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  • Children’s Contrast Sensitivity Function in Relation to Organophosphate Insecticide Prenatal Exposure in the Mother-Child PELAGIE Cohort
    Neurotoxicology (IF 3.1) 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 3.1) 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 3.1) 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 3.1) 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 3.1) 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 3.1) 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 3.1) 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 3.1) 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 3.1) 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 Regional Volumes Associated with Total Psychopathy Scores in an Adult Population with Childhood Lead Exposure
    Neurotoxicology (IF 3.1) 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.

  • 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 3.1) 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 3.1) 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 3.1) 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 3.1) 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 3.1) 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.

  • Aminochrome decreases NGF, GDNF and induces neuroinflammation in organotypic midbrain slice cultures
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-26
    Fillipe M. de Araújo, Rafael S. Ferreira, Cleide S. Souza, Cleonice Creusa dos Santos, Tácio L.R.S. Rodrigues, Juliana Helena C. e Silva, Juciano Gasparotto, Daniel Pens Gelain, Ramon S. El-Bachá, Maria de Fátima D. Costa, José Claudio M. Fonseca, Juan Segura-Aguilar, Silvia L. Costa, Victor Diogenes A. Silva

    Recent evidence shows that aminochrome induces glial activation related to neuroinflammation. This dopamine derived molecule induces formation and stabilization of alpha-synuclein oligomers, mitochondria dysfunction, oxidative stress, dysfunction of proteasomal and lysosomal systems, endoplasmic reticulum stress and disruption of the microtubule network, but until now there has been no evidence of effects on production of cytokines and neurotrophic factors, that are mechanisms involved in neuronal loss in Parkinson's disease (PD). This study examines the potential role of aminochrome on the regulation of NGF, GDNF, TNF-α and IL-1β production and microglial activation in organotypic midbrain slice cultures from P8 - P9 Wistar rats. We demonstrated aminochrome (25 µM, for 24 h) induced reduction of GFAP expression, reduction of NGF and GDNF mRNA levels, morphological changes in Iba1+ cells, and increase of both TNF-α, IL-1β mRNA and protein levels. Moreover, aminochrome (25 µM, for 48 h) induced morphological changes in the edge of slices and reduction of TH expression. These results demonstrate neuroinflammation, as well as negative regulation of neurotrophic factors (GDNF and NGF), may be involved in aminochrome-induced neurodegeneration, and they contribute to a better understanding of PD pathogenesis.

  • Bisphenol A – induced changes in the enteric nervous system of the porcine duodenum
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-22
    Kamila Szymanska, Slawomir Gonkowski

    Bisphenol A (BPA) is an organic compound from the phenolic group commonly used for the production of plastics. The use of BPA in food and drinking water containers carries a significant risk to human health since BPA can be washed out and enter consumables. BPA entering the human body with food shows a multi-directional effect and causes disorders in the functioning of many systems and organs. There is no current knowledge about the effects of BPA on the enteric nervous system. The purpose of the present study was to verify the influence of BPA on tolerable daily intake (TDI) dose (0.05 mg/kg body weight/day) and a dose ten times higher than TDI (0.5 mg/kg body weight/day) administered for 28 days on the porcine duodenum. The neurochemical characterization of the enteric neurons to five active neuronal substances was then investigated: substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), vesicular acetylcholine transporter (VAChT) or cocaine- and amphetamine-regulated transcript peptide (CART) with double immunofluorescence method. Both doses of BPA caused visible changes in duodenal immunoreactivity to the majority of neuronal factors studied and the obtained results show that even TDI dose may affect the living organism.

  • Neurotoxicity screening of new psychoactive substances (NPS): effects on neuronal activity in rat cortical cultures using microelectrode arrays (MEA)
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-20
    Anne Zwartsen, Laura Hondebrink, Remco HS Westerink

    While the prevalence and the use of new psychoactive substances (NPS) is steadily increasing, data on pharmacological, toxicological and clinical effects is limited. Considering the large number of NPS available, there is a clear need for efficient in vitro screening techniques that capture multiple mechanisms of action. Neuronal cultures grown on multi-well microelectrode arrays (mwMEAs) have previously proven suitable for neurotoxicity screening of chemicals, pharmaceuticals and (illicit) drugs. We therefore used rat primary cortical cultures grown on mwMEA plates to investigate the effects of eight NPS (PMMA, α-PVP, methylone, MDPV, 2 C-B, 25B-NBOMe, BZP and TFMPP) and two ‘classic’ illicit drugs (cocaine, methamphetamine) on spontaneous neuronal activity. All tested drugs rapidly and concentration-dependently decreased the weighted mean firing rate (wMFR) and the weighted mean burst rate (wMBR) during a 30 min acute exposure. Of the ‘classic’ drugs, cocaine most potently inhibited the wMFR (IC50 9.8 µM), whereas methamphetamine and the structurally-related NPS PMMA were much less potent (IC50 100 µM and IC50 112 µM, respectively). Of the cathinones, MDPV and α-PVP showed comparable IC50 values (29 µM and 21 µM, respectively), although methylone was 10-fold less potent (IC50 235 µM). Comparable 10-fold differences in potency were also observed between the hallucinogenic phenethylamines 2 C-B (IC50 27 µM) and 25B-NBOMe (IC50 2.4 µM), and between the piperazine derivatives BZP (IC50 161 µM) and TFMPP (IC50 19 µM). All drugs also inhibited the wMBR and concentration-response curves for wMBR and wMFR were comparable. For most drugs, IC50 values are close to the estimated human brain concentrations following recreational doses of these drugs, highlighting the importance of this efficient in vitro screening approach for classification and prioritization of emerging NPS. Moreover, the wide range of IC50 values observed for these and previously tested drugs of abuse, both within and between different classes of NPS, indicates that additional investigation of structure-activity relationships could aid future risk assessment of emerging NPS.

  • Maternal exposure to silver nanoparticles are associated with behavioral abnormalities in adulthood; Role of mitochondria and innate immunity in developmental toxicity
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-14
    Shayan Amiri, Aliakbar Yousefi-Ahmadipour, Mir-Jamal Hosseini, Arya Haj-Mirzaian, Majid Momeny, Heshmat Hosseini-Chegeni, Tahmineh Mokhtari, Sharmin Kharrazi, Gholamreza Hassanzadeh, Seyed Mohammad Amini, Somayeh Jafarinejad, Mahmoud Ghazi-Khansari
  • Memantine decreases neuronal degeneration in young rats submitted to LiCl-pilocarpine-induced status epilepticus
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-12
    Kamila Cagliari Zenki, Eduardo Kalinine, Eduardo R. Zimmer, Thainá Garbino dos Santos, Ben Hur Marins Mussulini, Luis Valmor Cruz Portela, Diogo Lösch de Oliveira

    Several works have demonstrated that status epilepticus (SE) induced-neurodegeneration appears to involve an overactivation of N-methyl-D-aspartate receptors and treatment with high-affinity NMDAR antagonists is neuroprotective against this brain damage. However, these compounds display undesirable side effects for patients since they block physiological NMDA receptor dependent-activity. In this context, memantine (MN), a well tolerable low-affinity NMDAR channel blocker, will be a promising alternative, since it does not compromise the physiological role of NMDA receptors on synaptic transmission. The aim of the present study was to investigate if MN could attenuate seizure severity and neuronal cell death caused by SE induced early in life. Wistar rats (15 days old; n = 6-8 per group) received memantine (20 mg/Kg i.p.) in six different treatments: 6 and 3h before SE onset; concomitant with pilocarpine; 15min and 1h after SE onset; and four consecutive administrations (15min, 6h, 12h, and 18h) after pilocarpine injection. Neurodegeneration was quantified by fluoro-jade C staining. Treatment with memantine increase latency to SE onset only in groups treated 3h before or concomitant with pilocarpine. In CA1 hippocampal subfield, memantine significantly reduced neurodegeneration at the following times: 3h prior SE-onset, concomitant with pilocarpine, and 15min after pilocarpine injection. For amygdala and thalamus, all post-SE onset treatments were able to decrease neurodegeneration. In conclusion, the present study showed that MN was neuroprotective against SE-induced neuronal death and this neuroprotection appears to be time- and region-dependent.

