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  • Saikosaponin d causes apoptotic death of cultured neocortical neurons by increasing membrane permeability and elevating intracellular Ca2+ concentration
    Neurotoxicology (IF 3.076) Pub Date : 2018-11-17
    Jing Zheng, Juan Chen, Xiaohan Zou, Fang Zhao, Mengqi Guo, Hongbo Wang, Tian Zhang, Chunlei Zhang, Wei Feng, Isaac N. Pessah, Zhengyu Cao

    Saikosaponins (SSs) are a class of naturally occurring oleanane-type triterpenoid saponins found in Radix bupleuri that has been widely used in traditional Chinese medicine. As the main active principals of Radix bupleuri, SSs have been shown to suppress mouse motor activity, impair learning and memory, and decrease hippocampal neurogenesis. In the present study, we investigated the effect of five SSs (SSa, SSb1, SSb2, SSc, and SSd) on neuronal viability and the underlying mechanisms in cultured murine neocortical neurons. We demonstrate that SSa, SSb1 and SSd produce concentration-dependent apoptotic neuronal death and induce robust increase in intracellular Ca2+ concentration ([Ca2+]i) at low micromolar concentrations with a rank order of SSd > SSa > SSb1, whereas SSb2 and SSc have no detectable effect on both neuronal survival and [Ca2+]i. Mechanistically, SSd-induced elevation in [Ca2+]i is the primary result of enhanced extracellular Ca2+ influx, which likely triggers Ca2+-induced Ca2+ release through ryanodine receptor activation, but not SERCA inhibition. SSd-induced Ca2+ entry occurs through a non-selective mechanism since blockers of major neuronal Ca2+ entry pathways, including L-type Ca2+ channel, NMDA receptor, AMPA receptor, Na+-Ca2+ exchanger, and TRPV1, all failed to attenuate the Ca2+ response to SSd. Further studies demonstrate that SSd increases calcein efflux and induces an inward current in neocortical neurons. Together, these data demonstrate that SSd elevates [Ca2+]i due to its ability to increase membrane permeability, likely by forming pores in the surface membrane, which leads to massive Ca2+ influx and apoptotic neuronal death in neocortical neurons.

    更新日期:2018-11-17
  • Early life exposure to extended general anesthesia with isoflurane and nitrous oxide reduces responsivity on a cognitive test battery in the nonhuman primate
    Neurotoxicology (IF 3.076) Pub Date : 2018-11-14
    John C. Talpos, John J. Chelonis, Mi Li, Joseph P. Hanig, Merle G. Paule

    Despite the widespread use of general anesthesia, a growing body of research suggests that anesthesia exposure early in life may be associated with acute neurotoxicity and lasting behavioral changes. To better evaluate the risk posed by early life anesthesia on cognitive development, infant rhesus monkeys were exposed to an anesthesia regimen previously shown to be neurotoxic and their cognitive development was subsequently measured using a translational operant test battery. On postnatal day 5 or 6, animals were exposed to 8 hours of isoflurane (n = 6, 1% isoflurane in a vehicle gas of 70% nitrous oxide and 30% oxygen) or a control condition (n = 8). Starting at 7 months of age, the monkeys were continuously trained and assessed on the NCTR Operant Test Battery (OTB). The OTB consists of cognitive tests which also exist in near identical forms for use in rats and humans, and includes tests of learning, memory, color discrimination, and motivation. Monkeys previously exposed to anesthesia showed a clear decrease in responding in a measure of motivation, as well as a lower response rate in a learning task. These data further support the hypothesis that prolonged anesthesia early in life may increase the risk of developing cognitive impairments later in life.

    更新日期:2018-11-15
  • OTILONIUM AND PINAVERIUM TRIGGER MITOCHONDRIAL-MEDIATED APOPTOSIS IN RAT EMBRYO CORTICAL NEURONS IN VITRO
    Neurotoxicology (IF 3.076) Pub Date : 2018-11-15
    Fernanda García-Alvarado, Giulia Govoni, Ricardo de Pascual, Cristina Ruiz-Ruiz, Alicia Muñoz-Montero, Luis Gandía, Antonio M.G de Diego, Antonio G. García

    In the frame of a repositioning programme with cholinergic medicines in clinical use searching for neuroprotective properties, we surprisingly found that spasmolytic antimuscarinics otilonium and pinaverium exhibited neurotoxic effects in neuronal cultures. We decided to characterize such unexpected action in primary cultures of rat embryo cortical neurons. Neurotoxicity was time- and concentration-dependent, exhibiting approximate EC50´s of 5 µM for both drugs. Seven antimuscarinic drugs endowed with a quaternary ammonium, and another 10 drugs with different cholinergic activities, carrying in their molecule a ternary ammonium did not exhibit neurotoxicity. Both drugs caused a concentration-dependent blockade of whole-cell inward currents through voltage-activated calcium channels (VACCs). Consistent with this, they also blocked the of K+-elicited [Ca2+] c transients. Neither antioxidant catalase, glutathione, n-acetylcysteine, nor melatonin protected against neurotoxicity of otilonium or pinaverium. However cyclosporine A, a blocker of the mitochondrial permeability transition pore, prevented the neurotoxic effects of otilonium and pinaverium monitored as the fraction of cells undergoing apoptosis. Furthermore, the caspase-9 and caspase-3 inhibitor Ac-LEHD-CHO mitigated the apoptotic neuronal death of both drugs by around 50%. Data are compatible with the hypothesis that otilonium and pinaverium elicit neuronal death by activating the intrinsic mitochondrial-mediated signaling pathway of apoptosis. This may have its origin in the mitigation of Ca2+ entry and the uncoupling of the Ca2+-dependent generation of mitochondrial bioenergetics, thus causing the opening of the mitochondrial mPTP to elicit apoptotic neuronal death.

