 h after SE, and reduced levels of glutamate uptake in the forebrain between 3 h and 12 h after SE. The forebrain region of adult zebrafish after SE is similar to the neurochemical limbic alterations that are seen in rodent models of SE. This study demonstrated that there is a time window in which to use the KA zebrafish model of SE to explore some of the known neurochemical alterations that have been observed in rodent models of epilepsy and epileptic human patients.
Metabolic effects of manganese in the nematode Caenorhabditis elegans through DAergic pathway and transcription factors activation Neurotoxicology (IF 3.076) Pub Date : 2018-04-16 Priscila Gubert, Bruna Puntel, Tassia Lehmen, Joshua P. Fessel, Pan Cheng, Julia Bornhorst, Lucas Siqueira Trindade, Daiana S. Avila, Michael Aschner, Felix A.A. Soares
Manganese (Mn) is an essential trace element for physiological functions since it acts as an enzymatic co-factor. Nevertheless, overexposure to Mn has been associated with a pathologic condition called manganism. Furthermore, Mn has been reported to affect lipid metabolism by mechanisms which have yet to be established. Herein, we used the nematode Caenorhabditis elegans to examine Mn’s effects on the dopaminergic (DAergic) system and determine which transcription factors that regulate with lipid metabolism are affected by it. Worms were exposed to Mn for four hours in the presence of bacteria and in a liquid medium (85 mM NaCl). Mn increased fat storage as evidenced both by Oil Red O accumulation and triglyceride levels. In addition, metabolic activity was reduced as a reflection of decreased oxygen consumption caused by Mn. Mn also affected feeding behavior as evidenced by decreased pharyngeal pumping rate. DAergic neurons viability were not altered by Mn, however the dopamine levels were significantly reduced following Mn exposure. Furthermore, the expression of sbp-1 transcription factor and let-363 protein kinase responsible for lipid accumulation control was increased and decreased, respectively, by Mn. Altogether, our data suggest that Mn increases the fat storage in C. elegans, secondary to DAergic system alterations, under the control of SBP-1 and LET-363 proteins.
Reduced maternal behavior caused by gestational stress is predictive of life span changes in risk-taking behavior and gene expression due to altering of the stress/anti-stress balance Neurotoxicology (IF 3.076) Pub Date : 2018-04-06 Eleonora Gatta, Jérôme Mairesse, Lucie Deruyter, Jordan Marrocco, Gilles Van Camp, Hammou Bouwalerh, Jean Marc Lo Guidice, Sara Morley-Fletcher, Ferdinando Nicoletti, Stefania Maccari
Exposure of the mother to adverse events during pregnancy is known to induce pathological programming of the HPA axis in the progeny, thereby increasing the vulnerability to neurobehavioral disorders. Maternal care plays a crucial role in the programming of the offspring, and oxytocin plays a key role in mother/pup interaction. Therefore, we investigated whether positive modulation of maternal behavior by activation of the oxytocinergic system could reverse the long-term alterations induced by perinatal stress (PRS; gestational restraint stress 3 times/day during the last ten days of gestation) on HPA axis activity, risk-taking behavior in the elevated-plus maze, hippocampal mGlu5 receptor and gene expression in Sprague-Dawley rats. Stressed and control unstressed dams were treated during the first postpartum week with an oxytocin receptor agonist, carbetocin (1 mg/kg, i.p.). Remarkably, reduction of maternal behavior was predictive of behavioral disturbances in PRS rats as well as of the impairment of the oxytocin and its receptor gene expression.Postpartum carbetocin corrected the reduction of maternal behavior induced by gestational stress as well as the impaired oxytocinergic system in the PRS progeny, which was associated with reduced risk-taking behavior. Moreover, postpartum carbetocin had an anti-stress effect on HPA axis activity in the adult PRS progeny and increased hippocampal mGlu5 receptor expression in aging. In conclusion, the activation of the oxytocinergic system in the early life plays a protective role against the programming effect by adverse experiences and could be considered as a novel and powerful potential therapeutic target for stress-related disorders.