  • Arsenic impairs insulin signaling in differentiated neuroblastoma SH-SY5Y cells
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-08
    Apichaya Niyomchan, Daranee Visitnonthachai, Sumitra Suntararuks, Pronrumpa Ngamsiri, Piyajit Watcharasit, Jutamaad Satayavivad

    A strong correlation between chronic arsenic exposure and neuropsychological disorders leads to a growing concern about a potential risk of arsenic related neurodegeneration. Evidently, brain insulin signaling contributes to physiological effects, including energy homeostasis, and learning and memory. Arsenic has been shown to impair insulin signaling in adipocytes and myocytes, however, this impairment has not yet been explored in neurons. Here we showed that NaAsO2 caused significant reduction in basal levels of glucose, plasma membrane glucose transporter, GLUT 3 and Akt phosphorylation in differentiated human neuroblastoma SH-SY5Y cells. NaAsO2 significantly decreased insulin-mediated glucose uptake, as well as GLUT1 and 3 membrane translocation. Furthermore, the ability of insulin to increase Akt phosphorylation, a well-recognized insulin signaling response, was significantly lessened by NaAsO2 treatment. In addition, the classical tyrosine phosphorylation response of insulin was reduced by NaAsO2, as evidenced by reduction of insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1(IRS-1). Moreover, NaAsO2 lowered the ratio of p110, a catalytic subunit to p85, a regulatory subunit of PI3K causing an imbalance between p110 and p85, the conditions reported to contribute to insulin sensitivity. Additionally, increment of IRS-1 interaction with GSK3β, and p85-PI3K were observed in NaAsO2 treated cells. These molecular modulations may be mechanistically attributed to neuronal insulin signaling impairment by arsenic.

  • Perfluorooctanesulfonate induces neuroinflammation through the secretion of TNF-α mediated by the JAK2 / STAT3 pathway
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-08
    Xiaoxu Chen, Xiaoke Nie, Jiamin Mao, Yan Zhang, Kaizhi Yin, Shengyang Jiang

    Perfluorooctanesulfonate (PFOS)-containing compounds are widely used in all aspects of industrial and consumer products. Recent studies indicated that PFOS is ubiquitous in environments and is considered to be a new type of persistent organic pollutant (POP). This has raised concerns regarding its adverse effects on human health. The nervous system is regarded as a sensitive target of environmental contaminants, including PFOS. Previous findings showed that PFOS can induce neurobehavioral deficits. However, the molecular mechanism underlying PFOS neurotoxicity remains obscure. Astrocyte activation and the resulting pro-inflammatory cytokine release play an integral role in protecting neurons from neurotoxin-mediated damage. If uncontrolled, sustained astrocyte activation may cause the secretion of excessive levels of pro-inflammatory cytokines that exacerbate the initial damage. In this study, we showed that PFOS could promote excessive secretion of tumor necrosis factor-α (TNF-α) in dose- and time-dependent manners in astrocytes. Furthermore, PFOS exposure could induce the phosphorylation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). This suggests that the JAK2/STAT3 signal transduction pathway is involved in PFOS-mediated astrocyte activation and secretion of TNF-α. Indeed, targeted blockage of the JAK2/STAT3 pathway prevented the phosphorylation of JAK and STAT3, and it also caused abnormal expression of TNF-α. Finally, we demonstrated that SH-SY5Y neuronal cells underwent rapid apoptosis via a TNF-α-dependent mechanism after exposure to PFOS-treated astrocyte-conditioned medium. In summary, our findings reveal that PFOS mediates a rapid activation of JAK2/STAT3 signal transduction in C6 astrocytes, which plays a pivotal role in the initiation of PFOS-mediated neurotoxicity.

  • Amelioration by Nitric oxide (NO) mimetics on neurobehavioral and biochemical changes in experimental model of Alzheimer’s disease in rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-06
    Harikesh Dubey, Kavita Gulati, Arunabha Ray

    The present study evaluated the effects of s-nitrosoglutathione (GSNO), a nitrosothiol and sustained NO releaser, on experimental model of sporadic Alzheimer`s disease (sAD) in rats. Levels of Aβ40, Aβ42 and BDNF were assessed in brain hippocampal homogenates for correlative purposes. Intracerebroventricular-Streptozotocin (icv-STZ) induced increased escape latencies (acquisition) and reduced time in target quadrant (probe trial) in Morris Water Maze (MWM) test at 3 months post icv-STZ administration. These behavioural changes were associated with increased Aβ depositions and lowered BDNF levels in brain hippocampal homogenates. Pre-treatment with GSNO (50 µg/kg/day), reduced the icv-STZ induced cognitive deficits in acquisition and probe trials in the MWM. The icv-STZ induced elevations in Aβ40 and Aβ42 and reduced levels of BDNF in hippocampal homogenates were also attenuated after GSNO treatment in these rats. The NO-precursor, L-arginine (100 mg/kg) induced similar effects on behavioural and biochemical parameters tested but was marginally less consistent as compared to those seen with GSNO. The results suggest that GSNO ameliorates the cognitive deficits and associated brain biochemical changes in this experimental model of sporadic AD, and NO-BDNF interactions could play crucial role in these effects.

  • Methamphetamine binge administration during late adolescence induced enduring hippocampal cell damage following prolonged withdrawal in rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-06
    Rubén García-Cabrerizo, Cristian Bis-Humbert, M. Julia García-Fuster

    A recent study from our laboratory demonstrated that binge methamphetamine induced hippocampal cell damage (i.e., impaired cell genesis) in rats when administered specifically during late adolescence (postnatal day, PND 54-57) and evaluated 24 h later (PND 58). The results also suggested a possible role for brain-derived neurotrophic factor (BDNF) regulating cell genesis and survival. This subsequent study evaluated whether these effects persisted in time as measured following prolonged withdrawal. Male Sprague-Dawley rats were treated (i.p.) with BrdU (2 x 50 mg/kg, 3 days, PND 48-50) followed by a binge paradigm (3 pulses/day, every 3 h, 4 days, PND 54-57) of methamphetamine (5 mg/kg, n=14, M) or saline (0.9% NaCl, 1 ml/kg, n=12, C). Following 34 days of forced withdrawal (PND 91), rats were killed 45 minutes after a challenge dose of saline (Sal: C-Sal, n=6; M-Sal, n=7) or methamphetamine (Meth: C-Meth, n=6; M-Meth, n=7). Neurogenesis markers (Ki-67: cell proliferation; NeuroD: early neuronal survival; BrdU: prolonged cell survival, 41-43 days old cells) were evaluated by immunohistochemistry while neuroplasticity markers (BDNF and Fos forms) were evaluated by Western blot. The main results showed that a history of methamphetamine administration (PND 54-57) induced enduring hippocampal cell damage (i.e., observed on PND 91) by decreasing cell survival (BrdU+ cells) and mature-BDNF (m-BDNF) protein content, associated with neuronal survival, growth and differentiation. Interestingly, m-BDNF regulation paralleled hippocampal c-Fos protein content, indicating decreased neuronal activity, and thus reinforcing the persisting negative effects induced by methamphetamine in rat hippocampus during prolonged withdrawal.

