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    Neurotoxicology (IF 3.263) Pub Date : 2020-01-25
    Cristina Eugenia Gallegos; Mariana Bartos; Fernanda Gumilar; Rita Raisman-Vozari; Alejandra Minetti; Carlos Javier Baier

    Pesticide exposure is associated with cognitive and psychomotor disorders. Glyphosate-based herbicides (GlyBH) are among the most used agrochemicals, and inhalation of GlyBH sprays may arise from frequent aerial pulverizations. Previously, we described that intranasal (IN) administration of GlyBH in mice decreases locomotor activity, increases anxiety, and impairs recognition memory. Then, the aim of the present study was to investigate the mechanisms involved in GlyBH neurotoxicity after IN administration. Adult male CF-1 mice were exposed to GlyBH IN administration (equivalent to 50 mg/kg/day of Gly acid, 3 days a week, during 4 weeks). Total thiol content and the activity of the enzymes catalase, acetylcholinesterase and transaminases were evaluated in different brain areas. In addition, markers of the cholinergic and the nigrostriatal pathways, as well as of astrocytes were evaluated by fluorescence microscopy in coronal brain sections. The brain areas chosen for analysis were those seen to be affected in our previous study. GlyBH IN administration impaired the redox balance of the brain and modified the activities of enzymes involved in cholinergic and glutamatergic pathways. Moreover, GlyBH treatment decreased the number of cholinergic neurons in the medial septum as well as the expression of the α7-acetylcholine receptor in the hippocampus. Also, the number of astrocytes increased in the anterior olfactory nucleus of the exposed mice. Taken together, these disturbances may contribute to the neurobehavioural impairments reported previously by us after IN GlyBH administration in mice.

  • 更新日期:2020-01-24
  • Radiation-induced impairment of optic nerve axonal transport in tree shrews and rats monitored by longitudinal manganese-enhanced MRI
    Neurotoxicology (IF 3.263) Pub Date : 2020-01-24
    Jun Yang; Qinqing Li; Dan Han; Chengde Liao; Pengfei Wang; Jingyan Gao; Zeyan Xu; Yifan Liu

    Purpose Radiation-induced optic neuropathy (RION) is a serious complication that occurs after radiation therapy of tumors in the vicinity of the optic nerve, yet its mechanism and imaging features are poorly understood. In this study, we employed manganese-enhanced MRI (MEMRI) to assess optic nerve axonal transport in tree shrews and rats after irradiation. Materials and methods A comparison of normal visual projections in tree shrews and rats was conducted by intravitreal MnCl2 injection followed by MRI. Adult male tree shrews and rats received a total dose of 20 Gy delivered in two fractions (10 Gy per fraction) within 5 days. Longitudinal MEMRI was conducted 5, 10, 20 and 30 weeks after radiation. At the end of observation, motor proteins involved in axonal transport were detected by western blotting, and the axon cytoskeleton was assessed by immunofluorescence. Results The eyeballs, lens sizes, vitreous volumes, optic nerves and superior colliculi of tree shrews were significantly larger than those of rats on MEMRI (P < 0.05). The Mn2+-enhancement of the optic nerve showed no significant changes at 5 and 10 weeks (P > 0.05) but decreased gradually from 20 to 30 weeks postirradiation (P < 0.05). The enhancement of the superior colliculus gradually decreased from 5 weeks to 30 weeks, and the decrease was most significant at 30 weeks (P < 0.05). The levels of the motor proteins cytoplasmic dynein-1, kinesin-1 and kinesin-2 in the experimental group were significantly decreased (P < 0.05). The immunofluorescence results showed that the α-tubulin, β-tubulin and SMI 31 levels in the experimental groups and control groups were not significantly different (P > 0.05). Conclusion Tree shrews show great advantages in visual neuroscience research involving MEMRI. The main cause of the decline in axonal transport in RION is an insufficient level of motor protein rather than damage to the axonal cytoskeletal structure. Longitudinal MEMRI can be used to detect changes in axonal transport function and to observe the relatively intact axon structure from the early to late stages after radiation administration.

  • Association of Audiometric Measures with plasma long chain polyunsaturated fatty acids in a high-fish eating population: The Seychelles Child Development Study
    Neurotoxicology (IF 3.263) Pub Date : 2020-01-23
    Mark S. Orlando; Adam C. Dziorny; Tanzy Love; Donald Harrington; Conrad F. Shamlaye; Gene Watson; Edwin van Wijngaarden; Grazyna Zareba; Philip W. Davidson; Maria S. Mulhern; Emeir M. McSorley; Alison J. Yeates; J.J. Strain; Gary J. Myers

    Objectives To determine if auditory function is associated with current long chain polyunsaturated fatty acids (LCPUFA) concentrations in a cohort of young adults who consume oceanic fish with naturally acquired methylmercury (MeHg). We measured participants plasma LCPUFA concentrations (total n-3, total n-6 and the n-6:n-3 ratio) and looked for an association with Auditory Brain Response (ABR) latencies and Otoacoustic Emissions (OAE) amplitudes. Design Auditory function of 534 participants from the Seychelles Child Development Study (SCDS) main cohort was examined at 19 years of age. Tests included standard pure-tone audiometry, tympanometry, ABR and both Click-Evoked OAE (CEOAE) and Distortion-Product OAE (DPOAE). Associations of LCPUFA status, measured at the time of examination, and auditory outcomes were examined using covariate-adjusted linear regression models. All models were adjusted for sex, prenatal and current MeHg exposure and hearing status. Results LCPUFA concentrations were similar for both sexes and when comparing participants with normal hearing (90.4%) to those who had a sensorineural hearing loss in one or both ears (9.6%). When looking at a subset of only hearing impaired participants, LCPUFA concentrations were similar in those participants who had a mild sensorineural hearing loss as compared with participants that had a moderate sensorineural hearing loss. LCPUFA concentrations were not correlated with current hair MeHg. LCPUFA concentrations were statistically significantly associated with only 6 of 174 ABR and OAE endpoints examined. Four of the 6 significant associations were present in only one sex. In female participants as n-6 concentrations increased, the ABR wave I absolute latency increased for a 60 dBnHL 19 click/sec stimulus. For male participants the interwave I-III latencies for a 60 dBnHL 69 clicks/sec stimulus increased as the n-6:n-3 LCPUFA ratio increased and the interwave I-V interval decreased for a 60 dBnHL 39 clicks/sec stimulus as the n-6 concentration increased. For both sexes interwave latencies were prolonged for the III-V interwave interval for an 80 dBnHL 39 clicks/sec as n-3 LCPUFA concentration increased. As the n-3 LCPUFA concentrations increased, the amplitude of the 6000 Hz DPOAE in the right ear increased for both sexes. As the n-6:n-3 ratio increased, the amplitude of the 1500 Hz DPOAE in the left ear decreased for females. The amplitude of the CEOAE was not associated with n-3, n-6 LCPUFA concentrations or the n-6:n-3 ratio. Conclusion There was no evidence to suggest LCPUFA status was associated with hearing acuity, ABR latencies or OAE amplitudes, even though our participants tended to have higher LCPUFA concentrations as compared to individuals consuming a more western diet. No association was observed between LCPUFA status and a participants hearing status (normal hearing or hearing loss). Although we found a few associations between current plasma LCPUFA status and ABR and OAE auditory endpoints examined, no clear pattern exists. Some of these associations would be considered detrimental resulting in prolonged ABR latencies or smaller OAE amplitudes, while others would be considered beneficial resulting in shortened ABR latencies or larger OAE amplitudes.

  • Perfluoroalkyl chemicals in neurological health and disease: Human concerns and animal models
    Neurotoxicology (IF 3.263) Pub Date : 2020-01-18
    DJ Piekarski; KR Diaz; MW McNerney

    Perfluoroalkyl acids (PFAAs) are man-made organic pollutants that are found ubiquitously in the environment and may impact human health. Here, we review the published literature concerning PFAA impacts on neurobiological, neuroendocrine, and neurobehavioral outcomes. We find that there are many mechanisms through which PFAAs may enter the brain and interact with biochemical endpoints to impact neurological function. These results are supported by epidemiological evidence in humans and experimental evidence in animals that demonstrate numerous and varied PFAA impacts on the nervous system. However, the methods commonly used in animal models of PFAA exposure result in durations of exposure and serum PFAA concentrations in blood that may not appropriately mimic human absorption, distribution, metabolism, and excretion. If animal models lack validity, confidence in mechanistic inferences regarding PFAA exposure and brain function is reduced, limiting these studies’ utility. Finally, we end by suggesting some potential impacts of PFAA exposure in human neurological health and disease states whose associations may not readily present themselves in the epidemiological literature.

  • Neurotoxic effects of aluminum are associated with its interference with estrogen receptors signaling
    Neurotoxicology (IF 3.263) Pub Date : 2020-01-13
    Ioannis Tsialtas; Vyron A. Gorgogietas; Maria Michalopoulou; Aggeliki Komninou; Eleni Liakou; Achilleas Georgantopoulos; Foteini D. Kalousi; Aikaterini G. Karra; Evagelia Protopapa; Anna-Maria G. Psarra

    Aluminum compounds have been observed in various brain regions, and their accumulation has been associated with many neurodegenerative disorders. Neurotoxic effects of aluminum are attributed to reactive oxygen species generation, induction of apoptosis and inflammatory reactions activation. Metaloestrogen activity of aluminum has also been linked to breast cancer progression and metastasis. In this study, taking into account the antiapoptotic and antioxidant activities of estrogens in neuronal cells, which are mediated by estrogen receptors, the possible estrogenic activity of aluminum in SH-SY5Y neuroblastoma cells was studied. Our results showed that aluminum in the form of aluminum chlorohydrate (ACH) exhibited no effect on estrogen receptors transcriptional activation, and differential effect on estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) protein levels. ACH caused reduction in ERβ protein levels, and increase in its mitochondrial localization. ACH-induced reduction in ERβ protein level may be linked, at least in part, to the ACH-induced increase in ERα protein level. This statement is based on our observations showing aluminum-induced reduction in the E2-induced increase in ERα S118 phosphorylation, in MCF-7 and SH-SH5Y cells. Phosphorylation at S118 residue is known to be associated with inhibition of the ubiquitin-induced proteolytic degradation of ERα, leading to its accumulation. Since it is known that ERα negatively regulate ERβ expression, increase in ERα, may contribute to reduction in ERβ levels and subsequent weakening of its antiapoptotic and antioxidant activity, justified by the observed reduction in procaspase -9, mitochondrial cytochrome c, Bcl2, BclxL and mitochondrial thioredoxin protein level, as well as by the increase in proapoptotic BAX level, in ACH treated SH-SY5Y cells. In addition, increase in mitochondrial ERβ localization may also trigger mitochondrial metabolism, suppress biosynthetic process of gluconeogenesis, as indicated by the observed reduction in the phosphoenolopyruvate carboxykinase protein level, and eventually lead to increase in reactive oxygen species (ROS) generation, known to be implicated in aluminum induced neurodegeneration. This statement was verified by the observed ACH–induced increase in ERβ mitochondrial localization, induction of the mitochondrial membrane depolarization and increase in ROS production, in neuronal-like differentiated SH-SY5Y cells.

