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Journal: Neurotoxicology

27

Okadaic acid (OKA) is one of the main polyether toxins produced by marine microalgae which causes diarrhetic shellfish poisoning. It is a selective and potent inhibitor of serine/threonine phosphatases 1 and 2A induces hyperphosphorylation of tau in vitro and in vivo. The reduced activity of phosphatases like, protein phosphatase 2A (PP2A) has been implicated in the brain of Alzheimer’s disease (AD) patients. It is reported that AD is a complex multifactorial neurodegenerative disorder and hyperphosphorylated tau proteins is a major pathological hallmark of AD. The molecular pathogenesis of AD includes an extracellular deposition of beta amyloid (Aβ), accumulation of intracellular neurofibrillary tangles (NFT), GSK3β activation, oxidative stress, altered neurotransmitter and inflammatory cascades. Several lines of evidence suggested that the microinfusion of OKA into the rat brain causes cognitive deficiency, NFTs-like pathological changes and oxidative stress as seen in AD pathology via tau hyperphosphorylation caused by inhibition of protein phosphatases. So, communal data and information inferred that OKA induces neurodegeneration along with tau hyperphosphorylation; GSK3β activation, oxidative stress, neuroinflammation and neurotoxicity which is a characteristic feature of AD pathology. Through this collected evidence, it is suggested that OKA induced neurotoxicity may be a novel tool to study Alzheimer’s disease pathology and helpful in development of new therapeutic approach.

Concepts: Alzheimer's disease, Protein structure, Enzyme, Neurology, Neurodegenerative disorders, Phosphatase

26

Parkinson’s disease is an age-associated disorder characterized by selective degeneration of dopaminergic neurons. The molecular mechanisms underlying the selective vulnerability of this subset of neurons are, however, not fully understood. Employing SH-SY5Y neuroblastoma cells and primary mesencephalic neurons, we here demonstrate a significant increase in cytosolic calcium after inhibition of mitochondrial complex I by means of MPP(+), which is a well-established environmental toxin-based in vitro model of Parkinson’s disease. This increase in calcium is correlated with a downregulation of the neuron-specific plasma membrane Ca(2+)-ATPase isoform 2 (PMCA2). Interestingly, two other important mediators of calcium efflux, sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), and Na(+)-Ca(2+)-exchanger (NCX), remained unaltered, indicating a specific role of PMCA2 in maintaining calcium homeostasis in neurons. The observed PMCA2 downregulation was accompanied by reduced levels of phosphorylated CREB protein, an intracellular signaling molecule and transcriptional regulator. In order to investigate the potential influence of PMCA2 on neuronal vulnerability, experimental downregulation of PMCA2 by means of siRNA was performed. The results demonstrate a significant impairment of cell survival under conditions of PMCA2 suppression. Hence, in our cell models increased cytosolic calcium levels as a consequence of insufficient calcium efflux lead to an increased vulnerability of neuronal cells. Moreover, overexpression of PMCA2 rendered the neurons significantly resistant to complex I inhibition. Our findings point towards a dysregulation of calcium homeostasis in Parkinson’s disease and suggest a potential molecular mechanism of neurodegeneration via PMCA2.

Concepts: Neuron, Cell nucleus, Signal transduction, Adenosine triphosphate, Cell membrane, Cell biology, Cytoplasm, Dopamine

25

Puerarin (PUE), an isoflavone purified from the root of Pueraria lobata (Chinese herb), has been reported to attenuate learning and memory impairments in the transgenic mouse model of Alzheimer’s disease(AD). In the present study, we tested PUE in a sporadic AD (SAD) mouse model which was induced by the intracerebroventricular injection of streptozotocin (STZ). The mice were administrated PUE (25, 50, or 100mg/kg/d) for 28 days. Learning and memory abilities were assessed by the Morris water maze test. After behavioral test, the biochemical parameters of oxidative stress (glutathione peroxidase (GSH-Px), superoxide dismutases (SOD), and malondialdehyde (MDA)) were measured in the cerebral cortex and hippocampus. The SAD mice exhibited significantly decreased learning and memory ability, while PUE attenuated these impairments. The activities of GSH-Px and SOD were decreased while MDA was increased in the SAD animals. After PUE treatment, the activities of GSH-Px and SOD were elevated, and the level of MDA was decreased. The middle dose PUE was more effective than others. These results indicate that PUE attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice. PUE may be a promising therapeutic agent for SAD.