  • Age-Dependent Behaviors, Seizure Severity and Neuronal Damage in Response to Nerve Agents or the Organophosphate DFP in Immature and Adult Rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-03
    Erika A. Scholl, Stephanie M. Miller-Smith, Steven L. Bealer, Mark J. Lehmkuhle, Jeffrey J. Ekstrand, F. Edward Dudek, John H. McDonough

    Exposure to nerve agents (NAs) and other organophosphates (OPs) can initiate seizures that rapidly progress to status epilepticus (SE). While the electrographic and neuropathological sequelae of SE evoked by NAs and OPs have been characterized in adult rodents, they have not been adequately investigated in immature animals. In this study postnatal day (PND) 14, 21 and 28 rat pups, along with PND70 animals as adult controls, were exposed to NAs (sarin, VX) or another OP (diisopropylfluorophosphate, DFP). We then evaluated behavioral and electrographic (EEG) correlates of seizure activity, and performed neuropathology using Fluoro-Jade B. Although all immature rats exhibited behaviors that are often characterized as seizures, the incidence, duration, and severity of the electrographic seizure activity were age-dependent. No (sarin and VX) or brief (DFP) EEG seizure activity was evoked in PND14 rats, while SE progressively increased in severity as a function of age in PND21, 28 and 70 animals. Fluoro-Jade B staining was observed in multiple brain regions of animals that exhibited prolonged seizure activity. Neuronal injury in PND14 animals treated with DFP was lower than in older animals and absent in rats exposed to sarin or VX. In conclusion, we found that NAs and an OP provoked robust SE and neuronal injury similar to adults in PND21 and PND28, but not in PND14, rat pups. Convulsive behaviors were often present independent of EEG seizures and were unaccompanied by neuronal damage. These differential responses should be considered when investigating medical countermeasures for NA and OP exposure in pediatric populations.

  • Myxobacterial Natural Products: An Under-Valued Source of products for Drug Discovery for Neurological Disorders
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-02
    Mona Dehhaghi, Fatemeh Mohammadipanah, Gilles J. Guillemin

    Age-related disorders impose noticeable financial and emotional burdens on society. This impact is becoming more prevalent with the increasing incidence of neurodegenerative diseases and is causing critical concerns for treatment of patients worldwide. Parkinson’s disease, Alzheimer’s disease, multiple sclerosis and motor neuron disease are the most prevalent and the most expensive to treat neurodegenerative diseases globally. Therefore, exploring effective therapies to overcome these disorders is a necessity. Natural products and their derivatives have increasingly attracted attention in drug discovery programs that have identified microorganisms which produce a large range of metabolites with bioactive properties. Myxobacteria, a group of Gram-negative bacteria with large genome size, produce a wide range of secondary metabolites with significant chemical structures and a variety of biological effects. They are potent natural product producers. In this review paper, we attempt to overview some secondary metabolites synthesized by myxobacteria with neuroprotective activity through known mechanisms including production of polyunsaturated fatty acids, reduction of apoptosis, immunomodulation, stress reduction of endoplasmic reticulum, stabilization of microtubules, enzyme inhibition and serotonin receptor modulation.

  • Brain derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB) and nicotine
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-02
    Rita Machaalani, Hui Chen

    Nicotine is the major neurotoxicant in cigarettes that affects many transmitter systems within the brain as well as other factors, including the growth factors. Brain derived neurotrophic factor (BDNF), is the most abundant growth factor in the brain and plays a critical role in early new neuron differentiation, development and synapsis growth, and the survival of fully developed neurons and synaptic activity. Over the past 3 decades, data has emerged on the effects of nicotine and cigarette smoke exposure on the expression of BDNF and its primary specific receptor tyrosine kinase receptor B (TrkB). This review summarizes data regarding the changes in brain BDNF expression after nicotine or cigarette smoke exposure, and discusses their implications considering BDNF’s functional roles.

  • SUMOylation, aging and autophagy in neurodegeneration
    Neurotoxicology (IF 3.1) Pub Date : 2018-03-02
    Shamini Vijayakumaran, Dean L. Pountney

    Protein homeostasis is essential for the wellbeing of several cellular systems. Post-translational modifications (PTM) coordinate various pathways in response to abnormal aggregation of proteins in neurodegenerative disease states. In the presence of accumulating misfolded proteins and toxic aggregates, the small ubiquitin-like modifier (SUMO) is associated with various substrates, including chaperones and other recruited factors, for refolding and for clearance via proteolytic systems, such as the ubiquitin-proteasome pathway (UPS), chaperone-mediated autophagy (CMA) and macroautophagy. However, these pathological aggregates are also known to inhibit both the UPS and CMA, further creating a toxic burden on cells. This review suggests that re-routing cytotoxic aggregates towards selective macroautophagy by modulating the SUMO pathway could provide new mechanisms towards neuroprotection.

  • Rotenone induces gastrointestinal pathology and microbiota alterations in a rat model of Parkinson’s disease
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-20
    Michaela E. Johnson, Andrea Stringer, Larisa Bobrovskaya

    While people are often aware of the motor symptoms in Parkinson’s disease (PD), few know of the many non-motor symptoms, which patients report have a greater impact on their quality of life. Gastrointestinal (GI) dysfunction is one of the most common non-motor symptoms, which can occur at any stage of PD, even years prior to diagnosis, and can affect all sections along the GI tract causing a range of symptoms including drooling, gastroparesis and constipation. We have investigated whether a neurotoxin model of PD- rotenone, a mitochondrial complex I inhibitor, is capable of reproducing the GI dysfunction seen clinically. Sprague-Dawley rats were administered 2.75 mg/kg rotenone, 5 days/week for 4 weeks, via intraperitoneal injection. Rats underwent behavioural testing, including the one-hour stool and gastric emptying tests before GI contents and tissues were collected for microbiota and histological analysis. Rats exposed to rotenone had more days with evidence of diarrhoea and significantly delayed gastric emptying, reproducing the clinical symptom of gastroparesis. Microbiota analysis revealed alterations in the small intestine and colon of rotenone-treated rats, relatively consistent with changes described in PD patients. Histological analysis demonstrated mucosal thickening and goblet cell hyperplasia in the colon of rotenone rats, which may be an adaptive response to the toxin or changes in GI microbiota. Our results indicate rotenone may be a good model for investigating the mechanisms involved with Parkinson’s GI symptoms and for screening potential therapeutic options as it is capable of recapitulating some key GI changes that occur during PD progression.