  • Chronic exposure to methylmercury induces puncta formation in cephalic dopaminergic neurons in Caenorhabditis elegans
    Neurotoxicology (IF 3.263) Pub Date : 2020-01-11
    Tao Ke; Aristidis Tsatsakis; Abel Santamaría; Félix Alexandre Antunes Soare; Alexey A. Tinkov; Anca Oana Docea; Anatoly Skalny; Aaron B. Bowman; Michael Aschner

    The neurotransmitter dopamine is a neuromodulator in the positive and negative regulation of brain circuits. Dopamine insufficiency or overload has been implicated in aberrant activities of neural circuits that play key roles in the pathogenesis of neurological and psychiatric diseases. Dopaminergic neurons are vulnerable to environmental insults. The neurotoxin methylmercury (MeHg) produces dopaminergic neuron damage in rodent as well as in Caenorhabditis elegans (C. elegans) models. Previous studies have demonstrated the utility of C. elegans as an alternative and complementary experimental model in dissecting out mechanism of MeHg-induced dopaminergic neurodegeneration. However, a sensitive pathological change that marks early events in neurodegeneration induced by environmental level of MeHg, is still lacking. By establishing a chronic exposure C. elegans model, for the first time, we have shown the propensity of MeHg (5 µM, 10 days) to induce bright puncta of dat-1::mCherry aggreagtes in the dendrites of cephalic (2 CEPs) dopaminergic neurons in a dose- and time-dependent manner, while these changes were not found in other dopaminergic neurons: anterior deirids (2 ADEs) and posterior deirids (2 PDEs), cholinergic neurons (2 AIYs) or glutamatergic neurons (2 PVDs). The bright puncta appear as an aggregation of mCherry proteins accumulating in dendrites. Further staining shows that the puncta were not inclusions in lysosome, or amyloid protein aggregates. In addition, features of the puncta including enlarged sphere shape (0.5–2 µm diameters), bright and accompanying with the shrinkage of the dendrite suggest that the puncta are likely composed of homologous mCherry molecules packaged at the dendritic site for exportation. Moreover, in the glutathione S-transferase 4 (gst-4) transcriptional reporter strain and RT-PCR assay, the expression levels of gst-4 and tubulins (tba-1 and tba-2) genes were not significantly modified under this chronic exposure paradigm, but gst-4 did show significant changes in an one day exposure paradigm. Collectively, these results suggest that CEP dopaminergic neurons are a sensitive target of MeHg, and the current exposure paradigm could be used as a model to investigate mechanism of dopaminergic neurotoxicity.

  • Inhibition of Fatty Acid Amide Hydrolase by Chlorpyrifos in Juvenile Rats Results in Altered Exploratory and Social Behavior as Adolescents
    Neurotoxicology (IF 3.263) Pub Date : 2020-01-10
    Russell L. Carr; Navatha Alugubelly; Kathryne de Leon; Louise Loyant; Afzaal N. Mohammed; M. Elizabeth Patterson; Matthew K. Ross; Nicole E. Rowbotham

    The organophosphorus insecticide chlorpyrifos (CPF) is suspected to cause developmental neurotoxicity in children leading to long term effects. Developmental exposure of rat pups to CPF at low levels disrupts degradation of the brain endocannabinoids through the inhibition of fatty acid amide hydrolase (FAAH) and decreases the reactivity of juvenile rats in an emergence test. In this study, we further investigated the effects of developmental CPF exposure on behavior but also included exposure to PF-04457845, a specific inhibitor of FAAH, for comparison of behavior altered by FAAH inhibition with behavior altered by CPF. Ten day old rat pups were exposed orally either to 0.5, 0.75, or 1.0 mg/kg CPF or 0.02 mg/kg PF-04457845 daily for 7 days. In an open field (day 23), the high CPF and PF-04457845 groups exhibited increased motor activity but no differences in the time spent in the field’s center. In an elevated plus maze (day 29), all treatment groups had increased open arm activity but ethological behaviors associated with anxiety were not altered. Behaviors in the maze associated with increased general activity and exploratory drive were increased. Social interactions (day 36) were measured and all treatment groups exhibited increased levels of play behavior. The similarities in behavior between PF-04457845 and CPF suggest that enhanced endocannabinoid signaling during the exposure period plays a role in the persistent alteration of behavior observed following developmental CPF exposure.

  • Neurotoxicity of green- synthesized magnetic iron oxide nanoparticles in different brain areas of Wistar rats
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-30
    Heba M. Fahmy; Esraa M. Aly; Faten F. Mohamed; Neveen A. Noor; Anwar A. Elsayed

    Aims The aim of the present study was to evaluate the toxicity of magnetic iron oxide nanoparticles (MIONs) which were synthesized using carob leaf extract on various brain areas of Wistar rats. Main methods Carob leaf synthesized-MIONs were characterized using different techniques: Dynamic Light Scattering (DLS), Transmission Electron Microscope (TEM), UV-Vis spectrophotometer, Fourier Transform infrared (FTIR), X-Ray Diffraction (XRD) and Atomic Force Microscope (AFM). The toxicity of MIONs in vivo was evaluated by: monitoring rat’s body weight, measuring iron content in different brain areas, evaluating some oxidative stress parameters, estimating acetylcholinesterase (AChE) in addition to histopathological investigations. Key findings The present study demonstrated no body weight changes of MIONs- treated rats. According to the conditions of the present study, the hippocampus and striatum were the most affected areas and demonstrated neuronal degeneration due to MIONs exposure. MIONs treatment of Wistar rats, also affected the iron homeostasis in both striatum and midbrain by decreasing iron content in these areas. The least affected areas were thalamus and cerebellum. The histopathological examination of brain areas demonstrated moderate neuronal degeneration in hippocampus and striatum, mild neuronal degeneration in cortex and slight degeneration in hypothalamus and pons-medulla areas were detected. Significance The results suggested that MIONs have a toxic impact on different brain areas and the effect varies according to the brain area.

  • Methionine and methionine sulfoxide induces neurochemical and morphological changes in cultured astrocytes: involvement of Na+, K+-ATPase activity, oxidative status, and cholinergic and purinergic signaling
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-25
    Mayara Sandrielly Pereira Soares; Nathalia Stark Pedra; Natália Pontes Bona; Anita Ávila de Souza; Fernanda Cardoso Teixeira; Juliana Hofstatter Azambuja; Angela TS Wyse; Elizandra Braganhol; Francieli Moro Stefanello; Roselia Maria Spanevello

    Hypermethioninemia is an inherited metabolic disorder characterized by high concentration of methionine (Met) and its metabolites such as methionine sulfoxide (Met-SO), which may lead to development of neurological alterations. The aim of this study was to investigate the in vitro effects of Met or Met-SO on viability, proliferation, morphology, and neurochemical parameters in primary culture of cortical astrocytes, after treatment with 1 or 2 mM Met or 0.5 mM Met-SO, for 24, 48, and 72 h. Met or Met-SO did not affect cell viability and proliferation but induced astrocyte hypertrophy. Acetylcholinesterase activity was increased, while Na+, K+-ATPase activity decreased by 2 mM Met, Met-SO, or Met (1 and 2 mM) + Met-SO (P < 0.05). ATP and AMP hydrolysis was decreased by Met (1 and 2 mM), Met-SO and Met (1 and 2 mM) + Met-SO treatment, while ADP hydrolysis was enhanced by Met-SO and Met (1 and 2 mM) + Met-SO (P < 0.05). Superoxide dismutase activity was increased by Met-SO and Met (1 and 2 mM) + Met-SO (P < 0.05). Catalase and glutathione S-transferase activities were reduced by Met or Met-SO treatment for 48 and 72h (P < 0.05). Reactive oxygen species and total thiol content was reduced by Met or Met-SO treatment for 24, 48, and 72h while nitrite and thiobarbituric acid reactive substance levels was increased under the same experimental conditions (P < 0.05). High concentrations of Met and Met-SO does not cause cell death but induced changes in astrocyte function. These alterations in astrocytic homeostasis may be associated with neurological symptoms found in hypermethioninemia.

  • Neurochemical and neuroinflammatory perturbations in two Gulf War Illness models: modulation by the immunotherapeutic LNFPIII
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-19
    J.M. Carpenter; H.E. Gordon; H.D. Ludwig; J.J. Wagner; D.A. Harn; T. Norberg; N.M. Filipov

    Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990-1991 Gulf War (GW) veterans suffer from it. This study sought to characterize the acute neurochemical (monoamine) and neuroinflammatory profiles of two established GWI animal models and examine the potential modulatory effects of the novel immunotherapeutic Lacto-N-fucopentaose III (LNFPIII). In Model 1, male C57BL/6 J mice were treated for 10 days with pyridostigmine bromide (PB) and permethrin (PM). In Model 2, a separate cohort of mice were treated for 14 days with PB and N,N-Diethyl-methylbenzamide (DEET), plus corticosterone (CORT) via drinking water on days 8-14 and diisopropylfluorophosphate (DFP) on day 15. LNFPIII was administered concurrently with GWI chemicals treatments. Brain and spleen monoamines and hippocampal inflammatory marker expression were examined by, respectively, HPLC-ECD and qPCR, 6 h post treatment cessation. Serotonergic (5-HT) and dopaminergic (DA) dyshomeostasis caused by GWI chemicals was apparent in multiple brain regions, primarily in the nucleus accumbens (5-HT) and hippocampus (5-HT, DA) for both models. Splenic levels of 5-HT (both models) and norepinephrine (Model 2) were also disrupted by GWI chemicals. LNFPIII treatment prevented many of the GWI chemicals induced monoamine alterations. Hippocampal inflammatory cytokines were increased in both models, but the magnitude and spread of inflammation was greater in Model 2; LNFPIII was anti-inflammatory, more so in the apparently milder Model 1. Overall, in both models, GWI chemicals led to monoamine disbalance and neuroinflammation. LNFPIII co-treatment prevented many of these disruptions in both models, which is indicative of its promise as a potential GWI therapeutic.

  • Polystyrene Nanoplastics (20 nm) are able to bioaccumulate and cause oxidative DNA damages in the brain tissue of zebrafish embryo (Danio rerio)
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-17
    Teoman Özgür Sökmen; Ekrem Sulukan; Medine Türkoğlu; Alper Baran; Mustafa Özkaraca; Saltuk Buğrahan Ceyhun
  • Graphene Oxide-induced Neurotoxicity on Neurotransmitters, AFD Neurons and Locomotive Behavior in Caenorhabditis elegans
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-17
    Mina Kim; Hyun-Jeong Eom; Inhee Choi; Jongki Hong; Jinhee Choi

    Graphene oxide (GO) and graphene-based nanomaterials have been widely applied in recent years, but their potential health risk and neurotoxic potentials remain poorly understood. In this study, neurotoxic potential of GO and its underlying molecular and cellular mechanism were investigated using the nematode, Caenorhabditis elegans. Deposition of GO in the head region and increased reactive oxygen species (ROS) was observed in C. elegans after exposure to GO. The neurotoxic potential of GO was then investigated, focusing on neurotransmitters contents and neuronal activity using AFD sensory neurons. The contents of all neurotransmitters, such as, tyrosine, tryptophan, dopamine, tyramine, and GABA, decreased significantly by GO exposure. Decreased fluorescence of Pgcy-8::GFP, a marker of AFD sensory neuron, by GO exposure suggested GO could cause neuronal damage on AFD neuron. GO exposure led decreased expression of ttx-1 and ceh-14, genes required for the function of AFD neurons also confirmed possible detrimental effect of GO to AFD neuron. To understand physiological meaning of AFD neuronal damage by GO exposure, locomotive behavior was then investigated in wild-type as well as in loss-of-function mutants of ttx-1 and ceh-14. GO exposure significantly altered locomotor behavior markers, such as, speed, acceleration, stop time, etc., in wild-type C. elegans, which were mostly rescued in AFD neuron mutants. The present study suggested the GO possesses neurotoxic potential, especially on neurotransmitters and AFD neuron in C. elegans. These findings provide useful information to understand the neurotoxic potential of GO and other graphene-based nanomaterials, which will guide their safe application.