    更新日期:2018-11-15
  • Cannabinoid-like Effects of Five Novel Carboxamide Synthetic Cannabinoids
    Neurotoxicology (IF 3.076) Pub Date : 2018-11-12
    Michael B. Gatch, Michael J. Forster

    A new generation of novel cannabinoid compounds have been developed as marijuana substitutes to avoid drug control laws and cannabinoid blood tests. 5F-MDMB-PINACA (also known as 5F-ADB, 5F-ADB-PINACA), MDMB-CHIMICA, MDMB-FUBINACA, ADB-FUBINACA, and AMB-FUBINACA (also known as FUB-AMB, MMB-FUBINACA) were tested for in vivo cannabinoid-like effects to assess their abuse liability. Locomotor activity in mice was tested to screen for locomotor depressant effects and to identify behaviorally-active dose ranges and times of peak effect. Discriminative stimulus effects were tested in rats trained to discriminate Δ9-tetrahydrocannabinol (3 mg/kg, 30-min pretreatment). 5F-MDMB-PINACA (ED50 = 1.1 mg/kg) and MDMB-CHIMICA (ED50 = 0.024 mg/kg) produced short-acting (30 min) depression of locomotor activity. ADB-FUBINACA (ED50 = 0.19 mg/kg), and AMB- FUBINACA (ED50 = 0.19 mg/kg) depressed locomotor activity for 60-90 min; whereas MDMB-FUBINACA (ED50 = 0.04 mg/kg) depressed locomotor activity for 150 min. AMB-FUBINACA produced tremors at the highest dose tested. 5F-MDMB-PINACA (ED50 = 0.07), MDMB-CHIMICA (ED50 = 0.01 mg/kg), MDMB-FUBINACA (ED50 = 0.051 mg/kg), ADB-FUBINACA (ED50 = 0.075 mg/kg) and AMB-FUBINACA (ED50 = 0.029) fully substituted for the discriminative stimulus effects of Δ9-THC following 15-min pretreatment. All 5 compounds decreased locomotor activity and produced discriminative stimulus effects similar to those of Δ9-THC, which suggests they may have abuse liability similar to that of Δ9-THC. AMB-FUBINACA may have an increased risk of toxicities in recreational users.

    更新日期:2018-11-12
  • 更新日期:2018-11-05
  • Heterozygous huntingtin promotes cadmium neurotoxicity and neurodegeneration in striatal cells via altered metal transport and protein kinase C delta dependent oxidative stress and apoptosis signaling mechanisms
    Neurotoxicology (IF 3.076) Pub Date : 2018-11-03
    Gunnar F. Kwakye, Jessica A. Jiménez, Morgan G. Thomas, Brett A. Kingsley, Matthew McIIvin, Mak A. Saito, Edmund M. Korley
    更新日期:2018-11-05
  • Involvement of oxidative stress in di-2-ethylhexyl phthalate (DEHP)-induced apoptosis of mouse NE-4C neural stem cells
    Neurotoxicology (IF 3.076) Pub Date : 2018-11-03
    Miaojing Wu, Linlin Xu, Chaxiang Teng, Xiao Xiao, Weihua Hu, Jiaxiang Chen, Wei Tu

    Di-2-ethylhexyl phthalate (DEHP) has been widely used as a plasticizer in industry and can cause neurotoxicity; however, the underlying mechanism remains unclear. In the study, we found that DEHP significantly inhibited viability of mouse NE-4C neural stem cells and caused lactate dehydrogenase (LDH) release from the cells. DEHP dramatically increased the levels of apoptosis-related proteins such as cleaved Caspase-8, cleaved Caspase-3 and Bax, as well as decreased Bcl-2 protein level. DEHP could also significantly increase the total numbers of AnnexinV-positive/PI-negative and AnnexinV-positive/PI-positive staining cells. Hoechst 33342 staining showed that marked DNA condensation and apoptotic bodies could be found in the ZnO NPs-treated cells. These results indicated that DEHP could induce apoptosis of NE-4C cells. Meanwhile, DEHP could significantly increase malondialdehyde (MDA) level, and decrease the content of glutathione (GSH) and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), respectively, implying that DEHP could induce oxidative stress of NE-4C cells. Furthermore, N-Acetyl-L-cysteine (NAC), an inhibitor of oxidative stress, could rescue the inhibition of cell viability and induction of apoptosis by DEHP. Taken together, our results showed that oxidative stress was involved in DEHP-induced apoptosis of mouse NE-4C cells.

    更新日期:2018-11-05
  • CARVACROL AMELIORATES BEHAVIORAL DISTURBANCES AND DNA DAMAGE IN THE BRAIN OF RATS EXPOSED TO PROPICONAZOLE
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-28
    Mohamed A. Elhady, Abdel Azeim A. Khalaf, Mervat M. Kamel, Peter A. Noshy

    Propiconazole (PCZ) is an ergosterol biosynthesis inhibiting fungicide. Carvacrol (CAR) is a monoterpenoid phenol that has various beneficial health effects. The current research was designed to study the impact of PCZ on the behavior of rats and its ability to induce DNA damage in neurons as well as to clarify the ameliorative effect of CAR against these toxic impacts. Sixty Sprague-Dawley rats were randomly and equally divided into 4 experimental groups and treated daily by oral gavage for 2 months as follows: Group 1 (control); group 2 treated with PCZ (75 mg/kg); group 3 treated with CAR (50 mg/kg) and group 4 treated with both PCZ and CAR. Behavioral tests demonstrated that exposure to PCZ had a deleterious effect on psychological, motor and cognitive neural functions. Additionally, antioxidant enzyme activities, SOD and GSH-Px, were declined in brain tissue following exposure to PCZ. Moreover, comet assay revealed a high percent of DNA damage in the brain of rats exposed to PCZ. On the other hand, CAR administration ameliorated the harmful effects induced by PCZ through a protective mechanism that involved the improvement of neural functions and attenuation of oxidative stress and DNA damage.