  • Hsp90 Co-chaperone p23 Contributes to Dopaminergic Mitochondrial Stress via Stabilization of PHD2: Implications for Parkinson’s disease
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-20
    Anand Rane, Subramanian Rajagopalan, Manuj Ahuja, Bobby Thomas, Shankar J. Chinta, Julie K. Andersen

    The heat shock factor 90 (hsp90) complex has long been associated with neuropathological phenotypes linked to Parkinson’s disease (PD) and its inhibition is neuroprotective in disease models. Hsp90 is conventionally believed to act by suppressing induction of hsp70. Here, we report a novel hsp70-independent mechanism by which Hsp90 may also contribute to PD-associated neuropathology. We previously reported that inhibition of the enzyme prolyl hydroxylase domain 2 (PHD2) in conjunction with increases in hypoxia-inducible factor 1 alpha (HIF1α) results in protection of vulnerable dopaminergic substantia nigra pars compacta (DAergic SNpc) neurons in in vitro and in vivo models of PD. We discovered an increased interaction between PHD2 and the p23:Hsp90 chaperone complex in response to mitochondrial stress elicited by the mitochondrial neurotoxin 1-methyl-4-phenylpyridine (MPP+) within cultured DAergic cells. Genetic p23 knockdown was found to result in decreases in steady-state PHD2 protein and activity and reduced susceptibility to MPP+ neurotoxicity. Administration of the p23 inhibitor gedunin was also neuroprotective in these cells as well as in human induced pluripotent stem cell (iPSC)-derived neurons. Our data suggests that mitochondrial stress-mediated elevations in PHD2 interaction with the p23-hsp90 complex have detrimental effects on the survival of DAergic neurons, while p23 inhibition is neuroprotective. We propose that neurotoxic effects are tied to enhanced PHD2 stabilization by the hsp90-p23 chaperone complex that is abrogated by p23 inhibition. This demonstrates a novel connection between two independent pathways previously linked to PD, hsp90 and PHD2-HIF1α, which could have important implications for here-to-fore unexplored mechanisms underlying PD neuropathology.

  • Development of neuropathology following soman poisoning and medical countermeasures
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-15
    Trond Myhrer, Espen Mariussen, Pål Aas

    Nerve agent-induced seizures can cause varying degrees of neuropathology depending on level of poisoning and duration of seizing. The intention of this review was to validate a novel approach for establishing effective treatment regimens against soman poisoning. Identification of seizure controlling sites in the forebrain of rats poisoned by soman was made by means of lesions, and the anticonvulsive properties of a number of relevant drugs were tested by microinfusions into the identified areas. By using these procedures, procyclidine emerged as the most potent drug. Its potency was confirmed in systemic studies and is further enhanced when combined with levetiracetam. Acute treatment with a combination of HI-6, levetiracetam and procyclidine (procyclidine regimen) can effectively manage supralethal poisoning by any of the classical nerve agents. Extended treatment with the procyclidine regimen is able to terminate residual “silent”, local epileptiform activity in the severely poisoned rats. Evident advantages are seen when the same regimen exerts both powerful anticonvulsant and neuroprotectant efficacies. According to the results presented, the new strategy for establishing therapies against soman-induced seizures appears to be valid.

  • Exposure to low level of lead during preweaning period increases metallothionein-3 expression and dysregulates divalent cation levels in the brain of young rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-13
    Abdur Rahman, Khalid M. Khan, Muddanna S. Rao

    Lead (Pb) is a neurotoxic heavy metal, but the mechanism of its neurotoxicity is not clearly understood. Expression of metallothioneins (MTs) is induced in response to heavy metal exposure as a protective mechanism against heavy metal toxicity. There are several isoforms of MTs (MT-1 to 4), of which MT-3 is the neuron specific isoform, which also has neurite growth inhibitory effects. Whereas, the induction of MT-1 and 2 in response to Pb has been reported, the effect of Pb on the expression of MT-3 in the brain has not been documented. This study aimed at investigating the effect of Pb exposure on the expression of MT-3 in the cerebrum and hippocampus. Wistar rat pups were exposed to Pb via their dams’ drinking water (0.2% lead acetate in deionized water) from postnatal day (PND) 0 to 21 and directly via drinking water until PND30. Expression of MT-3 was measured by Western blot and quantitative RT-PCR. MT-3 localization was done by immunohistochemistry. Divalent metal ions were analysed by atomic absorption spectrophotometry. Levels of Pb in blood and cerebrum were significantly increased, while that of copper (Cu), zinc (Zn) and manganese (Mn) were significantly decreased in the Pb-exposed rats at both PND21 and PND30. MT-3 protein was significantly increased in the cerebrum (by 2.5-fold) and in hippocampus (1.4 to 3.2-fold) in both PND21 and PND30 Pb-exposed rats over controls. MT-3 gene expression also increased in the cerebrum (by 42%), and in the hippocampus (by 65% and 43% in the PND21 and PND30 rats, respectively), in the Pb-exposed rats over controls, but the increase was statistically significant (p < 0.05) only in the PND30 rats. Pb exposure significantly increased (p < 0.05) percentage of MT-3 immunoreactive cells in Cornu Ammonis and dentate gyrus regions in the PND21 rats, and in the Cornu Ammonis 1, dentate gyrus and cortex regions in the PND30 rats. Our data thus provide convincing evidence that exposure to low levels of Pb during preweaning period increases the expression of MT-3 in the brain of rats.

  • Color vision impairments with low-level methylmercury exposure of an Amazonian population – Brazil
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-09
    Cláudia Feitosa-Santana, Givago da Silva Souza, Esaú Sirius Ventura Pupo, Anderson Raiol Rodrigues, Maria Izabel Tentes Cortes, Dora Fix Ventura

    Land exploitation that follows deforestation and mining can result in soil erosion and the release of mercury to the waters of rivers in the Amazon Basin. Inorganic mercury is methylated by bacteria that are present in the environment and it serves as a source of human contamination through fish consumption in the form of methylmercury. Long-term exposure to low-level methylmercury in the riverside populations can lead to nervous system alterations, some of which are visual impairments such as loss of luminance contrast sensitivity, restricted visual fields and color vision defects. The present study sought to examine color vision in a group of adults living in the central Brazilian Amazon who were exposed to low-levels of methylmercury. Total Hg concentrations were measured from hair collected at the time of the testing. The D15d and FM100 color vision arrangement tests were applied in a population of 36 (22 males) and 42 (25 males). Controls were healthy volunteers from the cities of São Paulo for the D15d and Belem for the FM100. There was a statistically significant difference in performance between those who were exposed and controls for both tests (p < 0.01 and p < 0.0001, respectively, Mann-Whitney U-test), meaning that adults living in this region of the Amazon made more mistakes on both tests when compared to controls. A linear regression was performed using Hg concentrations and test scores. Hg concentrations accounted for 7% and 2% of color D15d and FM100 arrangement test errors, respectively. Although other studies have previously found color vision impairment in the Amazon, they tested individuals on the east side of the Amazon, while this study was conducted in the central Amazon region. These results suggest that long-term exposure to low-level methylmercury in riverside populations is wider spread in the Amazon Basin than previously verified. This information is needed to implement public health policies that will ensure a safer environment for the Amazonian population.

  • Environmental manganese exposure and associations with memory, executive functions, and hyperactivity in Brazilian children
    Neurotoxicology (IF 3.1) 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.