  • Using the Delayed Spatial Alternation Task to Assess Environmentally Associated Changes in Working Memory in Very Young Children
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-16
    Megan K. Horton; Laura Zheng; Ashley Williams; John T. Doucette; Katherine Svensson; Deborah Cory-Slechta; Marcela Tamayo-Ortiz; Mariana Torres-Calapiz; David Bellinger; Lourdes Schnaas; Martha María (Mara) Téllez Rojo; Robert Wright

    Background Working memory (WM) is critical for problem solving and reasoning. Beginning in infancy, children show WM capacity increasing with age but there are few validated tests of WM in very young children. Because rapid brain development may increase susceptibility to adverse impacts of prenatal neurotoxicant exposure, such as lead, tests of WM in very young children would help to delineate onset of developmental problems and windows of susceptibility. Purpose Our objective was to assess the feasibility of administering a Delayed Spatial Alternation Task (DSAT) to measure WM among 18- and 24-month old children enrolled in an ongoing longitudinal birth cohort study and compare DSAT performance with age and general cognitive development. We further explored whether prenatal lead exposure impacted DSAT performance. Methods We assessed 457 mother-child pairs participating in the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) Study in Mexico City. The DSAT and Bayley Scales of Infant Development (BSID-III) were administered at 18- and 24-months. Lead was measured in maternal blood collected during pregnancy (MBPb) and in a subsample of children at 24-months (CBPb). We regressed DSAT measures on MBPb and CBPb, child sex, and maternal age, education, socioeconomic status, and household smoking. We compared DSAT performance to BSID-III performance with adjusted residuals. Results 24-month children perform better on the DSAT than 18-month children; 24-month subjects reached a higher level on the DSAT (3.3 (0.86) vs. 2.4 (0.97), p < 0.01), and had a higher number of correct responses (20.3 vs. 17.2, p < 0.01). In all DSAT parameters, females performed better than males. Maternal education predicted better DSAT performance; household smoking predicted worse DSAT performance. A higher number of correct responses was associated with higher BSID-III Cognitive scales at 18 months (r = 0.20, p < 0.01) and 24 months (r = 0.27, p < 0.01). MBPb and CPBb did not significantly predict DSAT performance. Conclusion Improved performance on the DSAT with increasing age, the positive correlation with the BSID-III cognitive and language scales and the correlation with common sociodemographic predictors of neurodevelopment demonstrate the validity of the DSAT as a test of infant development.

  • Rutin restores neurobehavioral deficits via alterations in cadmium bioavailability in the brain of rats exposed to cadmium
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-10
    Ganiyu Oboh, Adeniyi A. Adebayo, Ayokunle O. Ademosun, Olanike G Olowokere

    Many plant foods are rich sources of rutin, a flavonoid with many biological activities and health benefits. Exposure to cadmium has been implicated in neurotoxicity and cognitive dysfunction in animal models. However, there is a dearth of information on the effect of rutin on the cadmium bioavailability in the brain of rats exposed to cadmium. Thus, the present study investigated the therapeutic efficacy of rutin in an animal model of cognitive impairment via alterations of cadmium bioavailability in cadmium-exposed rats. Animals were divided into six groups (n = 6): group 1 served as control, groups 2 and 3 are normal rats received 25 and 50 mg/kg of rutin respectively, group 4 received cadmium (5 mg/kg), while groups 5 and 6 are cadmium-exposed rats treated with 25 and 50 mg/kg rutin respectively via oral administration for 21 days. Rutin was administered 30 min after cadmium administration each day. The spatial working memory of the exposed and treated rats was assessed using Morris water maze and Y-Maze tasks. Furthermore, the residual level of cadmium ion in the brain of the rats was estimated. The cholinesterase (AChE and BChE) activities and nitric oxide level were determined. Besides, the level of oxidative stress markers (ROS and MDA) was assessed. Results revealed that rutin significantly reduced cadmium bioavailability in the brain of cadmium-exposed rats. Moreso, cadmium increased cholinesterase (AChE and BChE) activities and level of oxidative stress markers in the brain, with a concomitant decrease in nitric oxide level. However, treatment with rutin decreased cholinesterase activities and the level of oxidative stress markers in cadmium-exposed rats. Also, rutin improved spatial working memory and learning processes as revealed by Morris water maze and Y-Maze tasks. Conclusively, rutin could be considered to possess cognitive-enhancing properties possibly through alterations of cadmium bioavailability in the brain of cadmium-exposed rats.

  • Ropinirole induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in Wistar rats
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-06
    Syed Suhail Andrabi, Heena Tabassum, Sabiha Parveen, Suhel Parvez

    Stroke is characterized by an initial ischemia followed by a reperfusion that promotes cascade of damage referred to as primary injury. The loss of mitochondrial function after ischemia, which is characterized by oxidative stress and activation of apoptotic factors is considered to play a crucial role in the proliferation of secondary injury and subsequent brain neuronal cell death. Dopamine D2 receptor agonist, Ropinirole, has been found to promote neuroprotection in Parkinson´s disease and restless leg syndrome. The current study was designed to test its efficacy in preclinical model of stroke. Previously it has been demonstrated that Ropinirole mediates its neuroprotection via mitochondrial pathways. Assuming this, we investigated the effect of Ropinirole on mitochondrial dysfunction, we have shown the positive effect of Ropinirole administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats underwent transient middle cerebral artery occlusion and then received the Ropinirole (10 mg and 20 mg/kg b.w.) at 6 h, 12 and 18 h post occlusion. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Our findings revealed a significant improvement with Ropinirole treatment in tMCAO animals. Staining of isolated brain slices from Ropinirole-treated rats with 2, 3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. Ropinirole treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that Ropinirole has a positive effect on mitochondrial bioenergetics. Ropinirole inhibited the translocation of cytochrome c from mitochondria to cytosol reduces the downstream apoptotic processes. In conclusion, these results demonstrate that Ropinirole treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies.

  • Developmental neurotoxicity of MDMA. A systematic literature review summarized in a putative adverse outcome pathway
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-05
    Marta Barenys, Ingrid Reverte, Stefan Masjosthusmann, Jesús Gómez-Catalán, Ellen Fritsche

    The increasing use of illegal drugs by pregnant women causes a public health concern because it is associated with health risks for mothers and their developing children. One of such drugs is MDMA (3,4-methylenedioxymethamphetamine) or ecstasy due to its high consumption in relevant age and sex groups and its adverse effects on human and rodent developing brains. To thoroughly review the current knowledge on the developmentally neurotoxic potential of MDMA we systematically collected and summarized articles investigating developmental neurotoxicity (DNT) of MDMA in humans and animals in in vivo and in vitro. In addition, we summarized the findings in a putative adverse outcome pathway (AOP). From an initial 299 articles retrieved from the bibliographic databases Web of Science, PubMed and DART, we selected 39 articles according to inclusion/exclusion criteria for data collection after title/abstract and full text screening. Of these 3 where epidemiological studies, 34 where in vivo studies in mice and rats and 2 were in vitro studies. The three epidemiological studies reported from the same longitudinal study and suggested that MDMA exposure during pregnancy impairs neuromotor function in infants. In rat, postnatal exposure towards MDMA also caused locomotor deficits as well as impaired spatial learning that might be associated with decreased serotonin levels in the hippocampus. In vitro MDMA caused cytotoxicity at high concentrations and effects on the serotonergic and neuritogenic alterations at lower concentrations which are in line with some of the in vivo alterations observed. Considering the adverse outcomes of developmental MDMA described in humans and in rodents we summarized the first putative AOP on developmental compound exposure leading to impaired neuromotor function in children. For generation of this AOP, MDMA exposure was taken as a model compound. In addition, we hypothesized a second AOP involving developmental disturbance of the dopaminergic system. However, further in vitro mechanistic studies are needed to understand the molecular initiating event(s) (MIE) triggering the downstream cascades and obtain consistent evidences causally linking the adverse outcome to effects at the cellular, organ and organism level.

  • Methamphetamine induces neuronal death: Evidence from rodent studies
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-05
    Sabrini Sabrini, Russell Bruce, Y. Wang Grace, C. Lin Joanne, J. Kirk Ian, E. Curley Louise

    Animal studies have consistently observed neuronal death following methamphetamine (MA) administration, however, these have not been systematically reviewed. This systematic review aims to present the evidence for MA-induced neuronal death in animals (rodents) and identify the regions affected. Locating the brain regions in which neuronal death occurs in animal studies will provide valuable insight into the linkage between MA consumption and the structural alterations observed in the human brain. The data were collected from three databases: Scopus, Ovid, and the Web of Science. Thirty-seven studies met the inclusion criteria and were divided into two sub-groups, i.e. acute and repeated administration. Twenty-six (of 27) acute and ten (of 11) repeated administration studies observed neuronal death. A meta-analysis was not possible due to different variables between studies, i.e. species, treatment regimens, withdrawal periods, methods of quantification, and regions studied. Acute MA treatment induced neuronal death in the frontal cortex, striatum, and substantia nigra, but not in the hippocampus, whereas repeated MA administration led to neuronal loss in the hippocampus, frontal cortex, and striatum. In addition, when animals self-administered the drug, neuronal death was observed at much lower doses than the doses administered by experimenters. There is some overlap in the regions where neuronal death occurred in animals and the identified regions from human studies. For instance, gray matter deficits have been observed in the prefrontal cortex and hippocampus of MA users. The findings presented in this review implicate that not only does MA induce neuronal death in animals, but it also damages the same regions affected in human users. Despite the inter-species differences, animal studies have contributed significantly to addiction research, and are still of great assistance for future research with a more relevant model of compulsive drug use in humans.

  • Potential mechanisms for phencyclidine/ketamine-induced brain structural alterations and behavioral consequences
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-05
    Cheng Wang, Amy Inselman, Shuliang Liu, Fang Liu

    Evidence of structural abnormalities in the nervous system of recreational drug [e.g., phencyclidine (PCP) or ketamine] users and/or preclinical animal research models suggests interference with the activity of multiple neurotransmitters, particularly glutamate neurotransmission. The damage to the central nervous system (CNS) may include neuronal loss, synaptic changes, disturbed neural network formation and reduced projections to subcortical fields. Notably, the reduced projections may considerably compromise the establishment of the subcortical areas, such as the nucleus accumbens located in the basal forebrain. With its abundant dopaminergic innervation, the nucleus accumbens is believed to be directly associated with addictive behaviors and mental disorders. This review seeks to delineate the relationship between PCP/ketamine-induced loss of cortical neurons and the reduced level of polysialic acid neural cell adhesion molecule (PSA-NCAM) in the striatum, and the likely changes in striatal synaptogenesis during development. The basic mechanism of how PSA-NCAM cell surface expression may be regulated will also be discussed, as well as the hypothesis that PSA-NCAM activity is critical to the regulation of synaptic protein expression. Overall, the present review will address the general hypothesis that damage/interruption of cortico-striatal communication and subcortical synaptogenesis could underlie the erratic/sensitization or addictive states produced by chronic or prolonged PCP/ketamine usage.

  • Inhibition of tyrosine kinase signaling by tyrphostin AG126 downregulates the IL-21/IL-21R and JAK/STAT pathway in the BTBR mouse model of autism
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-04
    Sheikh F. Ahmad, Mushtaq A. Ansari, Ahmed Nadeem, Saleh A. Bakheet, Sary Alsanea, Khaled A. Al-Hosaini, Hafiz M. Mahmood, Mohammad Z. Alzahrani, Sabry M. Attia

    Autism spectrum disorder (ASD) comprises a broad range of neurodevelopmental disorders that are associated with deficits in social interaction and communication. The tyrosine kinase inhibitor tyrphostin AG126 represents a promising therapeutic agent for several neuroinflammatory disorders. There are currently no treatments available that can improve ASD and we previously showed that AG126 treatment exerts beneficial effects on BTBR T+ Itpr3tf/J (BTBR) mice, a model for autism that shows the core features of ASD; however, the immunological mechanisms and molecular targets associated with this effect were previously unclear. This study was undertaken to delineate the neuroprotective effect of AG126 on BTBR mice. Here, using this mouse model, we investigated the effects of AG126 administration on IL-21R, IL-21, IL-22, TNF-α, NOS2, STAT3, IL-27, and Foxp3 production by CD8+ T cells in the spleen by flow cytometry. We further explored the mRNA and protein expression of IL-21, IL-22, IL-1β, TNF-α, NOS2, JAK1, STAT3, IL-27, and Foxp3 in brain tissue by RT-PCR, and western blotting. We found that BTBR mice treated with AG126 exhibited significant decreases in IL-21R-, IL-21-, IL-22-, TNF-α-, NOS2-, STAT3-producing, and increases in IL-27- and Foxp3-producing, CD8+ T cells. Our results further demonstrated that AG126 treatment effectively decreased IL-21, IL-22, IL-1β, TNF-α, NOS2, JAK1, and STAT3, and increased IL-27 and Foxp3 mRNA and protein expression in brain tissues. Our findings suggest that AG126 elicits a neuroprotective response through downregulation of the IL-21/IL-21R and JAK/STAT pathway in BTBR mice, which could represent a promising novel therapeutic target for ASD treatment.

  • Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists
    Neurotoxicology (IF 3.263) Pub Date : 2019-12-04
    Suren B. Bandara, Dennis R. Carty, Vikrant Singh, Danielle J. Harvey, Natalia Vasylieva, Brandon Pressly, Heike Wulff, Pamela J. Lein

    Previous studies demonstrated that pentylenetetrazole (PTZ), a GABA type A receptor (GABAAR) antagonist, elicits seizure-like phenotypes in larval zebrafish (Danio rerio). Here, we determined whether the GABAAR antagonists, tetramethylenedisulfotetramine (TETS) and picrotoxin (PTX), both listed as credible chemical threat agents, similarly trigger seizures in zebrafish larvae. Larvae of three, routinely used laboratory zebrafish lines, Tropical 5D, NHGRI and Tupfel long fin, were exposed to varying concentrations of PTZ (used as a positive control), PTX or TETS for 20 min at 5 days post fertilization (dpf). Acute exposure to PTZ, PTX or TETS triggered seizure behavior in the absence of morbidity or mortality. While the concentration-effect relationship for seizure behavior was similar across zebrafish lines for each GABAAR antagonist, significantly less TETS was required to trigger seizures relative to PTX or PTZ. Recordings of extracellular field potentials in the optic tectum of 5 dpf Tropical 5D zebrafish confirmed that all three GABAAR antagonists elicited extracellular spiking patterns consistent with seizure activity, although the pattern varied between chemicals. Post-exposure treatment with the GABAAR positive allosteric modulators (PAMs), diazepam, midazolam or allopregnanolone, attenuated seizure behavior and activity but did not completely normalize electrical field recordings in the optic tectum. These data are consistent with observations of seizure responses in mammalian models exposed to these same GABAAR antagonists and PAMs, further validating larval zebrafish as a higher throughput-screening platform for antiseizure therapeutics, and demonstrating its appropriateness for identifying improved countermeasures for TETS and other convulsant chemical threat agents that trigger seizures via GABAAR antagonism.

  • Twice subacute MPTP administrations induced time-dependent dopaminergic neurodegeneration and inflammation in midbrain and ileum, as well as gut microbiota disorders in PD mice
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-29
    Wenjun Xie, Jieying Gao, Rong Jiang, Xinrong Liu, Feng Lai, Yong Tang, Hong Xiao, Yan Jia, Qunhua Bai

    Parkinson's disease (PD) is a common progressive neurodegenerative disease. PD produces a pathological state in the intestine and disordered gut microbiota (GM), which may be important for the pathogenesis and progression of PD, but it is not clear. To explore the conditions and characteristics of intestinal pathology and GM disorders when PD-related injuries occur, we used twice 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subacute administration with an interval of 3 weeks (each was an intraperitoneal injection of 25 mg/kg MPTP for 5 consecutive days). We observed the changes in intestinal and brain immune status, intestinal barrier function and GM in different injury states one day, one week, and three weeks after the first stimulus and one day and one week after the second stimulus. Our study found that two subacute administrations of MPTP induced dopaminergic (DAergic) neuron injury and inflammation in the midbrain and ileum, impaired intestinal barrier function and GM disorders closely related to administration. These changes recovered after the first administration, but after repeated administration, some indicators showed more dramatic changes than during the first administration. Our results suggest that the intestinal tract is sensitive to PD-related injury, and the GM is susceptible to disturbances caused by intestinal function, which may be concerned in local immune disorders of the intestine.

  • Exploring interactions between xenobiotics, microbiota, and neurotoxicity in zebrafish
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-26
    Luísa B. Bertotto, Tara R. Catron, Tamara Tal

    Susceptibility to xenobiotic exposures is variable. One factor that might account for this is the microbiome, which encompasses all microorganisms, their encoded genes, and associated functions that colonize a host organism. Microbiota harbor the capacity to affect the toxicokinetics and toxicodynamics of xenobiotic exposures. The neurotoxicological effects of environmental chemicals may be modified by intestinal microbes via the microbiota-gut-brain axis. This is a complex, bi-directional signaling pathway between intestinal microbes and the host nervous system. As a model organism, zebrafish are extremely well-placed to illuminate mechanisms by which microbiota modify the developmental neurotoxicity of environmental chemicals. The goal of this review article is to examine the microbiota-gut-brain axis in a toxicological context, specifically focusing on the strengths and weaknesses of the zebrafish model for the investigation of interactions between xenobiotic agents and host-associated microbes. Previous studies describing the relationship between intestinal microbes and host neurodevelopment will be discussed. From a neurotoxicological perspective, studies utilizing zebrafish to assess links between neurotoxicological outcomes and the microbiome are emphasized. Overall, there are major gaps in our understanding the mechanisms by which microbiota interact with xenobiotics to cause or modify host neurotoxicity. In this review, we demonstrate that zebrafish are an ideal model system for studying the complex relationship between chemical exposures, microorganisms, and host neurotoxicological outcomes.

  • Neuronal specific and non-specific responses to cadmium possibly involved in neurodegeneration: A toxicogenomics study in a human neuronal cell model
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-16
    M. Forcella, P. Lau, M. Oldani, P. Melchioretto, A. Bogni, L. Gribaldo, P. Fusi, C. Urani
  • Role of monocarboxylate transporter 4 in Alzheimer disease
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-16
    Ping Hong, Xiaoyi Zhang, Shichao Gao, Peichang Wang

    The pathological process of Alzheimer disease (AD) is closely related to energy metabolism disorders. In the nervous system, monocarboxylate transporter 4 (MCT4) is expressed in the glial cell membrane and is responsible for transporting intracellular lactic acid. In this study, we found that MCT4 expression was elevated in the cerebrospinal fluid of patients with mild cognitive impairment. Two- and three-month-old APPswe/PS1dE9 (APP/PS1) mice and C57 mice were studied. The APP/PS1 mice began to show cognitive decline at 3 months of age and MCT4 in the hippocampus of 2- and 3-month old APP/PS1 mice was higher than that of C57 mice. This change is similar to that in people with mild cognitive impairment. Subsequently, MCT4 overexpression/siRNA lentiviral particles were used to establish stable primary astrocytes. Overexpression and knockdown of MCT4 had no significant effect on glial cell apoptosis. Transfected astrocytes were co-cultured with neurons. Overexpression of cytoplasmic MCT4 increased the expression of Aβ42, γ-secretase, and CD147 in the co-culture system; in addition, the growth ability of primary neurons decreased significantly, extracellular lactic acid increased, and neuronal apoptosis increased. In AD model mice, siMCT4 injection improved cognitive ability, reduced neuronal apoptosis, and reduced γ-secretase expression. Taken together, these results suggest that MCT4 is involved in energy metabolism during early pathological processes in AD, and suppression of MCT4 represents a new potential neuroprotective factor for AD.

  • Quantum dot conjugated saporin activates microglia and induces selective substantia nigra degeneration
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-15
    Jeffery Landrigan, Zach Dwyer, Sheryl Beauchamp, Ruth Rodriguez, Teresa Fortin, Shawn Hayley

    Parkinson's disease (PD) is characterized by profound microglial driven inflammatory processes and the loss of dopamine neurons of the substantia nigra (SNc). Both microglia and dopamine neurons that are affected in the SNc are particularly vulnerable to environmental toxicants and finding more selective ways of targeting these cell types is of importance. Quantum dots (QDs) might be a useful vehicle for selectively delivering toxicants to microglia and owing to their fluorescent capability, they can be microscopically tracked within the cell. Accordingly, we assessed the impact of QDs alone and QDs conjugated to the ribosomal toxin, saporin, upon SNc microglia and dopamine neurons. We found that intra-SNc infused QDs selectively entered microglia and induced morphological changes consistent with an activated state. QDs conjugated to saporin also caused a significant loss of dopamine neurons and motor coordination (on a rotarod test) deficits, along with an increase in the inflammatory microglial actin regulatory factors, WAVE2. These data suggest that QDs might be a viable route for toxicant delivery and also has an added advantage of being fluorescently visible. Ultimately, we found SNc neurons to be exceptionally vulnerable to QD-saporin and suggest that this could be a novel targeted approach to model PD-like inflammatory pathology.

  • Blood manganese levels during pregnancy and postpartum depression: A Cohort Study among Women in Mexico
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-12
    Nia McRae, Ghalib Bello, Katherine Svensson, Maritsa Solano-González, Rosalind J. Wright, Megan M. Niedzwiecki, Mariana Torres Calapiz, Chitra Amarasiriwardena, Lourdes Schnaas, Marcela Tamayo-Ortiz, Martha M. Téllez-Rojo, Robert O. Wright

    Background Occupational studies have shown an association between elevated Mn exposure and depressive symptoms. Blood Mn (BMn) naturally rises during pregnancy due to mobilization from tissues, suggesting it could contribute to pregnancy and postpartum depressive symptoms. Objectives To assess the association between BMn levels during pregnancy and postpartum depression (PPD), creating opportunities for possible future interventions. Methods We studied 561 women from the reproductive longitudinal Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) cohort in Mexico City. BMn was measured at the 2nd and 3rd trimesters, as well as delivery. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess PPD symptoms at 12-months postpartum. We used a generalized linear model assuming a Poisson distribution to assess the association between BMn levels and PPD, with adjustments for age, stress and depressive symptoms during pregnancy, education, socioeconomic status, and contemporaneous blood lead levels. Results The mean ± standard deviation (SD) EPDS score at 12-months postpartum was 6.51 ± 5.65, and 17.11% of women met the criteria for possible PPD (score ≥ 13). In adjusted models, BMn during the 3rd trimester (β: 0.13, 95% CI: 0.04-0.21) and BMn levels averaged at the 2nd and 3rd trimester (β: 0.14, 95% CI: 0.02-0.26) had a positive association with EPDS scores at 12 months postpartum. BMn at the 2nd trimester (β: 0.07, 95% CI: -0.09-0.22) and delivery (β: 0.03, 95% CI: -0.04-0.10) had a non-significant positive association with EPDS scores at 12-months postpartum. Stress and depressive symptoms during pregnancy was associated with higher EPDS scores at 12-months postpartum in all of the adjusted models but were only significant when either BMn during 3rd trimester or BMn averaged across 2nd and 3rd trimester was assessed as the exposure. Discussion Our results demonstrate that elevated BMn levels during pregnancy predict PPD symptoms and could be a potential pathway for intervention and prevention of PPD.

  • Heat-shock protein 70 (HSP70) polymorphisms affect the risk of coke-oven emission-induced neurobehavioral damage
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-12
    Feng-jie Tian, Wei-xing Li, Yi Lyu, Ping Zhang, Jian-bing Mu, Qiu-ling Pei, Jin-ping Zheng

    Objectives Epidemiology studies indicated that coke-oven workers with long-term exposure to polycyclic aromatic hydrocarbons (PAHs) often have some neurobehavioral abnormalities especially impairment for cognitive function, while the underlying mechanisms are not fully understood. Numerous studies have indicated the antioxidant and anti-apoptosis roles of heat shock protein 70 (Hsp70). The genetic polymorphisms in HSP70 genes are associated with multiple diseases including neurotoxicity. However, it is unclear whether HSP70 polymorphisms are related to the neurotoxicity of PAH. We, therefore, investigate the possible association between HSP70 polymorphisms and neurobehavioral abnormalities. Methods 188 coke-oven workers and 137 control workers were recruited in this study. Emotional and cognitive function was assessed using the WHO/NCTB. HSP70 polymorphisms (HSP70-1 G190C, HSP70-2 G1267 A and HSP70-hom T2437C) were checked by PCR-RFLP. Results The results indicated that HSP70-1 CC genotypes in coke-oven workers were associated with poor neurobehavioral performance such as the attention /response speed and visual perception/memory, while the HSP70-2 AA genotypes were associated with lower short-term auditory memory. Conclusions HSP70-1 CC and HSP70-2 AA genotypes in coke-oven workers may increase the risk for neurobehavioral damage, especially attention, learning and memory.