    更新日期:2018-10-30
  • Adolescent methylmercury exposure: Behavioral mechanisms and effects of sodium butyrate in mice
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-29
    Steven R. Boomhower, M. Christopher Newland

    Methylmercury (MeHg), an environmental neurotoxicant primarily found in fish, produces neurobehavioral impairment when exposure occurs during gestation. Whether other developmental periods, such as adolescence, display enhanced vulnerability to the behavioral effects of MeHg exposure is only beginning to be explored. Further, little is known about the effects of repeated administration of lysine deacetylase inhibitors, such as sodium butyrate (NaB), on operant behavior. In Experiment 1, male C57BL6/n mice were exposed to 0, 0.3, and 3.0 ppm MeHg (n = 12 each) via drinking water from postnatal days 21 to 60 (murine adolescence). As adults, mice were trained to lever press under an ascending series of fixed-ratio schedules of milk reinforcement selected to enable the analysis of three important parameters of operant behavior using the framework provided by Mathematical Principles of Reinforcement. Adolescent MeHg exposure dose-dependently increased saturation rate, a measure of the retroactive reach of a reinforcer, and decreased minimum response time relative to controls. In Experiment 2, the behavioral effects of repeated NaB administration both alone and following adolescent MeHg exposure were examined. Male C57BL6/n mice were given either 0 or 3.0 ppm MeHg during adolescence and, before behavioral testing, two weeks of once daily i.p. injections of saline or 0.6 g/kg NaB (n = 12 in each cell). Adolescent MeHg exposure again increased saturation rate but did not significantly alter minimum response time. NaB also increased saturation rate in both MeHg exposure groups. These data suggest that the behavioral mechanisms of adolescent MeHg exposure and NaB may be related to the impact of reinforcement on prior responses. Specifically, MeHg and NaB concentrated the effects of reinforcers onto the most recent responses.

    更新日期:2018-10-30
  • ANTIAPOPTOTIC EFFECT OF TAURINE AGAINST NMDA-INDUCED RETINAL EXCITOTOXICITY IN RATS
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-30
    Lidawani Lambuk, Igor Iezhitsa, Renu Agarwal, Nor Salmah Bakar, Puneet Agarwal, Nafeeza Mohd Ismail

    Objective N-methyl-D-aspartate (NMDA) excitotoxicity has been proposed to mediate apoptosis of retinal ganglion cells (RGCs) in glaucoma. Taurine (TAU) has been shown to have neuroprotective properties, thus we examined anti-apoptotic effect of TAU against retinal damage after NMDA exposure. Methodology. Sprague-Dawley rats were divided into 5 groups of 33 each. Group 1 was administered intravitreally with vehicle and group 2 was similarly injected with NMDA (160 nmol). Groups 3, 4 and 5 were injected with TAU (320 nmol) 24 hours before (pre-treatment), in combination (co-treatment) and 24 hours after (post-treatment) NMDA exposure. Seven days after injection, rats were sacrificed; eyes were enucleated, fixed and processed for morphometric analysis, TUNEL and caspase-3 staining. Optic nerve morphology assessment was done using toluidine blue staining. The estimation of BDNF, pro/anti-apoptotic factors (Bax/Bcl-2) and caspase-3 activity in retina was done using ELISA technique. Results. Severe degenerative changes were observed in retinae after intravitreal NMDA exposure. The retinal morphology in the TAU pre-treated group appeared more similar to the control retinae and demonstrated a higher number of nuclei than the NMDA group both per 100 µm length (by 1.5-fold, p < 0.001) and per 100 µm2 area (by 1.41-fold, p < 0.05) of the GCL. After NMDA exposure, visible axonal swelling was observed in optic nerve sections. In comparison with the changes observed in the NMDA treated group, the TAU treated group showed fewer prominent changes; axonal swelling was less frequent and less marked. Additionally, no marked glial cell changes were observed in the TAU-pretreated group. All TAU treated groups, particularly the pre-treated group, showed a significant decrease in the NMDA-induced optic nerve damage, with a 50% reduction (p < 0.001) in the mean grading compared to NMDA group. For the same, there was 25% decrease in co- and post-treatment groups, as compared with the NMDA group. Pre-treatment with TAU abolished apoptotic response to NMDA as indicated by decrease in the number of TUNEL- and caspase-3-positive cells. TAU pre-treatment also increased the Bcl-2 level (by 2.80-fold, p < 0.001) and decreased the level of Bax (by 34%, p < 0.01), and activity of caspase-3 (by 36%, p < 0.001) compared to NMDA group. In conclusion, our study revealed that pre-treatment with TAU prevents NMDA-induced retinal cell apoptosis more effectively than co- and post-treatment with TAU.

    更新日期:2018-10-30
  • Silencing brain catalase expression reduces ethanol intake in developmentally-lead-exposed rats
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-30
    M.S. Mattalloni, Paula A. Albrecht, C. Salinas-Luypaert, Romina Deza-Ponzio, M.E. Quintanilla, M. Herrera-Marschitz, L.M. Cancela, M. Rivera-Meza, M.B. Virgolini
    更新日期:2018-10-30
  • Exposure to Pesticides and the Prevalence of Diabetes in a Rural Population in Korea
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-24
    Sungjin Park, Sung-Kyung Kim, Jae-Yeop Kim, Kyungsuk Lee, Jung Ran Choi, Sei-Jin Chang, Choon Hee Chung, Kyu-Sang Park, Sung-Soo Oh, Sang-Baek Koh