  • Neurobehavioral effects of 1,2-propanediol in zebrafish (Danio rerio)
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-09
    Andrey Massarsky, Ayham Abdel, Lilah Glazer, Edward D. Levin, Richard T. Di Giulio

    The use of electronic cigarettes (e-cigarettes) is increasing despite insufficient information concerning their long-term effects, including the effects of maternal e-cigarette use on pre- and postnatal development. Our previous study demonstrated that developmental exposure to 1,2-propanediol (a principal component of e-cigarette liquid) affected early development of zebrafish, causing reduced growth, deformities, and hyperactive swimming behavior in larvae. The current study extends assessment of the developmental toxicity of 1,2-propanediol by examining additional long-term behavioral effects. We demonstrate that embryonic/larval exposure of zebrafish to 1,2-propanediol (0.625% or 1.25%) not only affected behavioral parameters in the larvae, but also caused persisting behavioral effects in adults after early developmental exposure. Additional parameters, including neural and vascular development in larvae, stress response in adults, and concentration of neurotransmitters dopamine and serotonin in adult brain were examined, in order to explain the behavioral differences. These additional studies did not find 1,2-propanediol exposure to significantly affect Tg(Neurog1:GFP) or the transcript abundance of neural genes (Neurog1, Ascl1a, Elavl3, and Lef1). Vascular development was not found to be affected by 1,2-propanediol exposure, as inferred from experiments with Tg(Flk1:eGFP) zebrafish; however, transcript abundance of vascular genes (Flk1, Vegf, Tie-2, and Angpt1) was decreased. No statistically significant changes were noted for plasma cortisol or brain neurotransmitters in adult fish. Lastly, analysis of gene transcripts involved with 1,2-propanediol metabolism (Adh5, Aldh2.1, and Ldha) showed an increase in Adh5 transcript. This is the first study to demonstrate that developmental exposure to 1,2-propanediol has long-term neurobehavioral consequences in adult zebrafish, showing that e-cigarettes contain substances potentially harmful to neurodevelopment.

  • Physiological assesment of vestibular function and toxicity in humans and animals
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-08
    Jordi Llorens, Angela Callejo, Erin A. Greguske, Alberto F. Maroto, Blanca Cutillas, Vanessa Martins-Lopes

    Physiological methods that can be similarly recorded in humans and animals have a major role in sensory toxicology, as they provide a bridge between human sensory perception data and the molecular and cellular data obtained in animal studies. Vestibular toxicity research lags well behind other sensory systems in many aspects, including the availability of methods for functional assessment in animals that could be robustly translated to human significance. Here we review the methods available for the assessment of vestibular function in both humans and laboratory animals, with an emphasis on their similarity or divergence, to highlight their potential utility for the predictive assessment of vestibular toxicity.

  • Cross-sectional study to assess the association of color vision with mercury hair concentration in children from Brazilian Amazonian riverine communities
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-08
    Joyce dos Santos Freitas, Eliza Maria da Costa Brito Lacerda, Isabelle Christine Vieira da Silva Martins, Dario Rodrigues Jr., Daniela Maria Oliveira Bonci, Maria Izabel Tentes Cortes, Tereza Cristina Oliveira Corvelo, Dora Fix Ventura, Luiz Carlos de Lima Silveira, Maria da Conceição Nascimento Pinheiro, Givago da Silva Souza

    Background Mercury exposure in the Brazilian Amazon region has been an important concern since the 1980s, when gold mining activities contaminated many Amazonian river basins and the fish therein. Mercury exposure in humans can lead to changes in neural function. The visual system has been used as a functional indicator of methylmercury (organic) and mercury vapour (inorganic) toxicity. Children are particularly vulnerable to this metal exposure. Objective To compare the color vision of children from riverine communities of mercury-exposed (Tapajós basin) and non-exposed Amazonian rivers (Tocantins basin). Methods The study sample was 176 children, aged 7 to 14 years old. Children from two locations in the mercury-exposed Tapajós river basin, Barreiras (n=71) and São Luiz do Tapajos (n=41), were compared to children from Limoeiro do Ajuru (n=64), a non-exposed area in the Tocantins river basin. No caregiver reported that any children had contact with mercury vapour during their lifetime, and probably most of the mercury in their bodies was obtained by fish consumption. Because of this, we decided to evaluate the mercury exposure by total mercury levels in hair samples, a good marker for organic mercury, and not in the urine, a marker for inorganic mercury. Color vision was assessed by the Lanthony Desaturated D-15 test. We used the Vingrys and King-Smith method (1988) to quantify the hue ordering test. The primary visual outcomes from this analysis were C-index (magnitude of the hue ordering error) and angle of the hue ordering. Results The Tapajós children had a higher mean hair mercury level (mean: 4.5 μg/g; range: 0.26-22.38 μg/g) than that of Tocantins children (mean: 0.49 μg/g; range: 0.03-1.91 μg/g) (p < 0.05). Mean difference was approximately 4.01 μg/g with a 95% confidence interval of 2.79 to 5.23. The results of the Lanthony D-15d test showed no significant difference between the C-index mean values of the Tapajós and Tocantins groups (p > 0.05). There was a weak linear correlation in the average C-index obtained from both eyes and the total mercury concentration. Multiple logistic regression analysis indicated that the location of the community and the age had a greater influence on the visual outcomes than the sex of the children and within-locale variation in mercury concentration. Conclusion Our results suggest a difference in one aspect of vision, that is, color vision, between children living in two different river basins in the Brazilian Amazon. The association may be related to Hg exposure but also appeared related to the location of the community and age.

  • Microglial activation and vascular responses that are associated with early thalamic neurodegeneration resulting from thiamine deficiency
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-07
    John F. Bowyer, Karen M. Tranter, Sumit Sarkar, Joseph P. Hanig

    Thiamine/ vitamin B1 deficiency can lead to behavioral changes and neurotoxicity in humans. This may due in part to vascular damage, neuroinflammation and neuronal degeneration in the diencephalon, which is seen in animal models of pyrithiamine-enhanced thiamine deficiency. However, the time course of the progression of these changes in the animal models has been poorly characterized. Therefore, in this study, the progression of: 1) activated microglial association with vasculature; 2) neurodegeneration; and 3) any vascular leakage in the forebrain during the progress of thiamine deficiency were determined. A thiamine deficient diet along with 0.25 mg/ kg/ d of pyrithiamine was used as the mouse model. Vasculature was identified with Cd-31 and microglia with Cd-11b and Iba1 immunoreactivity. Neurodegeneration was determined by FJc labeling. The first sign of activated microglia within the thalamic nuclei were detected after 8 d of thiamine deficiency, and by 9 d activated microglia associated primarily with vasculature were clearly present but only in thalamus. At the 8 d time point neurodegeneration was not present in thalamus. However at 9 d, the first signs of neurodegeneration (FJc+ neurons) were seen in most animals. Over 80% of the microglia were activated at 10 d but almost exclusively in the thalamus and the number of degenerating neurons was less than 10% of the activated microglia. At 10 d, there were sporadic minor changes in IgG presence in thalamus indicating minor vascular leakage. Dizocilpine (0.2 to 0.4 mg/ kg) or phenobarbital (10 to 20 mg/ kg) was administered to groups of mice from day 8 through day 10 to block neurodegeneration but neither did. In summary, activated microglia start to surround vasculature 1 to 2 d prior to the start of neurodegeneration. This response may be a means of controlling or repairing vascular damage and leakage. Glutamate excitotoxicity and vascular leakage likely only play a minor role in the early neurodegeneration resulting from thiamine deficiency. However, failure of dysfunctional vasculature endothelium to supply sufficient nutrients to neurons could be contributing to the neurodegeneration.