A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice Neurotoxicology (IF 3.076) Pub Date : 2018-04-03 Fanny Demars, Kristen Clark, Megan S. Wyeth, Emily Abrams, Paul S. Buckmaster
Harmful blooms of domoic acid (DA)-producing algae are a problem in oceans worldwide. DA is a potent glutamate receptor agonist that can cause status epilepticus and in survivors, temporal lobe epilepsy. In mice, one-time low-dose in utero exposure to DA was reported to cause hippocampal damage and epileptiform activity, leading to the hypothesis that unrecognized exposure to DA from contaminated seafood in pregnant women can damage the fetal hippocampus and initiate temporal lobe epileptogenesis. However, development of epilepsy (i.e., spontaneous recurrent seizures) has not been tested. In the present study, long-term seizure monitoring and histology was used to test for temporal lobe epilepsy following prenatal exposure to DA. In Experiment One, the previous study’s in utero DA treatment protocol was replicated, including use of the CD-1 mouse strain. Afterward, mice were video-monitored for convulsive seizures from 2-6 months old. None of the CD-1 mice treated in utero with vehicle or DA was observed to experience spontaneous convulsive seizures. After seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. None of the mice treated in utero with DA displayed the hilar neuron loss that occurs in patients with temporal lobe epilepsy and in the mouse pilocarpine model of temporal lobe epilepsy. In Experiment Two, a higher dose of DA was administered to pregnant FVB mice. FVB mice were tested as a potentially more sensitive strain, because they have a lower seizure threshold, and some females spontaneously develop epilepsy. Female offspring were monitored with continuous video and telemetric bilateral hippocampal local field potential recording at 1-11 months old. A similar proportion of vehicle- and DA-treated female FVB mice spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequency and duration were similar in both groups. Seizure frequency was lower than that of positive-control pilocarpine-treated mice, but seizure duration was similar. None of the mice treated in utero with vehicle or DA displayed hilar neuron loss or intense mossy fiber sprouting, a form of aberrant synaptic reorganization that develops in patients with temporal lobe epilepsy and in pilocarpine-treated mice. FVB mice that developed epilepsy (vehicle- and DA-treated) displayed mild mossy fiber sprouting. Results of this study suggest that a single subconvulsive dose of DA at mid-gestation does not cause temporal lobe epilepsy in mice.
Sex modulated effects of sarin exposure in rats: toxicity, hypothermia and inflammatory markers Neurotoxicology (IF 3.076) Pub Date : 2018-04-03 Z. Pittel, E. Grauer, R. Gez, Y. Shlomovich, S. Baranes, S. Chapman
This work focused on sex differences in rats exposed to sarin. Females were found to be more sensitive to sarin toxicity (LD50 67 µg/kg) than males (88 µg/kg), showed less acute hypothermic effects than males (at 120 min post sarin, 3.1 ± 1.1 and 4.5 ± 1 °C decrease, respectively), but with a significant slower recovery over days. Females’ temperature response to the cholinergic agonist oxotremorine (0.25 mg/kg, im) was more pronounced than that of males (at 30 min, 3.13 ± 0.27 and 2.13 ± 0.19 °C decrease, respectively) and both sexes recovered within 2 h of exposure. 24 h after sarin exposure (80 µg/kg followed 1 min later by TA treatment (TMB4 7.5 mg/kg and atropine 5 mg/kg)( a 255% increase in plasma MCP-1 in males but not in females was recorded. In the brain, TIMP-1 increased 43 fold in females and 25 fold in males, compared to control rats. MCP-1 increased 8 fold in females only. TNFα increased in both sexes, but the increase in female brain was higher than that recorded in males. IL-6 increased in females but not in males. IL-1β increased in both sexes. This work clearly demonstrates significant sex modulation effects on measures of toxicity, hypothermia and inflammatory markers in brain and plasma 24 h following exposure to sarin. In general, females seem to be more sensitive to the toxicity of sarin, but may be better protected against its brain damage. In light of these and other findings, the efficacy of the various available treatments, as well as those being developed, should be evaluated in both sexes.