    Background Among the adverse health effects of exposure to pesticides, an association with diabetes has been reported. However, there is a lack of epidemiologic studies on the health effects of exposure to pesticides, particularly investigating the association between occupational pesticide exposure and diabetes prevalence. Purpose The present study examined the association between pesticide exposure and prevalence of diabetes in a rural population in Korea. Methods This cross-sectional study used data from the Korea Farmers Cohort study, and included 2559 participants in the baseline survey between November 2005 and January 2008. We performed a clinical examination including blood sampling and assessed data on diabetes diagnosis, demographics, and pesticide exposure. Logistic regression was performed to evaluate the association between pesticide exposure and diabetes prevalence, adjusting for age, sex, monthly income, and marital status. In addition, a stratified analysis by body mass index (BMI) was conducted, with two categories: normal weight (<25 kg/m2) and overweight or obese (≥25 kg/m2). Results At baseline, the prevalence of diabetes was 9.30%. Pesticide exposure was associated with the risk of diabetes after adjustment for covariates. In the analysis stratified by BMI, all the variables related to pesticide exposure were associated with prevalence of diabetes in the overweight or obese group, whereas no significant association was found in the normal weight group. Conclusion Exposure to pesticides was associated with diabetes, and this association was stronger in overweight or obese individuals than in normal weight individuals. Further longitudinal studies that consider information on BMI are necessary.

    更新日期:2018-10-25
  • 6-Hydroxydopamine induces different mitochondrial bioenergetics response in brain regions of rat
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-22
    Débora F. Gonçalves, Aline A. Courtes, Diane D. Hartmann, Pamela C. da Rosa, Débora M. Oliveira, Félix A.A. Soares, Cristiane L. Dalla Corte

    Mitochondrial dysfunction has been demonstrated to have a central role in Parkinson Disease (PD) pathophysiology. Some studies have indicated that PD causes an impairment in mitochondrial bioenergetics; however, the effects of PD on brain-region specific bioenergetics was never investigated before. This study aimed to evaluate mitochondrial bioenergetics in different rat brain structures in an in vitro model of PD using 6-OHDA. Rat brain slices of hippocampus, striatum, and cortex were exposed to 6-OHDA (100 µM) for 1 hour and mitochondrial bioenergetic parameters, peroxide production, lactate dehydrogenase (LDH) and citrate synthase (CS) activities were analyzed. Hippocampus slices exposed to 6-OHDA presented increased peroxide production but, no mitochondrial adaptive response against 6-OHDA damage. Cortex slices exposed to 6-OHDA presented increased oxygen flux related to oxidative phosphorylation and energetic pathways exchange demonstrated by the increase in LDH activity, suggesting a mitochondrial compensatory response. Striatum slices exposed to 6-OHDA presented a decrease of oxidative phosphorylation and decrease of oxygen flux related to ATP-synthase indicating an impairment in the respiratory chain. The co-incubation of 6-OHDA with n-acetylcysteine (NAC) abolished the effects of 6-OHDA on mitochondrial function in all brain regions tested, indicating that the increased reactive oxygen species (ROS) production is responsible for the alterations observed in mitochondrial bioenergetics. The present results indicate a brain-region specific response against 6-OHDA, providing new insights into brain mitochondrial bioenergetic function in PD. These findings may contribute to the development of future therapies with a target on energy metabolism.

    更新日期:2018-10-23
  • Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-16
    Lindsay T. Michalovicz, Alicia R. Locker, Kimberly A. Kelly, Julie V. Miller, Zachary Barnes, Mary Ann Fletcher, Diane B. Miller, Nancy G. Klimas, Mariana Morris, Stephen M. Lasley, James P. O’Callaghan

    Gulf War Illness (GWI) is a chronic multi-symptom disorder experienced by as many as a third of the veterans of the 1991 Gulf War; the constellation of “sickness behavior” symptoms observed in ill veterans is suggestive of a neuroimmune involvement. Various chemical exposures and conditions in theater have been implicated in the etiology of the illness. Previously, we found that GW-related organophosphates (OPs), such as the sarin surrogate, DFP, and chlorpyrifos, cause neuroinflammation. The combination of these exposures with exogenous corticosterone (CORT), mimicking high physiological stress, exacerbates the observed neuroinflammation. The potential relationship between the effects of OPs and CORT on the brain versus inflammation in the periphery has not been explored. Here, using our established GWI mouse model, we investigated the effects of CORT and DFP exposure, with or without a chronic application of pyridostigmine bromide (PB) and N,N-diethyl-meta-toluamide (DEET), on cytokines in the liver and serum. While CORT primed DFP-induced neuroinflammation, this effect was largely absent in the periphery. Moreover, the changes found in the peripheral tissues do not correlate with the previously reported neuroinflammation. These results not only support GWI as a neuroimmune disorder, but also highlight the separation between central and peripheral effects of these exposures.

    更新日期:2018-10-17
  • Eurobehavioral and oxidative stress alterations following methylmercury and retinyl palmitate co-administration in pregnant and lactating rats and their offspring
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-11
    Pedro Espitia-Pérez, Suelen Marin Albino, Lyda Espitia-Pérez, Hugo Brango, Helen da Rosa, Alexandre Kleber Silveira, Diogo Pompéu Moraes, Camila Cerveira, Moara Mingori, Camila Tiefensee Ribeiro, Daniel Pens Gelain, Carlos Eduardo Schnorr, José Cláudio Fonseca Moreira
    更新日期:2018-10-12
  • Multiple effects of the herbicide glufosinate-ammonium and its main metabolite on neural stem cells from the subventricular zone of newborn mice
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-10
    Justyne Feat-Vetel, Vanessa Larrigaldie, Géraldine Meyer-Dilhet, Ameziane Herzine, Camille Mougin, Anthony Laugeray, Thierry Gefflaut, Olivier Richard, Valérie Quesniaux, Céline MontécotDubourg, Stéphane Mortaud
    更新日期:2018-10-10
  • Prenatal exposure to organochlorine pesticides and early childhood communication development in British girls
    Neurotoxicology (IF 3.076) Pub Date : 2018-10-05
    Zuha Jeddy, Katarzyna Kordas, Kristen Allen, Ethel V. Taylor, Kate Northstone, W. Dana Flanders, Gonza Namulanda, Andreas Sjodin, Terryl J. Hartman