  • The Relationship between Plasma Al Levels and Multi-domain Cognitive Performance among In-service Aluminum-exposed Workers at the SH Aluminum Factory in China: A Cross-sectional Study
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-10
    Shanshan Wang, Huaxing Meng, Nan Shang, Junhong Guo, Ting Zhang, Shuhui Zhang, Yuqing Zhao, Huifang Zhang, Qinli Zhang, Qiao Niu

    Background Aluminum (Al) exerts neurotoxic effects following overexposure. We previously reported worse cognitive performance in workers exposed to Al than non-exposed individuals. Cognition involves multiple domains. The effect of Al on multi-domain cognition has been studied for decades, but still remains controversial. Objective To explore the relationship between plasma Al levels and multi-domain cognitive performance among in-service aluminum-exposed workers at the SH Aluminum Factory in China and identify possible types of early cognitive damage caused by exposure to aluminum. Methods Eight hundred thirty-one in-service aluminum-exposed workers at the SH Aluminum Factory in China were investigated. The plasma Al concentrations were measured using inductively coupled plasma-mass spectrometry (ICP-MS) and served as an internal exposure indicator. The participants were divided into four subgroups based on the quartiles of plasma Al concentrations, namely, the Q1, Q2, Q3, and Q4 subgroups. Cognitive function was assessed using the Mini-mental State Examination (MMSE) and the clock-drawing test (CDT). Multi-domain cognition was evaluated using sub-tests of the MMSE and the CDT. Results The average plasma Al concentration was 15.26 (8.28, 27.02) µg/L. The neurobehavioral tests showed negative correlations between plasma Al levels and total CDT scores and executive/visuospatial cognitive performance, and a positive correlation between plasma Al levels and CDT-position errors (all P<0.05). Additionally, dose-response relationships between higher plasma Al levels and lower total CDT scores, worse executive/visuospatial cognitive performance, and more error rates in the CDT-position were observed (all Ptrend<0.05). However, no significant correlations or trends were observed between plasma Al levels and other cognitive domains (all P>0.05). The results from the multivariate logistic regression model and restricted cubic spline models of dose-response relationships were consistent with the results obtained from the general linear model. All potential confounders, such as age, marital status, education, income, type of work, and smoking and drinking habits, were considered. Conclusion Based on the results, aluminum exposure may exert a substantial effect on impairing executive/visuospatial functions in multi-domain cognition at the early stage, particularly the identification of spatial positions.

  • Morin attenuates ifosfamide-induced neurotoxicity in rats via suppression of oxidative stress, neuroinflammation and neuronal apoptosis
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-10
    Hamit Çelik, Sefa Kucukler, Selim Çomaklı, Selçuk Özdemir, Cuneyt Caglayan, Ahmet Yardım, Fatih Mehmet Kandemir

    Ifosfamide (IFA), a commonly used chemotherapeutic drug, has been frequently associated with encephalopathy and central nervous system toxicity. The present study aims to investigate whether morin could protect against acute IFA-induced neurotoxicity. Morin was administered to male rats once daily for 2 consecutive days at doses of 100 and 200 mg/kg body weight (BW) orally. IFA (500 mg/kg BW; i.p.) was administered on second day. The results showed that morin markedly inhibited the production of acetylcholinesterase (AChE), butrylcholinesterase (BChE), carbonic anhydrase (CA), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and nuclear factor erythroid 2-related factor 2 (Nrf-2) induced by IFA. Morin ameliorated IFA-induced lipid peroxidation, glutathione (GSH) depletion, and decrease antioxidant enzyme activities, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Histopathological changes and immunohistochemical expressions of c-Jun N-terminal kinase (JNK) and c-Fos in the IFA-induced brain tissues were decreased after administration of morin. Furthermore, morin was able to down regulate the levels of inflammatory and apoptotic markers such as nuclear factor kappa B (NF-κB), neuronal nitric oxide synthase (nNOS), tumor necrosis factor-α (TNF-α), p53, cysteine aspartate specific protease-3 (caspase-3) and B-cell lymphoma-2 (Bcl-2). Taken together, our results demonstrated that morin elicited a typical chemoprotective effect on IFA-induced acute neurotoxicity.

  • Putting findings from the Seychelles Child Development Study into perspective: The importance of a historical special issue of the Seychelles Medical and Dental Journal
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-07
    P.W. Davidson, E. van Wijngaarden, C. Shamlaye, J.J. Strain, G.J. Myers

    We are pleased to introduce this special issue of Neurotoxicology. It reproduces Volume 7, Number 1 of the Seychelles Medical and Dental Journal (SMDJ), initially published in November, 2004. Publication of the SMDJ was discontinued in 2005 and the manuscripts it published are no longer accessible to the scientific community. The papers in this special issue lay the background for the Seychelles Child Development Study (SCDS) and provide valuable data on the MeHg exposures that occurred at Niigata, Japan. They are relevant to the ongoing debate over whether the consumption of fish and consequently low-level exposure to methylmercury (MeHg) is a risk to human health.

  • Plasma trimethylamine N-oxide, a gut microbe–generated phosphatidylcholine metabolite, is associated with autism spectrum disorders
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-05
    Lijuan Quan, Jinping Yi, Yue Zhao, Feng Zhang, Xiao-Tong Shi, Zhen Feng, Haylie L. Miller

    Objective The compositions of the gut microbiota and its metabolites were altered in individuals with Autism Spectrum Disorder (ASD). The aim of this study was to assess whether plasma levels of gut-derived metabolite trimethylamine N-oxide (TMAO) were associated with ASD and the degree of symptom severity. Methods From September 2017 to January 2019, a total of three hundred and twenty-eight Chinese children (164 with ASD and 164 their age-sex matched control subjects) aged 3-8 years were included. TMAO levels in plasma were determined using high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS). Logistic regression analysis was used to examine the TMAO-ASD association. Results In the study, the median age of the ASD group was 5 years (interquartile range [IQR], 4-6 years) and 129 (78.7%) were boys. The median plasma levels of TMAO in children with ASD and typically-developing (TD) children at admission were 4.2 (IQR, 3.0-5.6) μmol/l and 3.0 (2.0-4.4) μmol/l, respectively (P < 0.001). For each 1 μmol/l increase of plasma TMAO, the unadjusted and adjusted risk of ASD would be increased by 54% (with the odds ratios [OR] of 1.54; 95% confidence intervals [CI]: 1.32–1.78; P < 0.001) and 27% (1.27 [1.10–1.45], P < 0.001), respectively. Symptom severity was classified as mild-to-moderate (CARS < 37) for 66 children with ASD (40.2%). In these children, the plasma levels of TMAO were lower than in the 98 children with ASD (59.8%) whose symptoms were classified as severe (CARS > 36) (3.5[2.5-4.9] μmol/l vs. 4.5(3.7-6.0) μmol/l; P < 0.001). For each 1 μmol/l increase of plasma TMAO, the unadjusted and adjusted risk of severe autism would be increased by 61% (with the OR of 1.61 [95% CI 1.28–2.01], P < 0.001) and 31% (1.31 [1.08–1.49], P < 0.001), respectively. Conclusions Elevated plasma levels of TMAO were associated with ASD and symptom severity.

  • Combined neurotoxic effects of cannabis and nandrolone decanoate in adolescent male rats
    Neurotoxicology (IF 3.263) Pub Date : 2019-11-05
    Marwa El-Sayed El-Shamarka, Rabab H. Sayed, Naglaa Assaf, Hala M. Zeidan, Adel F. Hashish

    Polydrug use among adolescence is a widespread phenomenon and has increased in the last few years. In particular, most nandrolone decanoate (Nan) abusers combine its use with cannabis (Can); thus, studying the consequences of this combination in adolescent subjects is important because potentiation of their effects may increase their neurotoxicity. The present study was designed to study the neurotoxic effects of Nan and Can, alone and in combination, in adolescent male rats by studying the behavioural, biochemical, and histopathological effects. Nan (15 mg/kg, s.c.) and Can (20 mg/kg, s.c.) were given alone or in combination to rats once daily for one month. The combined administration of Can and Nan induced learning and spatial memory deficits, hypo-locomotion, anxiety and aggression in adolescent rats as evidenced by the Morris water maze, open field, elevated plus maze, and defensive aggression tests. In parallel, rats treated with the combination showed severe deleterious effects in the hippocampal and prefrontal cortex (PFC) neural architecture along with a decrease in brain-derived neurotropic factor. Furthermore, combined administration of Can and Nan increased oxidative stress (significantly increased malondialdehyde and nitric oxide levels and reduced glutathione content), elevated brain pro-inflammatory cytokines (tumour necrosis factor alpha and interleukin 1 beta), and upregulated caspase-3, caspase-8, and caspase-9 mRNA expression and cytochrome c levels. In conclusion, abuse of both Can and Nan conferred greater neurotoxic effects than either drug alone that were at least partially attributed to oxidative stress, inflammation, and intrinsic and extrinsic apoptosis in the hippocampus and PFC of rats.

  • Cognitive profile of patients with manganese-methcathinone encephalopathy
    Neurotoxicology (IF 3.263) Pub Date : 2019-10-31
    Margus Ennok, Katrin Sikk, Sulev Haldre, Pille Taba

    Manganese-methcathinone encephalopathy (MME) is a rare parkinsonian syndrome described in drug addicts who have self-injected a home-made mixture containing methcathinone and manganese. We assessed 14 patients with MME and compared their results with 14 matched control subjects. The patients had a parkinsonian syndrome with symmetrical bradykinesia, dystonias, and postural, gait and speech impairment, with moderate restrictions in activities of daily living. Their cognitive status was assessed with the Russian version of the Wechsler Adult Intelligence Scale (WAIS) and with tests of attention (Trail Making Test, Bourdon-Wiersma Dot Cancellation Test), memory (Auditory Verbal Learning Test, Rey-Osterrieth Complex Figure), motor skills (Grooved Pegboard), visuospatial skills (Money Road Map Test, Benton Judgment of Line Orientation), and executive abilities (Verbal Fluency, 5-Point Test, Wisconsin Card Sorting Test). Only a few significant differences emerged. After controlling for multiple comparisons, the results in the WAIS Object Assembly subtest, the Grooved Pegboard test (dominant and nondominant hand) and the Verbal Fluency test remained significant.