Concepts: Psychology, Oxidative stress, Cerebral cortex, Memory, Hippocampus, Attenuation, Glutathione peroxidase, Kudzu

25

In the cuprizone model of demyelination, the neurotoxin cuprizone is fed to mice to induce a reproducible pattern of demyelination in the brain. Cuprizone is a copper chelator and it has been hypothesized that it induces a copper deficiency in the brain which leads to demyelination. To test this hypothesis and investigate the possible role of other transition metals in the model, we fed C57Bl/6 mice a standard dose of cuprizone (0.2% dry chemical to dry food weight) for six weeks then measured levels of copper, manganese, iron, and zinc in regions of the brain and visceral organs. As expected, this treatment induced demyelination in the mice. We found, however, that while the treatment significantly reduced copper concentrations in the blood and liver in treated animals, there was no significant difference in concentrations in brain regions relative to control. Interestingly, cuprizone disrupted concentrations of the other transition metals in the visceral organs, with the most notable changes being decreased manganese and increased iron in the liver. In the brain, manganese concentrations were also significantly reduced in the cerebellum and striatum. These data suggest a possible role of manganese deficiency in the brain in the cuprizone model.

Concepts: Iron, Aluminium, Metal, Zinc, Copper, Transition metals, Transition metal, Chromium

22

Neurodegenerative disorders including Parkinson’s disease (PD) are believed to be caused by oxidative stress and mitochondrial dysfunction. Exposure to environmental agents such as pesticides has been implicated in the etiology of sporadic PD. Paraquat (PQ), a widely used herbicide, induces PD symptoms in laboratory animals including Drosophila. PQ acts as a free radical generator and induces oxidative damage, which is implicated in neuronal cell death. Drosophila model of PQ-induced PD offers a convenient tool for mechanistic studies and, to assess the neuroprotective potential of natural antioxidants. We have investigated the neuroprotective potential of 4-Hydroxyisophthalic acid (DHA-I), a novel bioactive molecule from the roots of Decalepis hamiltonii, against PQ-induced locomotor impairment and neurodegeneration in Drosophila melanogaster. Our study shows that PQ treatment results in movement disorder associated with oxidative stress-mediated mitochondrial damage and neurodegeneration in the brain as evident by ultrastructural observations. Treatment with DHA-I markedly attenuated locomotor deficits, oxidative stress, mitochondrial damage, and neurodegenerative changes induced by PQ in Drosophila. Our results show that DHA-I could be a promising natural antioxidant and a neuroprotective molecule targeting oxidative stress-mediated mitochondrial dysfunction with therapeutic potential for neurodegenerative disorders.

Concepts: Antioxidant, Oxidative stress, Oxidative phosphorylation, Neurology, Radical, Neurodegenerative disorders, Parkinson's disease, Free-radical theory

15

Bisphenol A (BPA) is a widely recognized endocrine disruptor prevalent in many household items. Because experimental and epidemiological data suggest links between prenatal BPA exposure and altered affective behaviors in children, even at levels below the current US FDA No Observed Adverse Effect Level (NOAEL) of 5mg/kg body weight (bw)/day, there is concern that early life exposure may alter neurodevelopment. The current study was conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and examined the full amygdalar transcriptome on postnatal day (PND) 1, with the hypothesis that prenatal BPA exposure would alter the expression of genes and pathways fundamental to sex-specific affective behaviors. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (2.5, 25, 250, 2500, or 25000μg/kg bw/day), a reference estrogen (0.05 or 0.5μg ethinyl estradiol (EE2)/kg bw/day), or vehicle. PND 1 amygdalae were microdissected and gene expression was assessed with qRT-PCR (all exposure groups) and RNAseq (vehicle, 25 and 250μg BPA, and 0.5μg EE2 groups only). Our results demonstrate that that prenatal BPA exposure can disrupt the transcriptome of the neonate amygdala, at doses below the FDA NOAEL, in a sex-specific manner and indicate that the female amygdala may be more sensitive to BPA exposure during fetal development. We also provide additional evidence that developmental BPA exposure can interfere with estrogen, oxytocin, and vasopressin signaling pathways in the developing brain and alter signaling pathways critical for synaptic organization and transmission.