    Background The developing brain is susceptible to exposure to neurodevelopmental toxicants such as pesticides. Aims We explored associations of prenatal serum concentrations of hexachlorobenzene (HCB), beta-Hexachlorocyclohexane (β-HCH), 2,2-Bis(4-chlorophenyl)-1,1-dichloroethene (p,p’-DDE) and 2,2-Bis(4-chlorophenyl-1,1,1-trichloroethane (p,p’-DDT) with maternal-reported measures of verbal and non-verbal communication in young girls. Study Design and Methods We studied a sample of 400 singleton girls and their mothers participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) using multivariable linear regression models adjusting for parity, Home Observation Measurement of the Environment (HOME) score, maternal age and education status, and maternal tobacco use during the first trimester of pregnancy. Exposure and Outcome Measures Maternal serum samples (collected at median 15 wks. gestation [IQR 10, 28]) were assessed for selected organochlorine pesticide levels. Communication was assessed at 15 and 38 months, using adapted versions of the MacArthur Bates Communicative Development Inventories for Infants and Toddlers (MCDI). Results At 15 months, girls born to mothers with prenatal concentrations of HCB in the highest tertile had vocabulary comprehension and production scores approximately 16% (p = 0.007) lower than girls born to mothers with concentrations in the lowest tertile. This association varied by maternal parity in that the evidence was stronger for daughters of nulliparous mothers. At 38 months, girls born to mothers with prenatal concentrations of HCB in the highest tertile had mean adjusted intelligibility scores that were 3% (p = 0.03) lower than those born to mothers with concentrations in the lowest tertile; however, results did not vary significantly by parity. Maternal concentrations of β-HCH and p,p’-DDE were not significantly associated with MCDI scores at 15 or 36 months. p,p’-DDT had an inconsistent pattern of association; a significant positive association was observed between p,p’-DDT with verbal comprehension scores at 15 months; however, at 38 months a significant inverse association was observed for p,p’-DDT with communicative scores. This inverse association for p,p’-DDT among older girls tended to be stronger among daughters of mothers who had lower depression scores. Conclusions Organochlorine pesticide exposure in utero may affect communication development.

    更新日期:2018-10-05
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  • 更新日期:2018-10-04
  • The Time Course of Blood Brain Barrier Leakage and its implications On the Progression of Methamphetamine-Induced Seizures
    Neurotoxicology (IF 3.076) Pub Date : 2018-09-30
    John F. Bowyer, Karen M. Tranter, Bonnie Robinson, Joseph P. Hanig, Madeline Faubion, Sumit Sarkar
    更新日期:2018-10-01
  • 007/s11916-015-0528-Gulf War agents pyridostigmine bromide and permethrin cause hypersensitive nociception that is restored after vagus nerve stimulation
    Neurotoxicology (IF 3.076) Pub Date : 2018-09-29
    Damir Nizamutidinov, Sanjib Mukherjee, Chenghao Deng, Harald M. Stauss, Lee A. Shapiro

    Gulf war illness (GWI) is a chronic multi-symptom disease that afflicts 25-33% of troops that were deployed in the 1990-1991 Gulf War. GWI symptoms include cognitive, behavioral and emotional deficits, as well as migraines and pain. It is possible that exposure to Gulf War agents and prophylactics contributed to the reported symptomology. Pyridostigmine bromide (PB) and permethrin (PER) were given to prevent nerve gas attacks and insect vector born disease, respectively. Previous studies have demonstrated that 10 days of exposure to these chemicals can cause symptoms analogous to those observed in GWI, including impairment of long-term memory in mice. Other studies using this model have shown chronic neuroinflammation, and chronic neuroinflammation can lead to altered nociceptive sensitivity. At 10-weeks after the 10-day PB and PER exposure paradigm, we observed lowered nociceptive threshold on the Von Frey test that was no longer evident at 28 weeks and 38 weeks months post-exposure. We further determined that vagus nerve stimulation, initiated at 38 weeks months after exposure, restores the lowered nociceptive sensitivity. Therefore, stimulating the vagus nerve appears to influence nociception. Future studies are need to elucidate possible mechanisms of this effect.

    更新日期:2018-09-29
  • Fluoride activates microglia, secretes inflammatory factors and influences synaptic neuron plasticity in the hippocampus of rats
    Neurotoxicology (IF 3.076) Pub Date : 2018-09-28
    Li Yang, Peiyu Jin, Xiaoyan Wang, Qing Zhou, Xiaoli Lin, Shuhua Xi

    Epidemiological studies have reported that highly fluoridated drinking water may significantly decrease the Intelligence Quotient (IQ) of exposed children. It is thought that synaptic plasticity is the basis of learning and memory skills in developing children. However, the effect on synaptic plasticity by activated microglia induced via fluoride treatment is less clear. Our previous research showed that fluoride ions activated microglia which then released pro-inflammatory cytokines. In this study, hippocampal-dependent memory status was evaluated in rat models sub-chronically exposed to fluoride in their drinking water. Microglial activation in the hippocampus was examined using immunofluorescence staining and the expression of synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), Long-term potentiation(LTP) and the expression of Amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) receptor subunit GluR2 as well as N-methyl-D-aspartate (NMDA) receptor subunit NMDAR2β of exposed rats. We found that fluoride exposure activated microglia and increased the expression of DAP12 and TREM2, as well as promoted pro-inflammatory cytokines secretion via ERK/MAPK and P38/MAPK signal pathways. Furthermore fluoride depressed LTP and decreased PSD-95 protein levels as well as expression of ionotropic glutamate receptors GluR2 and NMDAR2β. We concluded that the role of fluoride on synaptic plasticity may be associated with neuroinflammation induced by microglia.