  • Neuroprotective mechanisms of selenium against arsenic-induced behavioral impairments in rats
    Neurotoxicology (IF 3.263) Pub Date : 2019-10-31
    Isaac A. Adedara, Adekola T. Fabunmi, Folashade C. Ayenitaju, Oluwadarasimi E. Atanda, Adetutu A. Adebowale, Babajide O. Ajayi, Olatunde Owoeye, Joao B.T. Rocha, Ebenezer O. Farombi

    Environmental pollution due to arsenic is associated with several adverse health effects including neurotoxicity in animals and humans. Selenium is a nutritionally essential trace metalloid well documented to elicit compelling pharmacological activities in vitro and in vivo. Report on the influence of selenium on arsenic-mediated behavioral derangement is lacking in literature. Hence, to fill this knowledge gap, rats were either exposed to arsenic per se in drinking water at 60 µg AsO2Na/L or co-administered with inorganic selenium at 0.25 mg/kg or organic selenium diphenyl diselenide (DPDS) at 2.5 mg/kg body weight for 45 successive days. Neurobehavioural data from rats in a new environment using video-tracking software evinced that inorganic and organic forms of selenium significantly (p < 0.05) abrogated arsenic-induced motor and locomotor insufficiencies such as increased negative geotaxis and fecal pellets numbers as well as the diminution in grip strength, body rotation, maximum speed, absolute turn angle and total distance travelled. The augmentation in the behavioral activities in rats co-administered with arsenic and both forms of selenium was substantiated using track and occupancy plots analyses. Selenium mitigated arsenic-induced decreases in glutathione level and acetylcholinesterase activity as well as the increase in oxidative stress and reactive oxygen and nitrogen species. Moreover, selenium diminished inflammatory parameters (myeloperoxidase activity, nitric oxide, tumour necrosis factor alpha and interleukin-1 beta levels), caspase-3 activity and ameliorated histological lesions in the cerebellum, cerebrum and liver of the rats. Collectively, selenium abated arsenic-induced behavioral derangements via anti-inflammation, antioxidant and anti-apoptotic mechanisms in rats.

  • IMM-H004 reduced okadaic acid-induced neurotoxicity by inhibiting Tau pathology in vitro and in vivo.
    Neurotoxicology (IF 3.263) Pub Date : 2019-09-29
    Yingying Wang,Xiuyun Song,Dandan Liu,Yu-Xia Lou,Piao Luo,Tianbi Zhu,Qi Wang,Naihong Chen

    This study aimed to explore effects and mechanisms of 004 (IMM-H004), a novel coumarin derivative, in OKA (okadaic acid)-induced AD (Alzheimer's disease)-like model. In vitro, MTT, LDH, and Annexin V/FITC flow cytometry assay were used to test cell survival. In vivo, OKA microinjection was conducted to simulate AD-like neuropathology. Morris water maze and Nissl staining were used to detect spatial memory function and neuronal damage respectively. Western blot and immunohistochemistry were used to study the mechanisms of 004 in Tau pathology. The results showed that 004 reduced cell death and increased survival in PC12 cells, and decreased neuronal injury in the hippocampus in rats. 004 improved learning and memory functions in OKA-treated rats. The mechanistic studies indicated that 004 inhibited phosphorylation of Tau protein by down-regulating the activity of protein kinases CDK5 and GSK3β and increasing PP2A activity. Overall, 004 improved spatial memory impairments and neuron cells injury induced by OKA; on the other hand, 004 inhibited Tau hyperphosphorylation by regulating CDK5, GSK3β and PP2A.

  • 更新日期:2019-11-01
  • Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity.
    Neurotoxicology (IF 3.263) Pub Date : 2017-09-19
    Nicholas B Miner,Josh S Elmore,Michael H Baumann,Tamara J Phillips,Aaron Janowsky

    Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock-out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2h apart, of MA (2.5, 5, or 10mg/kg). Temperature data were recorded during the treatment day. Additionally, striatal tissue was collected 2 or 7days following MA administration for analysis of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. MA elicited an acute hypothermic drop in body temperature in Taar1-WT mice, but not in Taar1-KO mice. Two days following treatment, DA and TH levels were lower in Taar1-KO mice compared to Taar1-WT mice, regardless of treatment, and were dose-dependently decreased by MA. GFAP expression was significantly increased by all doses of MA at both time points and greater in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. Seven days later, DA levels were decreased in a similar pattern: DA was significantly lower in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. TH levels were uniformly decreased by MA, regardless of genotype. These results indicate that activation of TAAR1 potentiates MA-induced hypothermia and TAAR1 confers sustained neuroprotection dependent on its thermoregulatory effects.

  • Effects of ketamine and its metabolites on ion currents in differentiated hippocampal H19-7 neuronal cells and in HEK293T cells transfected with α-hslo subunit.
    Neurotoxicology (IF 3.263) Pub Date : 2012-12-12
    Mei-Han Huang,Kuan-Hua Lin,Sheue-Jiun Chen,Ai-Yu Shen,Fang-Tzu Wu,Sheng-Nan Wu

    Ketamine (KT), a dissociative anesthetic, is known to induce schizophrenia-like psychosis. The percentage of KT abuse has recently grown fast despite KT being a controlled drug. The mechanism of KT actions is related to the inhibition of NMDA receptors. Whether KT produces other effects on ion currents in hippocampal neurons remains unclear. In this study, we attempted to evaluate the possible effects of KT and other related compounds on ion currents in hippocampal neuron-derived H19-7 cells. This drug exerted an inhibitory effect on Ca(2+)-activated K(+) current (IK(Ca)) in these cells with an IC(50) value of 274 μM. Pimaric acid (30 μM) or abietic acid (30 μM), known to stimulate large-conductance Ca(2+)-activated K(+) channels, reversed KT-induced inhibition of I(K)(Ca). In HEK293T cells expressing a-humans low poke, KT-induced inhibition of I(K)(Ca) still existed. Dehydronorketamine (300 μM) had little or no effect on the IK(Ca) amplitude, while norketamine (300 μM) slightly but significantly suppressed it. In inside–out configuration, KT applied to the intracellular face of the membrane did not alter single channel conductance of large-conductance Ca(2+)-activated K(+) (BKCa) channels; however, it did significantly reduce the probability of channel openings. Addition of KT was effective in depressing the peak amplitude of voltage-gated Na(+) current. Moreover, the presence of KT was noted to enhance the amplitude of membrane electroporation-induced inward currents (IMEP) in differentiated H19-7 cells. KT-stimulated IMEP was reversed by further application of LaCl(3) (100 μM), but not by NMDA (30 μM). The modulations by this compound of ion channels may contribute to the underlying mechanisms through which KT and its metabolites influence the electrical behavior of hippocampal neurons if similar findings occur in vivo.

  • Cardiac autonomic activity and blood pressure among Inuit children exposed to mercury.
    Neurotoxicology (IF 3.263) Pub Date : 2012-12-12
    Beatriz Valera,Gina Muckle,Paul Poirier,Sandra W Jacobson,Joseph L Jacobson,Eric Dewailly

    BACKGROUND Studies conducted in the Faeroe Islands and Japan suggest a negative impact of mercury on heart rate variability (HRV) among children while the results regarding blood pressure (BP) are less consistent. OBJECTIVE To assess the impact of mercury on HRV and BP among Nunavik Inuit children. METHODS A cohort of 226 children was followed from birth to 11 years old. Mercury concentration in cord blood and in blood and hair at 11 years old were used as markers of prenatal and childhood exposure, respectively. HRV was measured using ambulatory 2 h-Holter monitoring while BP was measured through a standardized protocol. Simple regression was used to assess the relationship of mercury to BP and HRV parameters. Multiple linear regressions were performed adjusting for covariates such as age, sex, birth weight, body mass index (BMI), height, total n-3 fatty acids, polychlorinated biphenyls (PCB 153), lead, selenium and maternal smoking during pregnancy. RESULTS Median cord blood mercury and blood mercury levels at 11 years old were 81.5 nmoL/L (IQR:45.0–140.0) and 14.5 nmol/L (IQR: 7.5–28.0), respectively. After adjusting for the covariates, child blood mercury was associated with low frequency (LF) (b = 0.21, p = 0.05), the standard deviation of R–R intervals (SDNN) (b = 0.26, p = 0.02), the standard deviation of R–R intervals measured over 5 min periods (SDANN) (b = 0.31, p = 0.01) and the coefficient of variation of R–R intervals (CVRR) (b = 0.06,p = 0.02). No significant association was observed with BP. CONCLUSION Mercury exposure during childhood seems to affect HRV among Nunavik Inuit children at school age.

  • Parkinson's disease and the environment: beyond pesticides.
    Neurotoxicology (IF 3.263) Pub Date : 2012-07-10
    W Michael Caudle,Thomas S Guillot,Carlos Lazo,Gary W Miller

  • Neuropharmacological specificity of brain structures involved in soman-induced seizures.
    Neurotoxicology (IF 3.263) Pub Date : 2012-07-10
    Jacob W Skovira,Tsung-Ming Shih,John H McDonough

    Pharmacological control of seizure activity following nerve agent exposure is critical in reducing neuropathology and improving survival in casualties. Three classes of drugs, anticholinergics, benzodiazepines and excitatory amino acid (EAA) antagonists, have been shown to be effective at moderating nerve agent-induced seizures. However, little is known about which brain structures are involved in producing the anticonvulsant response. This study evaluated drugs from each class, injected directly into one of three specific brain structures, the perirhinal cortex, the entorhinal cortex, or the mediodorsal thalamus, for their ability to modulate seizures induced by the nerve agent soman. The drugs evaluated were the anticholinergic scopolamine, the benzodiazepine midazolam, and the EAA antagonist MK-801. For each drug treatment in each brain area, anticonvulsant ED₅₀ values were calculated using an up-down dosing procedure over successive animals. There was no statistical difference in the anticonvulsant ED₅₀ values for scopolamine and MK-801 in the perirhinal and entorhinal cortices. MK-801 pretreatment in the mediodorsal thalamus had a significantly lower anticonvulsant ED₅₀ value than any other treatment/injection site combination. Midazolam required significantly higher doses than scopolamine and MK-801 in the perirhinal and entorhinal cortices to produce an anticonvulsant response and was ineffective in the mediodorsal thalamus. These findings support the contention that specific neuroanatomical pathways are activated during nerve agentinduced seizures and that the discrete brain structures involved have unique pharmacological thresholds for producing an anticonvulsant response. This study is also the first to show the involvement of the mediodorsal thalamus in the control of nerve agent-induced seizures.

  • 更新日期:2019-11-01
  • Low doses of nicotine-induced fetal cardiovascular responses, hypoxia, and brain cellular activation in ovine fetuses.
    Neurotoxicology (IF 3.263) Pub Date : 2009-05-22
    Junchang Guan,Caiping Mao,Feicao Xu,Liyan Zhu,Yujuan Liu,Chongsong Geng,Lubo Zhang,Zhice Xu

    Prenatal exposure to nicotine is associated with a variety of adverse outcomes. The present study investigated the effect of low doses of nicotine during pregnancy on fetal blood gases, cardiovascular system, and cellular activation in the brain. Intravenous administration of nicotine 10 or 25 microg/kg into ewe did not affect maternal blood gases, blood pressure, and heart rate. Maternal administration of nicotine also had no effect on fetal blood electrolyte concentrations, osmolality levels, and lactic acid levels. However, it significantly reduced fetal blood pO2 levels and oxygen saturation, increased fetal arterial blood pressure and decreased heart rate in utero. In addition, exposure to low doses of nicotine increased the expression of Fos in the paraventricular nucleus (PVN) and subfornic organ (SFO) in the fetal brain. The data demonstrated that even low doses of nicotine could impact significantly on fetal cardiovascular and central nervous systems, as well as oxygen status, and suggested a toxic risk to fetuses of exposure to low levels nicotine or second-hand smoking during pregnancy.

  • Effects of the organochlorine pesticide methoxychlor on dopamine metabolites and transporters in the mouse brain.
    Neurotoxicology (IF 3.263) Pub Date : 2009-05-22
    Rosemary A Schuh,Jason R Richardson,Rupesh K Gupta,Jodi A Flaws,Gary Fiskum

    Pesticide exposure has been suggested as a risk factor in developing Parkinson's disease (PD). While the molecular mechanism underlying this association is not clear, several studies have demonstrated a role for mitochondrial dysfunction and oxidative damage in PD. Although data on specific pesticides associated with PD are often lacking, several lines of evidence point to the potential involvement of the organochlorine class of pesticides. Previously, we have found that the organochlorine pesticide methoxychlor (mxc) causes mitochondrial dysfunction and oxidative stress in isolated mitochondria. Here, we sought to determine whether mxc-induced mitochondrial dysfunction results in oxidative damage and dysfunction of the dopamine system. Adult female CD1 mice were dosed with either vehicle (sesame oil) or mxc (16, 32, or 64 mg/kg/day) for 20 consecutive days. Following treatment, we observed a dose-related increase in protein carbonyl levels in non-synaptic mitochondria, indicating oxidative modification of mitochondrial proteins which may lead to mitochondrial dysfunction. Mxc exposure also caused a dose-related decrease in striatal levels of dopamine (16-31%), which were accompanied by decreased levels of the dopamine transporter (DAT; 35-48%) and the vesicular monoamine transporter 2 (VMAT2; 21-44%). Because mitochondrial dysfunction, oxidative damage, and decreased levels of DAT and VMAT2 are found in PD patients, our data suggest that mxc should be investigated as a possible candidate involved in the association of pesticides with increased risk for PD, particularly in highly exposed populations.