Concepts: Gene, Hypothalamus, Pregnancy, Gene expression, Developmental biology, Bisphenol A, Xenoestrogen, RNA splicing

10

Childhood developmental disorders and related problems such as learning disabilities and attention deficit hyperactivity disorder (ADHD) account for a growing burden on the family, education and health care systems. Exposure to environmental chemicals such as bisphenol A (BPA) and phthalates may play a role in the development of child behavioral problems. Using cross-sectional data from Cycle 1 of the Canadian Health Measures Survey (CHMS), we examined the potential association between urinary concentrations of BPA and various phthalate metabolites and child learning and behavioral problems, considering important covariates such as gender, blood lead and environmental tobacco smoke (ETS). The Strengths and Difficulties Questionnaire (SDQ) outcomes of interest were emotional symptoms, hyperactivity/inattention, and a total difficulties score with borderline and abnormal scores grouped together and compared with children with normal scores. Other outcomes studied included any reported learning disability, a subset of learning disabilities reported as ADD/ADHD (attention deficit disorder) and use of psychotropic medications in the past month. Among children ages 6-11 years, the prevalences of any learning disability, ADD, and ADHD were 8.7%, 1.5% and 2.8%, respectively. Estimated prevalences for SDQ hyperactivity/inattention, emotional symptoms and total difficulties scores were 16.9%, 15.0%, and 13.0%, respectively. Child’s urinary BPA was associated with taking psychotropic medications (OR 1.59; 95% CI 1.05-2.40). Urinary MBzP concentration was significantly associated with emotional symptoms in girls (OR 1.38 95% CI 1.09-1.75) but not in boys (OR 1.05 95% CI 0.82-1.36).) Blood lead was significantly associated with several of the outcomes examined, with a significant interaction observed between prenatal smoking and blood lead for the total difficulties score (OR=10.57; 95% CI 2.81-39.69 vs. OR=1.98; 95% CI 1.41-2.79 if mother did not smoke during pregnancy). Although limited by the cross-sectional nature of the study which precludes examining causation, the results suggest that although some indicators of child behavior were significantly associated with their urinary BPA and phthalate concentrations, the major chemical associated with adverse behavioral indicators was lead.

Concepts: Attention, Educational psychology, Attention-deficit hyperactivity disorder, Hyperactivity, ADHD predominantly inattentive, Methylphenidate, Learning disability

9

East Liverpool, Ohio, the site of a hazardous waste incinerator and a manganese (Mn) processor, has had air Mn concentrations exceeding United States Environmental Protection Agency reference levels for over a decade. Save Our County, Inc., a community organization, was formed to address community environmental health concerns related to local industry. Researchers from the University of Cincinnati partnered with Save Our County to determine if air Mn had an impact on the neurocognitive function of children in the community.

Concepts: Pollution, United States Environmental Protection Agency, Ohio River, Ohio, Hazardous waste, Environmental health, Cincinnati, University of Cincinnati

7

Multiple sclerosis (MS) is a chronic disease of the central nervous system with an unidentified etiology. We systematically reviewed the literature on the possible risk factors associated with MS disease onset, relapses and progression from 1960-2012 by accessing six databases and including relevant systematic reviews, meta-analyses, case-control or cohort studies. The focus was on identifying modifiable risk factors. Fifteen systematic reviews and 169 original articles were quality assessed and integrated into a descriptive review. Best evidence, which included one or more prospective studies, suggested that lower exposure to sunlight and/or lower serum vitamin D levels were associated with an increased risk of developing MS onset and subsequent relapses, but a similar quality of evidence was lacking for disease progression. Prospective studies indicated that cigarette smoking may increase the risk of MS as well as accelerate disease progression, but whether smoking altered the risk of a relapse was largely unknown. Infections were implicated in both risk of developing MS and relapses, but data for progression were lacking. Specifically, exposure to the Epstein-Barr virus, particularly if this manifested as infectious mononucleosis during adolescence, was associated with increased MS risk. Upper respiratory tract infections were most commonly associated with an increase in relapses. Relapse rates typically dropped during pregnancy, but there was no strong evidence to suggest that pregnancy itself altered the risk of MS or affected long-term progression. Emerging research with the greatest potential to impact public health was the suggestion that obesity during adolescence may increase the risk of MS; if confirmed, this would be of major significance.

Concepts: Nervous system, Vitamin D, Medicine, Epidemiology, Multiple sclerosis, Respiratory system, Meta-analysis, Upper respiratory tract infection

4

There is considerable discussion over the possible harm caused by fetal exposure to mercury, but evidence of such harm is contradictory at levels commonly found in populations with moderate intakes of fish. Further information is needed to inform debate and clarify policy recommendations.

Concepts: Debate