  • Comparison of quantitative T2 and ADC mapping in the assessment of 3-nitropropionic acid-induced neurotoxicity in rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-07
    Serguei Liachenko, Jaivijay Ramu, Merle G. Paule, Joseph Hanig

    To assess the relative performance of MRI T2 relaxation and ADC mapping as potential biomarkers of neurotoxicity, a model of 3-nitropropionic acid (NP)-induced neurodegeneration in rats was employed. Male Sprague-Dawley rats received NP (N = 20, 16-20 mg/kg, ip or sc) or saline (N = 6, 2 ml/kg, ip) daily for 3 days. MRI was performed using a 7 tesla system employing quantitative T2 and ADC mapping based on spin echo pulse sequence. All maps were skull stripped and co-registered and the changes were quantified using baseline subtraction and anatomical segmentation. Following the in vivo portion of the study, rat brains were histologically examined. Four NP-treated rats were considered responders based on their MRI and histology data. T2 values always increased in the presence of toxicity, while ADC changes were bidirectional, decreasing in some lesion areas and increasing in others. In contrast to T2 in some cases, ADC did not change. The effect sizes of T2 and ADC signals suggestive of neurotoxicity were 2.64 and 1.66, respectively, and the variability of averaged T2 values among anatomical regions was consistently lower than that for ADC. The histopathology data confirmed the presence of neurotoxicity, however, a more detailed assessment of the correlation of MRI with histology is needed. T2 mapping provides more sensitive and specific information than ADC about changes in the rat brain thought to be associated with neurotoxicity due to a higher signal-to-noise ratio, better resolution, and unidirectional changes, and presents a better opportunity for biomarker development.

  • Agathisflavone, a flavonoid derived from Poincianella pyramidalis (Tul.), enhances neuronal population and protects against glutamate excitotoxicity
    Neurotoxicology (IF 3.1) Pub Date : 2018-02-06
    Cleide dos Santos Souza, Maria Socorro grangeiro, Erica Patricia Lima Pereira, Cleonice Creusa dos Santos, Alessandra Bispo da Silva, Geraldo Pedral Sampaio, Daiana Dias Ribeiro Figueiredo, Jorge Mauricio David, Juceni Pereira David, Victor Diogenes Amaral da Silva, Arthur Morgan Butt, Silvia Lima Costa

    Flavonoids are bioactive compounds that are known to be neuroprotective against glutamate-mediated excitotoxicity, one of the major causes of neurodegeneration. The mechanisms underlying these effects are unresolved, but recent evidence indicates flavonoids may modulate estrogen signaling, which can delay the onset and ameliorate the severity of neurodegenerative disorders. Furthermore, the roles played by glial cells in the neuroprotective effects of flavonoids are poorly understood. The aim of this study was to investigate the effects of the flavonoid agathisflavone (FAB) in primary neuron-glial co-cultures from postnatal rat cerebral cortex. Compared to controls, treatment with FAB significantly increased the number of neuronal progenitors and mature neurons, without increasing astrocytes or microglia. These pro-neuronal effects of FAB were suppressed by antagonists of estrogen receptors (ERα and ERβ). In addition, treatment with FAB significantly reduced cell death induced by glutamate and this was associated with reduced expression levels of pro-inflammatory (M1) microglial cytokines, including TNFα, IL1β and IL6, which are associated with neurotoxicity, and increased expression of IL10 and Arginase 1, which are associated with anti-inflammatory (M2) neuroprotective microglia. We also observed that FAB increased neuroprotective trophic factors, such as BDNF, NGF, NT4 and GDNF. The neuroprotective effects of FAB were also associated with increased expression of glutamate regulatory proteins in astrocytes, namely glutamine synthetase (GS) and Excitatory Amino Acid Transporter 1 (EAAT1). These findings indicate that FAB acting via estrogen signaling stimulates production of neurons in vitro and enhances the neuroprotective properties of microglia and astrocytes to significantly ameliorate glutamate-mediated neurotoxicity.

  • Minocycline diminishes the rotenone induced neurotoxicity and glial activation via suppression of apoptosis, nitrite levels and oxidative stress
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    Dinesh Kumar Verma, Dhirendra Kumar Singh, Sonam Gupta, Parul Gupta, Abhishek Singh, Joyshree Biswas, Sarika Singh
  • Caloric restriction ameliorates acrolein-induced neurotoxicity in rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    Ying-Juan Huang, Li Zhang, Lan-Ying Shi, Yuan-Yuan Wang, Yu-Bin Yang, Bin Ke, Ting-Ying Zhang, Jian Qin

    Objective Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and oxidative damage induced by acrolein is hypothesized to involve in the etiology of Alzheimer’s disease (AD). Calorie restriction (CR) is the only non-genetic intervention that has consistently been verified to retard aging by ameliorating oxidative stress. Therefore, we investigated the effects of CR on acrolein-induced neurotoxicity in Sprague-Dawley (SD) rats. Methods A total of 45 weaned and specific-pathogen-free SD rats (male, weighing 180–220 g) were gavage-fed with acrolein (2.5 mg/kg/day) and fed ab libitum of 10 g/day or 7 g/day (representing 30% CR regimen), or gavage-fed with same volume of tap water and fed al libitum as vehicle control for 12 weeks. After behavioral test conducted by Morris Water Maze, SD rats were sacrificed and brain tissues were prepared for histochemical evaluation and Western blotting to detect alterations in oxidative stress, BDNF/TrkB pathway and key enzymes involved in amyloid precursor protein (APP) metabolism. Results Treatment with 30% CR in SD rats significantly attenuated acrolein-induced cognitive impairment. Oxidative damage including deletion of glutathione and superoxide dismutase and sharp rise in malondialdehyde were notably improved by 30% CR. Further study suggested that 30% CR showed protective effects against acrolein by modulating BDNF/TrkB signaling pathways. Moreover, 30% CR restored acrolein-induced changes of APP, β-secretase, α-secretase and receptor for advanced glycation end products. Conclusion These findings suggest that CR may provide a promising approach for the treatment of AD, targeting acrolein.

  • Assessment of brain oxygenation imbalance following soman exposure in rats
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    Kevin Lee, Sara Bohnert, Ying Wu, Cory Vair, John Mikler, G. Campbell Teskey, Jeff F. Dunn

    Nerve agents (NAs) are potent organophosphorus (OP) compounds with applications in chemical warfare. OP compounds act by inhibiting acetylcholinesterase (AChE). Soman (O-pinacolyl methylphosphonofluoridate) is one of the most potent NAs. It is well known that small doses of NAs can be lethal, and that even non-lethal exposure leads to long-term mental debilitation/neurological damage. However, the neuropathology following exposure to sub-lethal nerve agents is not well understood. In this study we examined changes in tissue oxygenation (pO2) in the cortex and hippocampus after a sub-lethal dose of soman [80–90 μg/kg; subcutaneous]. pO2 changes can provide information regarding oxygen delivery and utilization and may be indicative of disruption in cerebral blood flow and/or metabolism. Changes in oxygenation were measured with chronically implanted oxygen sensors in awake and freely moving rats. Measurements were taken before, during, and after soman-induced convulsive seizures. Soman exposure resulted in an immediate increase in pO2 in the cortex, followed by an even greater increase that precedes the onset of soman-induced convulsive seizures. The rise in hippocampus pO2 was delayed relative to the cortex, although the general pattern of brain oxygenation between these two regions was similar. After convulsive seizures began, pO2 levels declined but usually remained hyperoxygenated. Following the decline in pO2, low frequency cycles of large amplitude changes were observed in both the cortex and hippocampus. This pattern is consistent with recurring seizures. Measuring real-time changes in brain pO2 provides new information on the physiological status of the brain following soman exposure. These results highlight that the measurement of brain oxygenation could provide a sensitive marker of nerve agent exposure and serve as a biomarker for treatment studies.