    更新日期:2018-09-28
  • Inhibition of NRF2 signaling and increased reactive oxygen species during embryogenesis in a rat model of retinoic acid-induced neural tube defects
    Neurotoxicology (IF 3.076) Pub Date : 2018-09-26
    Dan Liu, Jia Xue, Yusi Liu, Hui Gu, Xiaowei Wei, Wei Ma, Wenting Luo, Ling Ma, Shanshan Jia, Naixuan Dong, Jieting Huang, Yanfu Wang, Zhengwei Yuan

    Exposure to retinoic acid (RA) during pregnancy increases the risk of serious neural tube defects (NTDs) in the developing fetus. The precise molecular mechanism for this process is unclear; however, RA is associated with oxidative stress mediated by reactive oxygen species. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of oxidative stress that directs the expression of antioxidant genes and detoxifying proteins to maintain redox homeostasis. We established a rat model of NTDs in which pregnant dams were administered all-trans (at)RA on gestational day 10, and oxidative stress levels and the spatiotemporal expression of NRF2 and its downstream targets were examined in the resulting embryos and in maternal blood. In the NTD group, total antioxidative capacity decreased and 8-hydroxy-2'-deoxyguanosine increased in maternal serum and fetal spinal cord tissues. Plasma GSH content, the GSH/GSSG ratio, and glutathione peroxidase activity in fetal spinal cords were lower in the NTD group relative to controls. We detected NRF2 protein reduction and concomitant upregulation of Kelch-like ECH-associated protein 1 (KEAP1) - a cytoplasmic inhibitor of NRF2 - in the NTD group. The mRNA and protein levels of downstream targets of NRF2 were downregulated in the spinal cords of NTD embryos. These data demonstrate substantial oxidative stress and NRF2 signaling pathway disruption in a model of NTDs induced by atRA. The inhibitory effects of atRA on NRF2 signaling may lower cellular defenses against RA-induced oxidative stress and could play important roles in NTD occurrence during embryonic development.

    更新日期:2018-09-27
  • Dexmedetomidine ameliorates lidocaine-induced spinal neurotoxicity via inhibiting glutamate release and the PKC pathway
    Neurotoxicology (IF 3.076) Pub Date : 2018-09-18
    Haiping Xu, Baisong Zhao, Yingjun She, Xingrong Song

    Dexmedetomidine, a selective α2 adrenergic agonist, has been shown to have neuroprotective and anti-apoptotic effects. To further investigate the underlying mechanisms, we used a rat model of spinal neurotoxicity induced by intrathecal administration of lidocaine. Four days after intrathecal catheter implantation, rats received an intraperitoneal injection of various doses of dexmedetomidine before an intrathecal injection of 20 µL 10% lidocaine. Dexmedetomidine-pretreated rats were also exposed to a selective α2-adrenergic antagonist (yohimbine) or a specific protein kinase C (PKC) inhibitor (Gö 6983) that selectively inhibits several PKC isoforms. Lidocaine injection significantly damaged the spinal cord: hind limb locomotor function was reduced and tail-flick latency was prolonged; significant spinal cord damage and neuronal apoptosis were identified using histological and TUNEL staining assays; increased glutamate release was detected using high performance liquid chromatography (HPLC) analysis; and increased expression of PKC and PKCβI was detected using Western blotting analysis. Pretreatment with dexmedetomidine ameliorated all of the lidocaine-induced effects; however, this protection was abolished when yohimbine or Gö 6983 was injected together with dexmedetomidine. Our results indicate that dexmedetomidine protects the spinal cord from lidocaine-induced spinal neurotoxicity through regulating PKC expression and glutamate release.

    更新日期:2018-09-19
  • Thymoquinone prevents cisplatin neurotoxicity in primary DRG neurons
    Neurotoxicology (IF 3.076) Pub Date : 2018-09-15
    Ramazan Üstün, Elif Kaval Oğuz, Ayşe Şeker, Hasan Korkaya

    Chemotherapy-induced peripheral neuropathy (CIPN) is a substantial, dose-limiting adverse effect that occurs in cancer patients. Cis-dichlorodiamine (II) platinum (CDDP, cisplatin) is a platinum-based chemotherapeutic agent that causes severe acute and chronic peripheral neuropathies in 30% of cancer patients. Thymoquinone (TQ), a leading bioactive constituent of Nigella sativa seeds, has been reported to have antioxidant, anti-inflammatory, anti-neoplastic and neuroprotective properties. Dorsal root ganglia (DRG) include different classes of primary sensory neurons, such as nociceptors, mechanoreceptors, and proprioceptive neurons. Here, we investigated the neuroprotective activity of TQ against cisplatin neurotoxicity in cultured DRG neurons. We prepared neuronal cultures from DRGs of adult mice, pre-treated them with or without varying doses of TQ prior to exposure of cells to cisplatin. The preparations were viewed under the scope before and after the treatment at 24 hr, 48 hr, and 72 hr time points. We analyzed neuronal cell viability and neurite outgrowths, and evaluated morphologic changes of neuronal or non-neuronal cells. TQ significantly increases the ability to extend neurites and neuronal cell viability when compared to the culture conditions which were treated with cisplatin only. Although we provide compelling evidence for the protective activity of TQ against chemotherapy-induced neurotoxicity, further detailed investigations in preclinical settings are warranted for its clinical use.