  • Blood lead, serum homocysteine, and neurobehavioral test performance in the third National Health and Nutrition Examination Survey.
    Neurotoxicology (IF 3.263) Pub Date : 2009-05-22
    Edward F Krieg,Mary Ann Butler

    Regression analysis was used to estimate and test for relationships between blood lead, serum folate, red blood cell folate, serum vitamin B12, serum homocysteine, and neurobehavioral test performance in adults, 20-59 years old, participating in the third National Health and Nutrition Examination Survey. The three neurobehavioral tests included in the survey were simple reaction time, symbol-digit substitution, and serial digit learning. Serum folate, red blood cell folate, and serum vitamin B12 decreased as the blood lead concentration increased. Serum homocysteine increased as the blood lead concentration increased. Serum homocysteine decreased as the serum folate and serum vitamin B12 concentrations increased. Neurobehavioral test performance was not related to the blood lead, serum folate, or serum vitamin B12 concentrations. In adults 20-39 years old, performance on the serial digit learning test improved as the serum homocysteine concentration increased. In adults 40-59 years old, neurobehavioral test performance was not related to the serum homocysteine concentration. Homocysteine may impair cognitive function by acting at N-methyl-D-aspartate receptors, and improve cognitive function by acting at N-methyl-D-aspartate or gamma-aminobutyric acid receptors.

  • Effect of alpha-cypermethrin and theta-cypermethrin on delayed rectifier potassium currents in rat hippocampal neurons.
    Neurotoxicology (IF 3.263) Pub Date : 2009-05-22
    Yu-Tao Tian,Zhao-Wei Liu,Yang Yao,Zhuo Yang,Tao Zhang

    Cypermethrin is a photostable synthetic pyrethroid and the most widely used Type II pyrethroid pesticide. The effects of two different stereoisomers of cypermethrin insecticides, alpha-cypermethrin and theta-cypermethrin, on the delayed rectifier potassium current (IK) in hippocampal neurons of rat, were studied using whole-cell patch clamp technique. Alpha-cypermethrin and theta-cypermethrin decreased the amplitude value of IK, and shifted the steady state activation curve of IK towards negative potential at any concentrations (10(-9) M, 10(-8) M, 10(-7) M). Furthermore, at higher concentration, alpha-cypermethrin (10(-7) M) and theta-cypermethrin (10(-8) M, 10(-7) M) had observable effects of the steady state inactivation of IK. The results suggest that IK is the target of alpha-cypermethrin and theta-cypermethrin, which may explain the mechanism of toxic effects of both steroeisomers of cypermethrin on mammalian neurons. Cypermethrin-altered properties of voltage gated delayed rectifier K+ channels may contribute to neurotoxicity by eliciting abnormal electrical discharges in hippocampal CA3 neurons.

  • Vincristine-induced fatal neuropathy in non-Hodgkin's lymphoma.
    Neurotoxicology (IF 3.263) Pub Date : 2008-08-30
    Sultan Tarlaci

    The vinca alkaloids are neurotoxic, usually causing a peripheral neuropathy, but cranial neuropathies are rare as side effects. We describe a case of vincristine-induced multiple cranial and autonomic neuropathy, and sensory-motor axonal peripheral neuropathy (pan-neuropathy), which is an extremely rare fatal complication of this drug. The patient developed fulminant cranial, peripheral and significant autonomic neuropathy.

  • First time, low dose citalopram use-related serotonin syndrome.
    Neurotoxicology (IF 3.263) Pub Date : 2008-01-24
    Suleyman Turedi,Ismet Eraydin,Abdulkadir Gunduz,Asim Kalkan,Ulku Hos

    Citalopram is a very potent and highly selective inhibitor of neuronal serotonin (5-hydroxytryptamine, or 5-HT). Serotonin syndrome is a rarely observed side-effect of Citalopram use. This report discusses a case of first time, low dose citalopram use-related serotonin syndrome presenting with confusion, hyperhidrosis, hyperreflexia, myoclonus and fever.

  • Association of chronic and current measures of lead exposure with different components of brainstem auditory evoked potentials.
    Neurotoxicology (IF 3.263) Pub Date : 2003-08-06
    Margit L Bleecker,D Patrick Ford,Karen N Lindgren,Karin Scheetz,Michael J Tiburzi

    Current blood lead (PbB) affects brainstem auditory evoked potentials (BAEPs) in children but whether a similar association exists in lead-exposed adults remains unclear. During an investigation of the neurobehavioral effects of occupational lead exposure we performed BAEPs on 359 English- and French-speaking, currently exposed, male, lead smelter workers having a mean (S.D.) age of 41 (9.0) years, employment duration of 17 (7.9) years, PbB of 28 (8.4)microg/dl, working-lifetime weighted average blood lead (TWA) of 39 (11.9) microg/dl, and working-lifetime integrated blood lead (IBL) index of 719 (421.0) microg.year/dl, the latter a measure of cumulative lead dose. BAEPs were performed at a click stimulation of 10s(-1) for 1000 repetitions, at an intensity 75dB above the threshold of the ear tested. Right-sided latencies for peak waves I, III, and V and the corresponding interpeak intervals (IPI) I-V, I-III, and III-V were chosen for analyses. Age correlated significantly with BAEPs, PbB, TWA, and IBL. Partial correlation analyses adjusting for age found PbB and TWA significantly associated with wave I latency r=0.13, P<0.01 and r=0.11, P<0.05, respectively, and IBL significantly associated with wave III latency r=0.16, P<0.01. The contribution of age, PbB, TWA and IBL to the variances of different BAEPs was assessed using multiple regression analysis. In the regression model of the full group, after the contribution of age, PbB and TWA accounted for significant variance of wave I, Deltar(2)=1.8, P<0.01 and Deltar(2)=1.2%, P<0.04, respectively, and IBL accounted for significant variance of wave III latency, Deltar(2)=2.8%, P=0.00 and I-III interpeak interval, Deltar(2)=1.4%, P<0.03. Four groups similar in age were created with increasing abnormalities based upon clinical cut-off scores for wave I latency and I-V interpeak interval. PbB, TWA, and IBL were significantly higher in the group with abnormalities of both latency in wave I and IPL I-V. Lead exposure interferes with BAEPs in a dose-dependent manner. Current lead exposure in this population of lead smelter workers preferentially affected conduction in the distal auditory nerve while chronic lead exposure appeared to impair conduction in the auditory nerve and the auditory pathway in the lower brainstem.

  • Development of the Behavioral Assessment and Research System (BARS) to detect and characterize neurotoxicity in humans.
    Neurotoxicology (IF 3.263) Pub Date : 2003-08-06
    Diane S Rohlman,Lincoln S Gimenes,David A Eckerman,Seong-Kyu Kang,Fayssal M Farahat,W Kent Anger

    The Behavioral Assessment and Research System (BARS) is a computer-based testing system designed to assess neurobehavioral function in humans. It was developed to provide a series or battery of neurobehavioral tests optimized for the detection of neurotoxicity in non-mainstream human populations, specifically people with limited education or literacy. Key to meeting this goal were simply-stated instructions divided into an elemental series of steps, a 9BUTTON response unit to replace the computer keyboard for responding, and spoken instructions. Modifications all underwent serial testing in target populations to successively hone the changes to be more effective. A similar process was followed when developing adjustable parameters, test reliability assessments, and when implementing these tests with populations from different cultural groups and children. The principles and experiences that guided the development of BARS should inform the development of future testing systems to ensure that the new tests can be used with non-mainstream populations, which may be increasingly subject to neurotoxic exposures.

  • Asymmetrical development of the monoamine systems in 2,4-dichlorophenoxyacetic acid treated rats.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    Analía Bortolozzi,Ricardo Duffard,Ana María Evangelista de Duffard

    The purpose of this study was to determine whether the regional brain biogenic amine levels in adult rats were altered by pre- and post-natal exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). Pregnant rats were daily orally exposed to 70 mg/kg per day of 2,4-D from gestation day (GD) 16 to post-partum day (PPD) 23. After weaning, the pups were assigned to one of two subgroups: T1 fed with untreated diet up to post-natal day (PND) 90 and T2 (maintained with 2,4-D diet up to PND 90). In addition, we wanted to know the effect of 2,4-D on lateralization in the monoamine systems of the basal ganglia of these adult rats and whether there was any correlation with the behavioral developmental pattern previously reported by us. In this study the content of noradrenaline (NA) was significantly increased in substantia nigra (SN) while it decreased in cerebellum in male and female rats of T2 group. The decreased dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovallinic acid (HVA) contents in cerebellum, midbrain, ventral tegmental area (VTA) and prefrontal cortex (PFc) showed an alteration in the mesocorticolimbic system. However, an increase of DA in SN and of DOPAC and HVA in nucleus accumbens (NAc) in both sexes and of DA and DOPAC (only in females) in striatum was detected. The contents of serotonin (5-hydroxytryptamine, 5-HT) were significantly increased in both sexes in PFc, striatum (St), midbrain, SN and cerebellum. Variations of any monoamine levels in NAc and VTA were determined. T1 rats were irreversibly altered: a diminution in DA and/or DOPAC levels in PFc, midbrain, VTA and cerebellum was determined. Indolamines of these rats were increased in both sexes in PFc and St. There was also a large increase in 5-HT levels in midbrain of male rats. Although no changes in the dopaminergic system with respect to their control values in any side of these brain structures were observed, DA and DOPAC levels were found to be decreased in the right side with respect to the left side in striata and accumbens nuclei in T2 female rats supporting the behavioral rotation previously registered by us in these rats. In addition, the increased 5-HT content detected in both the right and left striata observed in this study could be the answer to the behaviors observed and to the early alterations in dopamine in basal ganglia by 2,4-D in neonatal exposed rats, mediated by a serotonergic modulation on the dopaminergic system.

  • The role of glycolysis and gluconeogenesis in the cytoprotection of neuroblastoma cells against 1-methyl 4-phenylpyridinium ion toxicity.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    Elizabeth Mazzio,Karam F A Soliman

    1-Methyl-4-phenylpyridinium (MPP+) is a mitochondrial Complex I inhibitor and is frequently used to investigate the pathological degeneration of neurons associated with Parkinson's disease (PD). In vitro, extracellular concentration of glucose is one of the most critical factors in establishing the vulnerability of neurons to MPP+ toxicity. While glucose is the primary energy fuel for the brain, central nervous system (CNS) neurons can also take up and utilize other metabolic intermediates for energy. In this study, we compared various monosaccharides, disaccharides, nutritive/non-nutritive sugar alcohols, glycolytic and gluconeogenic metabolic intermediates for their cytoprotection against MPP+ in murine brain neuroblastoma cells. Several monosaccharides were effective against MMP+ (500 microM) including glucose, fructose and mannose, which restored cell viability to 109 +/- 5%, 70 +/- 5%, 99 +/- 3% of live controls, respectively. Slight protective effects were observed in the presence of 3-phosphoglyceric acid and glucose-6-phosphate; however, no protective effects were exhibited by galactose, sucrose, sorbitol, mannitol, glycerol or various gluconeogenic and ketogenic amino acids. On the other hand, fructose 1,6 bisphosphate and gluconeogenic energy intermediates [pyruvic acid, malic acid and phospho(enol)pyruvate (PEP)] were neuroprotective against MPP+. The gluconeogenic intermediates elevated intracellular levels of ATP and reduced propidium iodide (PI) nucleic acid staining to live controls, but did not alter the MPP(+)-induced loss of mitochondrial O2 consumption. These data indicate that malic acid, pyruvic acid and PEP contribute to anaerobic substrate level phosphorylation. The use of hydrazine sulfate to impede gluconeogenesis through PEP carboxykinase (PEPCK) inhibition heightened the protective effects of energy substrates possibly due to attenuated ATP demands from pyruvate carboxylase (PC) activity and pyruvate mitochondrial transport. It was concluded from these studies that several metabolic intermediates are effective in fueling anaerobic glycolysis during mitochondrial inhibition by MPP+.