  • Electrical stimulation or MK-801 in the inferior colliculus improve motor deficits in MPTP-treated mice
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    L. Melo-Thomas, A.L. Gil-Martínez, L. Cuenca, C. Estrada, A. Gonzalez-Cuello, R.K. Schwarting, M.T. Herrero

    The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. Additionally, the IC has been implicated in processing sensorimotor responses. Glutamatergic and GABAergic manipulations in the IC can improve motor deficits as demonstrated by the animal model of haloperidol-induced catalepsy. However, how the IC influences motor function remains unclear. We investigated the effects of either intracollicular deep brain stimulation (DBS) or microinjection of the glutamatergic antagonist MK-801 or the agonist NMDA in C57BL/6J mice chronically treated with saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After DBS or microinjections, the mice were submitted to rotarod and open field tests, respectively. DBS in the IC was effective to increase the time spent on the rotarod in MPTP-treated mice. After unilateral microinjection of MK-801, but not NMDA, MPTP-treated mice increased the distance travelled in the open field (p < 0.05). In conclusion, intracollicular DBS or MK-801 microinjection can improve motor performance in parkinsonian mice suggesting the IC as a new and non-conventional therapeutic target in motor impairment.

  • The Association between Early-life Relative Telomere Length and Childhood Neurodevelopment
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-31
    Marina Oktapodas Feiler, Deven Patel, Huiqi Li, Philip J. Meacham, Gene E. Watson, Conrad Shamlaye, Alison Yeates, Karin Broberg, Edwin van Wijngaarden

    Purpose To examine the association between telomere length and neurodevelopment in children. Methods We examined the relationship between relative telomere length (rTL) and neurodevelopmental outcomes at 9 and 30 months, and 5 years of age in children enrolled in the Seychelles Child Development Study Nutrition Cohort 1 (NC1). Relative telomere length was measured in cord blood and in child blood at age five. Multivariable linear regression examined associations between neurodevelopmental outcomes and rTL adjusting for relevant covariates. Results Mean rTL was 1.18 at birth and 0.71 at age five. Increased cord blood rTL was associated with better scores on two neurodevelopmental tests, the psychomotor developmental index (β = 4.01; 95% confidence interval (CI) = 0.17, 7.85) at age 30 months, and the Woodcock Johnson test of achievement letter-word score (β=2.88; CI = 1.21-4.56) at age five. The Woodcock Johnson test of achievement letter-word score remained statistically significant after two outliers were excluded (β=2.83; CI = 0.69, 4.97); the psychomotor developmental index did not (β = 3.62; CI = −1.28, 8.52). None of the neurodevelopmental outcomes at age five were associated with five-year rTL. Conclusion Although increased cord blood rTL was associated with better test scores for a few neurodevelopmental outcomes, this study found little consistent evidence of an association between rTL and neurodevelopment. Future studies with a larger sample size, longer follow-up, and other relevant biological markers (e.g. oxidative stress) are needed to clarify the role of rTL in neurodevelopment and its relevance as a potential surrogate measure for oxidative stress in the field of developmental neurotoxicity.

  • Prenatal exposure to valproic acid alters the development of excitability in the postnatal rat hippocampus
    Neurotoxicology (IF 3.1) Pub Date : 2018-01-05
    Yukiko Fueta, Yuko Sekino, Sachiko Yoshida, Yasunari Kanda, Susumu Ueno

    Prenatal valproic acid (VPA) exposure is a well-known animal model of autism spectrum disorder (ASD) that produces alterations in embryonic and adult neurogenesis as well as adolescent/adulthood neurobehavioral phenotypes. However, the effects of prenatal VPA exposure on neural network excitability, especially during the synaptogenic period around eye opening, are not fully understood. In this study, we orally administered VPA (300 mg/kg) to pregnant Wistar rats on gestation day 15 and subsequently performed field potential recording in the CA1 area of hippocampal slices obtained from control (saline-exposed) and VPA-exposed rat pups between postnatal day (PND) 13 and PND18. In control slices, we observed an abrupt enhancement of stimulation-dependent responses including population spike (PS) amplitudes and field excitatory postsynaptic potential (fEPSP) slopes at PND16, which coincided with the average day of eye opening. In contrast, VPA-exposed pups exhibited delayed eye opening (PND17) and gradual rather than abrupt increases in PS amplitudes and fEPSP slopes over the duration of the synaptogenic period. We next investigated the involvement of ambient GABA in PS generation using bicuculline methiodide (BMI), a γ-aminobutyric acid type A (GABAA) receptor antagonist. In control slices, BMI enhanced PS amplitudes during PND14–15 (before eye opening) and had little effect thereafter during PND16–17; a subsequent regression model analysis of BMI ratios (the ratio of PS amplitudes in the presence and absence of BMI) indicated a possible developmental change between these periods. In contrast, almost identical regression models were obtained for BMI ratios during PND14–15 and PND16–17 in the VPA-exposed group, indicating the absence of a developmental change. Our results suggest that prenatal VPA exposure accelerates the development of hippocampal excitability before eye opening. Moreover, our experimental model can be used as a novel approach for the evaluation of developmental neurotoxicity.

  • Occupational exposure to extremely low frequency magnetic field and risk of Alzheimer disease: A systematic review and meta-analysis
    Neurotoxicology (IF 3.1) 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 < .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.

  • The brains of bats foraging at wastewater treatment works accumulate arsenic, and have low non-enzymatic antioxidant capacities
    Neurotoxicology (IF 3.1) 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 (WWTW) – 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 WWTW, 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 WWTW 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 WWTW 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 WWTW 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.

  • Developmental Exposure to Low Level Ambient Ultrafine Particle Air Pollution and Cognitive Dysfunction
    Neurotoxicology (IF 3.1) 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 behaivors 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 hr/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.

  • 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 3.1) 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.

  • LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells
    Neurotoxicology (IF 3.1) 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.

  • Can we predict intermediate syndrome? A review
    Neurotoxicology (IF 3.1) 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.

  • 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 3.1) 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.

  • 17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-26
    Edward Pajarillo, James Johnson Jr., Judong Kim, Pratap Karki, Deok-Soo Son, Michael Aschner, Eunsook Lee

    Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson’s disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity.

  • A magnetic resonance imaging study of early brain injury in a rat model of acute DFP intoxication
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-26
    Brad A. Hobson, Douglas J. Rowland, Suangsuda Supasai, Danielle J. Harvey, Pamela J. Lein, Joel R. Garbow

    Current treatments for seizures induced by organophosphates do not protect sufficiently against progressive neurodegeneration or delayed cognitive impairment. Developing more effective therapeutic approaches has been challenging because the pathogenesis of these delayed consequences is poorly defined. Using magnetic resonance imaging (MRI), we previously reported brain lesions that persist for months in a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP). However, the early spatiotemporal progression of these lesions remains unknown. To address this data gap, we used in vivo MRI to longitudinally monitor brain lesions during the first 3 d following acute DFP intoxication. Adult male Sprague Dawley rats acutely intoxicated with DFP (4 mg/kg, sc) were MR imaged at 6, 12, 18, 24, 48, 72 h post-DFP, and their brains then taken for correlative histology to assess neurodegeneration using FluoroJade C (FJC) staining. Acute DFP intoxication elicited moderate-to-severe seizure activity. T2-weighted (T2w) anatomic imaging revealed prominent lesions within the thalamus, piriform cortex, cerebral cortex, hippocampus, corpus striatum, and substantia nigra that corresponded to neurodegeneration, evident as bands of FJC positive cells. Semi-quantitative assessment of lesion severity demonstrated significant regional variation in the onset and progression of injury, and suggested that lesion severity may be modulated by isoflurane anesthesia. These results imply that the timing of therapeutic intervention for attenuating brain injury following OP intoxication may be regionally dependent, and that longitudinal assessment of OP-induced damage by MRI may be a powerful tool for assessing therapeutic response.