    更新日期:2018-09-17
  • Changes in VIP-, SP- and CGRP- like immunoreactivity in intramural neurons within the pig stomach following supplementation with low and high doses of acrylamide
    Neurotoxicology (IF 3.076) Pub Date : 2018-09-14
    Katarzyna Palus, Michał Bulc, Jarosław Całka

    Acrylamide is one of the food toxins to which the human body is exposed. Although researchers’ interest in acrylamide has been growing in recent years, the knowledge of its effect on the gastrointestinal tract, especially on intramural neurons which form the enteric nervous system is scarce. The aim of this experiment was to determine the influence of acrylamide, administered at doses equivalent to the human tolerable daily intake (TDI, 0.5 µg/kg b.w./day) and ten times higher than the TDI (5 µg/kg b.w./day), on the distribution of vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene related peptide (CGRP) expression intramural neurons of the domestic pig stomach. Using double immunofluorescent labelling we revealed that the ENS neurons underwent adaptive changes in response to the supplementation of acrylamide, which manifested themselves as increased expression of VIP, SP and CGRP, both in intramural neurons and by an increase in the nerve density in submucous and muscular layers in the porcine stomach. These substances take part in defensive reactions of neurons and transmission of sensory reactions may play an important role in protecting the stomach against the harmful effect of acrylamide. Moreover, it has been shown that acrylamide induces a significant response of ENS neurons even in TDI dose, which suggests that it is not neutral to the body. These findings may be the basis for further toxicological studies addressing the question if currently permitted minimal content of acrylamide in the food does jeopardize the health of human consumers?

    更新日期:2018-09-15
  • 更新日期:2018-09-15
  • AMPA-induced extracellular Zn2+ influx into nigral dopaminergic neurons causes movement disorder in rats
    Neurotoxicology (IF 3.076) Pub Date : 2018-08-31
    Haruna Tamano, Hiroki Morioka, Ryusuke Nishio, Azusa Takeuchi, Atsushi Takeda

    On the basis of the findings that the rapid influx of extracellular Zn2+ into nigral dopaminergic neurons causes dopaminergic neurodegeneration, here we report that AMPA causes movement disorder in rats. AMPA markedly increased turning behavior in response to apomorphine 1 and 2 weeks after AMPA injection into the substantia nigra pars compacta (SNpc), while AMPA-induced movement disorder was suppressed by co-injection of intracellular Zn2+ chelators, i.e., ZnAF-2DA and TPEN, suggesting that AMPA-induced movement disorder is due to intracellular Zn2+ dysregulation. Furthermore, AMPA markedly induced loss of nigrostriatal dopaminergic neurons 2 weeks after AMPA injection into the SNpc, while AMPA-induced neurodegeneration was also suppressed in the SNpc and the striatum by co-injection of ZnAF-2DA and TPEN. AMPA rapidly increased nigral intracellular Zn2+ after AMPA injection into the SNpc and this increase was blocked by co-injection of TPEN. These results indicate that AMPA receptor activation rapidly increases influx of extracellular Zn2+ into nigral dopaminergic neurons and causes nigrostriatal dopaminergic neurodegeneration, resulting in movement disorder in rats. The evidence that AMPA-induced intracellular Zn2+ dysregulation causes movement disorder via nigrostriatal dopaminergic neurodegeneration suggests that AMPA receptors, probably Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors are potential targets for overcoming Parkinson's syndrome.

    更新日期:2018-09-01
  • Addition of Ketamine to Standard-of-Care Countermeasures for Acute Organophosphate Poisoning Improves Neurobiological Outcomes
    Neurotoxicology (IF 3.076) Pub Date : 2018-08-30
    Jeffrey David Lewine, Waylon Weber, Andrew Gigliotti, Jacob D. McDonald, Melanie Doyle-Eisele, Nitin Bangera, Kim Paulson, Christy Magcalas, Derek A. Hamilton, Efrain Garcia, Robert Raulli, Judith Laney

    Rats poisoned with sarin enter into a hyper-cholinergic crisis characterized by excessive salivation, respiratory distress, tremors, seizures, and death. Through the use of rescue medications and an anticonvulsant, death can be avoided in many animals, with the long-term consequences of poisoning partly ameliorated, especially when countermeasures are made available immediately after exposure. However, when anticonvulsant measures are delayed by as little as 30 minutes, clinical, neurological, cognitive, and psychiatric abnormalities may persist long after the initial exposure. This study sought to determine if the addition of the NMDA receptor agonist Ketamine to human standardof-care countermeasures consisting of two rescue medications (2-PAM and atropine) and an anti-convulsant (Midazolam), would afford protection against persistent neurobiological compromise. Rats were exposed to sarin (105 μg/kg via subcutaneous injection), and treated 1 min later with 2-PAM and Atropine Methyl Nitrate (IM) to minimize mortality. One of four anti-convulsant protocols was then initiated at 50 minutes postsarin:Midazolam alone (MDZ, a single injection (IM) at 0.66 mg/kg); Ketamine alone (KET, a series of five injections (IM) of Ketamine at 7.5 mg/kg, 90 minutes apart); Midazolam + low dose Ketamine (MDZ + lowKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential doses of ketamine (IM) at 2.5 mg/kg, starting at the time of Midazolam dosing and then 90 minutes apart); Midazolam + high dose Ketamine (MDZ + highKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential injections of 7.5 mg/kg Ketamine (IM), starting at the time of Midazolam dosing and then 90 minutes apart). Animals were preassigned to groups culled at post-exposure Days 1, 7 or 30, for histopathology. For all surviving animals, EEG activity was monitored through skull electrodes for 24-hours beginning immediately after sarin exposure. Surviving animals also underwent 24-hour EEG monitoring on Days 6, 13, and/or 29, post-sarin. Memory assessment using the Morris Water Maze was performed on Days 1, 4, 7, 14 and 30. Following sarin exposure, 85% of surviving animals demonstrated status epilepticus within 20 minutes. Each of the anti-convulsant protocols was sufficient to stop convulsions within 1 hour of anti-convulsant administration, but all of the animals still showed signs of electrographic status for an additional 2-12 hours, without substantial differentiation between treatment groups. However, for post-sarin hours 13-24, the MDZ + highKET group showed significantly less severe EEG abnormalities than the MDZ and KET groups (Mood's Median Test, p < 0.005). At one month post-exposure, 90% of animals that had received Midazolam alone still showed evidence of some epileptiform activity. In contrast, 90% of animals that had received Midazolam + high dose Ketamine combination therapy had EEG profiles that were within normal limits. This difference in EEG outcomes was highly significant (Mood's Median Test, p < 0.001). Likewise, on the water maze, the majority of animals that had received Midazolam combined with either high or low dose Ketamine therapy returned to near baseline levels of mnemonic performance within 2 weeks, whereas the majority of the animals that had received midazolam alone or ketamine alone demonstrated persistent and significant memory impairments even at one month postexposure (Mood's Median Test, p < 0.005). With respect to neuronal necrosis, animals in the MDZ + highKET group showed significantly less overall damage than animals in other treatment groups (Mood's Median Test, p < 0.001). Of special note were findings in the hippocampus, where only 12% of animals in the MDZ + highKET group showed evidence of necrosis on H&E staining, whereas 100% of animals in the KET group, 70% of animals in the MDZ group, and 40% of animals in the MDZ + lowKET group showed evidence of hippocampal necrosis. Overall, the data demonstrate that Ketamine augmentation of an atropine, 2PAM, and Midazolam standard-ofcare for sarin exposure provides clinically-relevant additional protection against the negative neurobiological consequences of sarin, even when initiation of the anti-convulsant countermeasures is delayed by 50 minutes.