Intranasal administration of sodium dimethyldithiocarbamate induces motor deficits and dopaminergic dysfunction in mice Neurotoxicology (IF 3.076) Pub Date : 2018-03-29 Josiel M. Mack, Tainara M. Moura, Débora Lanznaster, Franciane Bobinski, Caio M. Massari, Tuane B. Sampaio, Ariana E. Schmitz, Luiz F. Souza, Roger Walz, Carla I. Tasca, Anicleto Poli, Richard L. Doty, Alcir L. Dafre, Rui D. Prediger
The primary etiology of Parkinson’s disease (PD) remains unclear, but likely reflects a combination of genetic and environmental factors. Exposure to some pesticides, including ziram (zinc dimethyldithiocarbamate), is a relevant risk factor for PD. Like some other environmental neurotoxicants, we hypothesized that ziram can enter the central nervous system from the nasal mucosa via the olfactory nerves. To address this issue, we evaluated the effects of 1, 2 or 4 days of intranasal (i.n., 1 mg/nostril/day) infusions of sodium dimethyldithiocarbamate (NaDMDC), a dimethyldithiocarbamate more soluble than ziram, on locomotor activity in the open field, neurological severity score and rotarod performance. We also addressed the effects of four daily i.n. NaDMDC infusions on olfactory bulb (OB) and striatal measures of cell death, reactive oxygen species (ROS), tyrosine hydroxylase, and the levels of dopamine, noradrenaline, serotonin, and their metabolites. A single i.n. administration of NaDMDC did not significantly alter the behavioral measures. Two consecutive days of i.n. NaDMDC administrations led to a transient neurological deficit that spontaneously resolved within a week. However, the i.n. infusions of NaDMDC for 4 consecutive days induced motor and neurological deficits for up to 7 days after the last NaDMDC administration and increased striatal TH immunocontent and dopamine degradation within a day of the last infusion. Pharmacological treatment with the anti-parkinsonian drugs L-DOPA and apomorphine improved the NaDMDC-induced locomotor deficits. NaDMDC increased serotonin levels and noradrenaline metabolism in the OB 24 h after the last NaDMDC infusion, ROS levels in the OB 2 hours after the last infusion, and striatum 2 and 24 hours after the last infusion. These results demonstrate, for the first time, that i.n. NaDMDC administration induces neurobehavioral and neurochemical impairments in mice. This accords with evidence that dimethyldithio-carbamate exposure increases the risk of PD and highlights the possibility that olfactory system could be a major route for NaDMDC entry to central nervous system.
Protective effects of pituitary adenylate cyclase activating polypeptide against neurotoxic agents Neurotoxicology (IF 3.076) Pub Date : 2018-03-28 D. Reglodi, A. Tamas, A. Jungling, A. Vaczy, A. Rivnyak, B.D. Fulop, E. Szabo, A. Lubics, T. Atlasz
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide highly expressed in the central and peripheral nervous system, where it exerts several neuromodulatory functions and is an important trophic and protective factor. PACAP has been shown to activate several protective pathways, mainly through its specific PAC1 receptor and protein kinase A, C and MAP kinases downstream. It has been shown to have very potent neuroprotective actions against different neurotoxic agents both in vitro and in vivo. The aim of the present review is to provide an overview on the neurotoxic injuries against which PACAP exerts protection, and to give an insight into its protective mechanism. We give a summary of the neuroprotective effects against the most commonly used neurotoxic agents, such as 6-OHDA, MPTP, glutamate and some less well-known neurotoxic compounds. Also endogenous PACAP has neuroprotective effects, known from studies in PACAP knockout mice or from blocking endogenous effects by antagonists. Altogether, the vast amount of data for the neuroprotective effects of PACAP give a firm background for its endogenous role as part of the neuroprotective machinery and its possible future therapeutic use as a neuroprotective factor.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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