  • Acrylamide neuropathy. III. Spatiotemporal characteristics of nerve cell damage in forebrain.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    E J Lehning,C D Balaban,J F Ross,R M LoPachin

    Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. (1998) 151:211-221] and in spinal cord, brainstem and cerebellum [NeuroToxicology (2002a) 23:397-414; NeuroToxicology (2002b) 23:415-429] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To conclude our studies of neurodegeneration in rat CNS during ACR neurotoxicity, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal argyrophilia in forebrain regions and nuclei. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.) and at selected times brains were removed and processed for silver staining. Results show that intoxication at either ACR dose-rate produced a terminalopathy, i.e. nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the higher ACR dose-rate caused early onset (day 5), widespread nerve terminal degeneration in most of the major forebrain areas, e.g. cerebral cortex, thalamus, hypothalamus and basal ganglia. At the lower dose-rate, nerve terminal degeneration in the forebrain developed early (day 7) but exhibited a relatively limited spatial distribution, i.e. anteroventral thalamic nucleus and the pars reticulata of the substantia nigra. Several hippocampal regions were affected at a later time point (day 28), i.e. CA1 field and subicular complex. At both dose-rates, argyrophilic changes in forebrain nerve terminals developed prior to the onset of significant gait abnormalities. Thus, in forebrain, ACR intoxication produced a pure terminalopathy that developed prior to the onset of significant neurological changes and progressed as a function of exposure. Neither dose-rate used in this study was associated with axon degeneration in any forebrain region. Our findings indicate that nerve terminals were selectively affected in forebrain areas and, therefore, might be primary sites of ACR action.

  • Acrylamide neuropathy. II. Spatiotemporal characteristics of nerve cell damage in brainstem and spinal cord.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    E J Lehning,C D Balaban,J F Ross,R M LoPachin

    Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. 151 (1998) 211] and cerebellum [NeuroToxicology 23 (2002) 397] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To continue morphological examination of ACR neurotoxicity in CNS, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal degeneration in brainstem and spinal cord. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.), and at selected times brains and spinal cord were removed and processed for silver staining. Results show that intoxication at the higher ACR dose-rate produced a nearly pure terminalopathy in brainstem and spinal cord regions, i.e. widespread nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the lower ACR dose-rate caused initial nerve terminal argyrophilia in selected brainstem and spinal cord regions. As intoxication continued, axon degeneration developed in white matter of these CNS areas. At both dose-rates, argyrophilic changes in brainstem nerve terminals developed prior to the onset of significant gait abnormalities. In contrast, during exposure to the lower ACR dose-rate the appearance of axon degeneration in either brainstem or spinal cord was relatively delayed with respect to changes in gait. Thus, regardless of dose-rate, ACR intoxication produced early, progressive nerve terminal degeneration. Axon degeneration occurred primarily during exposure to the lower ACR dose-rate and developed after the appearance of terminal degeneration and neurotoxicity. Spatiotemporal analysis suggested that degeneration began at the nerve terminal and then moved as a function of time in a somal direction along the corresponding axon. These data suggest that nerve terminals are a primary site of ACR action and that expression of axonopathy is restricted to subchronic dosing-rates.

  • Butyl benzyl phthalate blocks Ca2+ signaling and catecholamine secretion coupled with nicotinic acetylcholine receptors in bovine adrenal chromaffin cells.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    Pei-Shan Liu,Chih-Ming Lin,Chien-Yuan Pan,Lung-Sen Kao,Fu-Wei Tseng

    Butyl benzyl phthalate (BBP), a plasticizer and an environmental pollutant, exerts genomic estrogenic-like effects via estrogen receptors. In addition to exerting genomic effects via intracellular steroid receptors, estrogen exerts non-genomic effects through interactions with membrane ion channels to lead the rapid alteration of neuronal excitability. Estradiol is known as to have modulating role on nicotinic acetylcholine receptors (nAChR). We investigated the possibility of BBP exerting non-genomic estrogenic-like effects on nAChR in bovine adrenal chromaffin cells. Our results show that BBP inhibited Ca2+ signaling induced by the nicotinic ligands carbachol, 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) and epibatidine (IC50 levels of 4.3, 4.1, 5.4 microM, respectively) as well as high K+ solution (IC50 50.9 microM). Additionally, in the electrophysiological observations, BBP blocked the inward current coupled with nAChR under the stimulation of carbachol. We, therefore, suggest that nAChR and voltage-gated Ca2+ channels are major and minor sites, respectively, of BBP action on the plasma membrane. The inhibitory effect of BBP on nAChR was found to be both noncompetitive and reversible, remaining unchanged as nAChR ligand concentration increased and decreased after washing. BBP was 10 times more potent than estradiol in inhibiting nAChR-coupled Ca2+ signals. We conclude that BBP exerts a novel rapidly inhibitory effect on nAChR.

  • Voltage-dependent block of sodium channels in mammalian neurons by the oxadiazine insecticide indoxacarb and its metabolite DCJW.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    Xilong Zhao,Tomoko Ikeda,Jay Z Yeh,Toshio Narahashi

    Indoxacarb is a newly developed insecticide with high insecticidal activity and low toxicity to non-target organisms. Its metabolite, DCJW, is known to block compound action potentials in insect nerves and to inhibit sodium currents in cultured insect neurons. However, little is known about the effects of these compounds on the sodium channels of mammalian neurons. We compared the effects of indoxacarb and DCJW on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels in rat dorsal root ganglion neurons by using the whole-cell patch clamp technique. Indoxacarb and DCJW at 1-10 microM slowly and irreversibly blocked both TTX-S and TTX-R sodium channels in a voltage-dependent manner. The sodium channel activation kinetics were not significantly modified by 1 microM indoxacarb or 1 microM DCJW. The steady-state fast and slow inactivation curves were shifted in the hyperpolarization direction by 1 microM indoxacarb or 1 microM DCJW indicating a higher affinity of the inactivated sodium channels for these insecticides. These shifts resulted in an enhanced block at more depolarized potentials, thus explaining voltage-dependent block, and an apparent difference in the sensitivity of TTX-R and TTX-S channels to indoxacarb and DCJW near the resting potential. Indoxacarb and its metabolite DCJW cause toxicity through their action on the sodium channels.

  • Monoamine oxidase and cigarette smoking.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    Joanna S Fowler,Jean Logan,Gene-Jack Wang,Nora D Volkow

    Current cigarette smokers have reduced monoamine oxidase (MAO) and there is evidence that this is a pharmacological effect of tobacco smoke exposure rather than a biological characteristic of smokers. This article summarizes human and animal studies documenting the inhibitory effects of tobacco smoke on MAO and discusses MAO inhibition in the context of smoking epidemiology, MAO inhibitor compounds in tobacco, reinvestigations of low platelet MAO in psychiatric disorders and smoking cessation.

  • Estradiol enhances the neurotoxicity of glutamate in GT1-7 cells through an estrogen receptor-dependent mechanism.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    Rei-Cheng Yang,Huei-Chuan Shih,Hseng-Kuang Hsu,Hwei-Chiu Chang,Chin Hsu

    Glutamate plays an important role in neuroendocrine regulation of reproduction through acting on the N-methyl-D-asparate receptor (NMDAR) in the preoptic area (POA). However, a larger dose of glutamate is neurotoxic. Estradiol (E2) increases the responsiveness of neurons to glutamate through activation and/or expression of NMDAR. In order to investigate whether estradiol modulates the neurotoxic effect of glutamate on the neurons through estrogen receptor (ER), immortalized GT1-7 cells, which simultaneously express ER and NMDAR were used. Tamoxifen and ICI 182,780, ER antagonist, were used to investigate whether the ER is involved in the effect of estradiol on glutamate-induced neurotoxicity. MK-801, a NMDAR antagonist, was used to confirm the enhancement of NMDAR-mediated neurotoxicity by estradiol. Neurotoxicity was evaluated by cell viability and LDH efflux. Cell death was observed by flow cytometry and DNA fragmentation. The results showed that: (1) estradiol (10 nM, incubated for 3 days) significantly enhanced the glutamate-induced neuronal death; (2) the percentages of necrosis and apoptosis were elevated after glutamate treatment, and estradiol significantly enhanced the glutamate-induced cell death; (3) glutamate-induced DNA fragmentation was enhanced by E2-pretreatment; (4) the induction of cell death and increase of LDH efflux after glutamate treatment were also enhanced by E2-pretreatment; (5) both the tamoxifen and ICI 182,780 abolished the estradiol-enhanced NMDAR expression and neurotoxicity of glutamate; (6) higher dose of MK-801 (2 microM) was needed in E2-pretreated cells than in non-E2-pretreated group to block the glutamate-induced neurotoxicity. These results suggested that pretreatment of estradiol might enhance the expression of NMDAR and subsequent glutamate-induced neurotoxicity on the GT1-7 cells through an ER-dependent manner.

  • Effects of the new herbicide fentrazamide on the glucose utilization in neurons and erythrocytes in vitro.
    Neurotoxicology (IF 3.263) Pub Date : 2003-02-05
    Gabriele Schmuck,Alexius Freyberger,Hans-Jürgen Ahr,Bernhard Stahl,Martin Kayser

    Treatment of rats with fentrazamide for 2 years at 3000 ppm (males) and 4000 ppm (females) led to an increased incidence and degree of axonal degeneration in sciatic nerve as well as to effects on red blood cells. The mechanism underlying these effects was investigated in vitro using various cell cultures (permanent rodent cell lines from the nervous system, liver, kidney, skeletal and heart muscle and fibroblasts, primary cortical neurons and erythrocytes from the rat). Added to cultured rat cortical neurons for 1 week, fentrazamide considerably decreased glucose consumption, ATP levels and mitochondrial membrane potential and lowered the GSH level, however, it had little impact on viability and neurofilaments and did not induce oxidative stress (ROS) over the first 2 h. After recovery for 1 week, in addition some destruction of neurofilaments had occurred probably secondary to the disturbance of energy production. These effects were prevented by pyruvate. Further studies indicated that fentrazamide primarily inhibited glucose utilization, most likely by interfering with glycolysis. Similar effects were found in erythrocytes treated with fentrazamide over a period of 7 days. Primarily, the glucose consumption was reduced after 1-day treatment, followed by a marked reduction of the energy supply at days 3 and 7. Comparable to the neurons, the GSH level was significantly reduced. A marked hemolysis of the red blood cells was then observed after prolonged treatment. The extensive energy demand and exclusive dependency on glucose utilization of neurons and erythrocytes may explain the specific vulnerability of motor neurons and erythrocytes. When comparing the concentrations necessary for inducing effects in vitro on neuronal cells and erythrocytes to the very low plasma concentrations of fentrazamide in treated rats it is suggested that only a small impact of fentrazamide on the energy status at high doses will occur in vivo. Therefore, aging of the rat as another factor compromising mitochondrial energy production in motor neurons must be considered as additional contribution for the induction of axonal degeneration. It is concluded that this effect of fentrazamide in rats poses no specific risk under the exposure conditions relevant to humans.

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上海纽约大学William Glover