    更新日期:2018-08-31
  • Effects of prenatal ethanol exposure on acoustic characteristics of ultrasonic vocalizations in rat pups
    Neurotoxicology (IF 3.076) Pub Date : 2018-08-29
    Mohd. Ashik Shahrier, Hiromi Wada

    Rat pups produce ultrasonic vocalizations (USVs) on isolation from their dam. Ultrasonic vocalization is a sensitive tool for evaluating social behavior between pups and their dam. Prenatal ethanol-exposure leads to a reduction in USVs and have the potential of inducing difficulties in social behavior between pups and their dam. However, effects of prenatal ethanol-exposure on the acoustic characteristics of USVs remain unclear. In this study, we recorded USVs produced by rat pups that were prenatally exposed to ethanol and examined their acoustic characteristics. Ethanol was administered to 13 pregnant rats in three stages by gradually increasing concentrations between gestational days (GDs) 8–20. From GDs 14–20, ethanol-containing tap water at concentrations of 30% and 15% (v/v) was administered to the high- and low-ethanol groups, respectively. Tap water without ethanol was given to the control group. On postnatal days (PNDs) 4, 8, 12, and 16, individual newly-born pups were isolated from their dam and littermates and USVs produced by them were recorded for 5 min. The number of USVs in the high-ethanol group was greater than that in both low-ethanol and control groups on PND 12. The mean, minimum, and maximum fundamental frequencies of USVs were elevated in the high-ethanol group compared with that in both low-ethanol and control groups. Higher amplitudes of USVs were produced by male pups in the high-ethanol group than in those in both low-ethanol and control groups on PND 12. These results suggest that prenatal ethanol exposure changed emotionality and accordingly, the high-ethanol group produced more USVs as distress calls.

    更新日期:2018-08-30
  • Prelimbic NMDA receptors stimulation mimics the attenuating effects of clozapine on the auditory electrophysiological rebound induced by ketamine withdrawal
    Neurotoxicology (IF 3.076) Pub Date : 2018-08-28
    Roberta Monteiro Incrocci, Franciely Paliarin, Manoel Jorge Nobre

    Ketamine (KET) is a non-competitive N-Methyl-D-aspartate (NMDA) receptors antagonist that intensifies sensory experiences, prompts hallucinations and delusions, exacerbates previously installed psychosis and disrupts physiological evoked potentials (AEPs). Pharmacologically, KET stimulates glutamate efflux in the medial prefrontal cortex, mainly in the prelimbic (PrL) sub-region. Efferences from this region exert a top-down regulatory control of bottom-up sensory processes either directly or indirectly. In the midbrain, the central nucleus of the inferior colliculus (CIC) plays a fundamental role in the processing of auditory ascending information related to sound localization, sensorimotor gating, and preattentive event-related potentials. Auditory hallucinations elicited during a psychotic outbreak are accompanied by CIC neural activation. Thus, it is possible that NMDA-mediated glutamate neurotransmission in the PrL indirectly modulates CIC neuronal firing. The aim of the present study was to assess the effects of KET on the latency and amplitude of AEPs elicited in the CIC of rats tested during KET effects and following withdrawal from the chronic administration. Changes on emotionally induced by KET treatment were evaluated with the use of the elevated zero maze (EZM). Unlike typical neuroleptics, the atypical antipsychotic clozapine (CLZ) potently blocks the disruption of the sensorimotor gating induced by NMDA antagonists. Therefore, the effects of KET withdrawal on AEPs were challenged with a systemic injection of CLZ. In addition, we further investigated the role of NMDA receptors of the PrL on the AEPs expression recorded in the CIC through intra-PrL infusions of NMDA itself. Our results showed that the processing of sensory information in the CIC is under indirect control of PrL. These data suggest that the long-term KET treatment disrupts the collicular auditory field potentials, possibly through influencing PrL glutamate activity on intrinsic 5-HT mechanisms in the dorsal raphe and CIC.

    更新日期:2018-08-29
  • 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.

    更新日期:2018-07-14
  • 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.

    更新日期:2018-05-01
  • 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.

    更新日期:2018-04-26
  • 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.

    更新日期:2018-04-25
  • 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.

    更新日期:2018-04-25
  • 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.

    更新日期:2018-04-25
  • 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.

    更新日期:2018-04-25
  • 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.

    更新日期:2018-04-25
  • 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.

    更新日期:2018-04-07
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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