  • Mechanism of Rhinella icterica (Spix, 1824) toad poisoning using in vitro neurobiological preparations
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-23
    Raquel Soares Oliveira, Allan Pinto Leal, Barbara Ogata, Carlos Gabriel Moreira de Almeida, Douglas Silva dos Santos, Leandro Homrich Lorentz, Cleci Menezes Moreira, Karla de Castro Figueiredo Bordon, Eliane Candiani Arantes, Tiago Gomes dos Santos, Cháriston André Dal Belo, Lúcia Vinadé

    The biological activity of Rhinella icterica toxic secretion (RITS) was evaluated on chick neuromuscular junctions, rat heart́s tissue and mice hippocampal slices. At chick biventer cervicis preparation, RITS (5, 10 and 20 μg/mL) produced a concentration-independent irreversible neuromuscular blockade, which was preceded by a transitory increase of muscle twitch tension with the lowest concentration, in 120 min recordings. In this set of experiments, RITS incubation partially prevented the curare neuromuscular blockade. The assessment of chick biventer cervicis muscle acetylcholinesterase (AChE) in the presence of RITS showed a significant inhibition of the enzyme, similarly to neostigmine. The incubation of muscles with digoxin or ouabain mimicked the poison activity by increasing the amplitude of the twitches followed by a progressive depression of the muscle strength. In addition, RITS demonstrated a digitalic-like activity, by inhibiting significantly the cardiac Na+, K+-ATPase. When the central nervous system was accessed, RITS induced an increase in the cell viability, in the lowest concentration. In addition, the poison protected slices subject to oxygen/glucose deprivation. Altogether, these data indicate that the poisonous extract of R. icterica is able to interfere with peripheral and central neurotransmission, probably due to a direct interaction with AChE, calcium channels and Na+, K+-ATPase. A further investigation upon the poison toxic components will unveil the components involved in such a pharmacological activity and the potential biotechnological application of this poison.

  • Neurotoxicity of carbon monoxide targets caudate-mediated dopaminergic system
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-22
    Tzu-Kuan Sun, Yen-Yu Chen, Shu-Hua Huang, Shih-Wei Hsu, Chen-Chang Lee, Wen-Neng Chang, Chi-Wei Huang, Chun-Chung Lui, Chia-Yi Lien, Ju-Ling Cheng, Chiung-Chih Chang

    The clinical features of parkinsonism in carbon monoxide (CO) intoxication have been associated with striatal-related neuronal networks. As parkinsonian and neuropsychiatric features are both related to presynaptic dopaminergic integrity, the aim of this study was to explore the clinical significance of 99mTcTRODAT-1 in grading neurobehavioral scores and parkinsonian severity in CO intoxication. We enrolled 64 patients with CO intoxication, including 29 with parkinsonism (parkinsonism[+] group) and 35 without (parkinsonism[−] group). All of the patients received 99mTcTRODAT-1 neuroimaging evaluations, comprehensive neurobehavioral tests and assessments of the severity of parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS)-part III motor score. Univariate and multivariate regression analyses were used to test the predictive factors and scores for a diagnosis of parkinsonism and its severity. The parkinsonism(+) group had significantly lower cognitive scores and higher neuropsychiatric total scores compared with the parkinsonism(−) group, both of which were independently related to the severity of parkinsonism. 99mTcTRODAT-1 regional caudate signals were correlated with tremors at rest, action or postural tremors of the hands, bradykinesia and hypokinesia, and visuospatial, verbal fluency, abstract thinking and digit backwards scores. Scores of the neurobehavioral tests and UPDRS items were highly correlated (p < 0.01). Our results validated the initial hypothesis in that neurobehavioral deficits and parkinsonian symptoms were highly related. This association was independent of demographic factors and initial carboxyhemoglobin level. Within the presynaptic dopaminergic circuit, the clinical role of the caudate in mediating the clinical symptoms in CO intoxication may outweigh the putamen.

  • Manganese chloride induces histone acetylation changes in neuronal cells: Its role in manganese-induced damage
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-16
    Zhenkun Guo, Zhipeng Zhang, Qingqing Wang, Jie Zhang, Lijin Wang, Qunwei Zhang, Huangyuan Li, Siying Wu

    Manganese neurotoxicity presents with Parkinson-like symptoms, with degeneration of dopaminergic neurons in the basal ganglia as the principal pathological feature. Manganese neurotoxicity studies may contribute to a better understanding of the mechanism of Parkinson’s disease. Here, we examined the effects of manganese on histone acetylation, a major epigenetic change in chromatin that can regulate gene expression, chromatin remodelling, cell cycle progression, DNA repair and apoptosis. In this study, we found that manganese chloride (MnCl2) may significantly suppress the acetylation of histone H3 and H4 in PC12 cells and SHSY5Y cells in a time-dependent manner. Then we tested the role of manganese chloride on histone acetyltransferase (HAT) and histone deacetylase (HDAC). The results showed that MnCl2 increased the activity of HDAC but decreased that of HAT in PC12 cells. Further experiments showed that MnCl2 selectively increased the expression levels of HDAC3 and HDAC4 rather than HDAC1 and HDAC2, but decreased that of HAT in PC12 cells and SHSY5Y cells. Pretreatment with the HAT inhibitor anacardic acid (AA) enhanced manganese-induced decrease in cell viability and apoptosis, but HDAC inhibition by TSA drug had an opposite effect in PC12 cells. Collectively, MnCl2 inhibited the acetylation of core histones in cell culture models of PD, and that inhibition of HDAC activity by TSA protects against manganese-induced cell death, indicating that histone acetylation may represent key epigenetic changes in manganese-induced dopaminergic neurotoxicity.

  • Early changes in M2 muscarinic acetylcholine receptors (mAChRs) induced by sarin intoxication may be linked to long lasting neurological effects
    Neurotoxicology (IF 3.1) Pub Date : 2017-11-08
    Zipora Pittel, Shlomi Lazar, Rellie Gez, Shira Chapman

    The effect of sarin on the binding parameters (KD & Bmax) of M2 muscarinic acetylcholine receptor (mAChR) was studied 24 h and 1 week post exposure. Male & female Sprague-Daweley rats were poisoned with 1XLD50 sarin (80 μg/kg, im) followed by treatment of trimedoxime bromide and atropine (7.5:5 mg/kg, im) 1 min later. Brains were removed and analyzed for M2 mAChR binding, using [3H]AFDX384, an M2 selective antagonist. A significant increase in KD of M2 mAChR was found in the cortex 24 h post poisoning, displaying elevation from 4.65 ± 1.16 to 8.45 ± 1.06 nM and 5.24 ± 0.93 to 9.29 ± 1.56 nM in male and female rats, respectively. A rise in KD was also noted 1 week following exposure from 5.04 ± 1.20 to 11.75 ± 2.78 and from 5.37 ± 1.02 to 11.66 ± 1.73 nM, presenting an added increase of 51 and 40% (compared to 24 h) in males and females, respectively. Analysis of M2 receptor density (Bmax) revealed a significant reduction of 68% in males and insignificant reduction of 22% in females, 24 h after sarin exposure which was followed by 37% recovery in males and 100% recovery in females, 1 week later. These results indicate that sarin induces a long-term decreased affinity in M2 mAChR (elevated KDs) and a transient effect on the number of this receptor subtype (Bmax). We hypothesize that the reduced affinity of the M2 receptors (negative auto-regulatory receptors) may cause long-term brain deficits by impairing the normal regulation release of ACh into the synaptic cleft.

  • Reducing occupational lead exposures: Strengthened standards for a healthy workforce
    Neurotoxicology (IF 3.1) 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.

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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