Multiple neurological effects associated with exposure to organophosphorus pesticides in man.

This article reviews available data regarding the possible association of organophosphorus (OP) pesticides with neurological disorders such as dementia, attention deficit hyperactivity disorder, neurodevelopment, autism, cognitive development, Parkinson's disease and chronic organophosphate-induced neuropsychiatric disorder. These effects mainly develop after repeated (chronic) human exposure to low doses of OP. In addition, three well defined neurotoxic effects in humans caused by single doses of OP compounds are discussed. Those effects are the cholinergic syndrome, the intermediate syndrome and organophosphate-induced delayed polyneuropathy. Usually, the poisoning can be avoided by an improved administrative control, limited access to OP pesticides, efficient measures of personal protection and education of OP pesticide applicators and medical staff.

Distinct dose-dependent effects of methamphetamine on real-time dopamine transmission in the rat nucleus accumbens and behaviors.

Methamphetamine (METH) is a potent psychostimulant that exerts many of its physiological and psychomotor effects by increasing extracellular dopamine (DA) concentrations in limbic brain regions. While several studies have focused on how potent, neurotoxic doses of METH augment or attenuate DA transmission, the acute effects of lower and behaviorally activating doses of METH on modulating DA regulation (release and clearance) through DA D2 autoreceptors and transporters remain to be elucidated. In this study, we investigated how systemic administration of escalating, subneurotoxic doses of METH (0.5-5 mg/kg, IP) alter extracellular DA regulation in the nucleus accumbens (NAc), in both anesthetized and awake-behaving rats through the use of in vivo fast-scan cyclic voltammetry. Pharmacological, electrochemical, and behavioral evidence show that lower doses (≤2.0 mg/kg, IP) of METH enhance extracellular phasic DA concentrations and locomotion as well as stereotypies. In contrast, higher doses (≥5.0 mg/kg) further increase both phasic and baseline DA concentrations and stereotypies but decrease horizontal locomotion. Importantly, our results suggest that acute METH-induced enhancement of extracellular DA concentrations dose dependently activates D2 autoreceptors. Therefore, these different METH dose-dependent effects on mesolimbic DA transmission may distinctly impact METH-induced behavioral changes. This study provides valuable insights regarding how low METH doses alter DA transmission and paves the way for future clinical studies on the reinforcing effects of METH.

Effects of long-term low dose saxitoxin exposure on nerve damage in mice.

Saxitoxin (STX), as a type of paralytic shellfish poisoning (PSP), is gaining widespread attention due to its long existence in edible shellfish. However, the mechanism underlying STX chronic exposure-induced effect is not well understood. Here, we evaluated the neurotoxicity effects of long-term low-dose STX exposure on C57/BL mice by behavioral tests, pathology analysis, and hippocampal proteomics analysis. Several behavioral tests showed that mice were in a cognitive deficiency after treated with 0, 0.5, 1.5, or 4.5 µg STX equivalents/kg body weight in the drinking water for 3 months. Compared with control mice, STX-exposed mice exhibited brain neuronal damage characterized by decreasing neuronal cells and thinner pyramidal cell layers in the hippocampal CA1 region. A total of 29 proteins were significantly altered in different STX dose groups. Bioinformatics analysis showed that protein phosphatase 1 (Ppp1c) and arylsulfatase A (Arsa) were involved in the hippo signaling pathway and sphingolipid metabolism pathway. The decreased expression of Arsa indicates that long-term low doses of STX exposure can cause neuronal inhibition, which is a process related to spatial memory impairment. Taken together, our study provides a new understanding of the molecular mechanisms of STX neurotoxicity.

Cognitive changes after methanol exposure: Longitudinal perspective.

BACKGROUND: From 2012 to 2013, there was a mass methanol poisoning outbreak in the Czech Republic. Methanol metabolites can cause specific lesions in the basal ganglia, subcortical white matter, and optic nerve. However, long-term sequelae of methanol poisoning on cognitive functioning have not yet been explored. The current study aimed to delineate the cognitive changes observed in methanol poisoning survivors in the seven years since 2012. METHODS: We conducted longitudinal research with repeated measurements in 2013, 2015, 2017 and 2019 to evaluate the development of cognitive changes after acute methanol poisoning. A complex neuropsychological battery consisted of tests of global cognitive performance, auditory and visual attention, executive functioning, learning and memory, working memory and language. Motor performance measures and depression scale were also included. RESULTS: Repeated measures ANOVA of four measurements with post-hoc tests showed a significant decline in the Mini-Mental State Examination (p = 0.007); however, other parameters were not significantly decreasing. In comparison to normative values, the z-scores for each test measure, in the memory domain, in particular, ranged from 43 to 60 % of participants below 1.5 SD. Mild to severe depression levels from the onset of poisoning improved during the seven years, returning to normal in up to 27 % of participants. CONCLUSION: In the longitudinal perspective, methanol poisoning survivors manifest progressive global cognitive decline and overall persistent below-average cognitive performance with some improvements in the frequency of depressive symptoms.

The preferences of women with ovarian cancer for oral versus intravenous recurrence regimens.

OBJECTIVE: To assess preferences of women with ovarian cancer regarding features of available anti-cancer regimens for platinum-resistant, biomarker-positive disease, with an emphasis on oral PARP inhibitor and standard intravenous (IV) chemotherapy regimens. METHODS: A discrete-choice-experiment preferences survey was designed, tested, and administered to women with ovarian cancer, with 11 pairs of treatment profiles defined using seven attributes (levels/ranges): regimen (oral daily, IV weekly, IV monthly); probability of progression-free (PFS) at 6 months (40%-60%); probability of PFS at 2 years (10%-20%); nausea (none, moderate); peripheral neuropathy (none, mild, moderate); memory problems (none, mild); and total out-of-pocket cost ($0 to $10,000). RESULTS: Of 123 participants, 38% had experienced recurrence, 25% were currently receiving chemotherapy, and 18% were currently taking a PARP inhibitor. Given attributes and levels, the relative importance weights (sum 100) were: 2-year PFS, 28; cost, 27; 6-month PFS, 19; neuropathy,14; memory problems, nausea, and regimen, all ≤5. To accept moderate neuropathy, participants required a 49% (versus 40%) chance of PFS at 6 months or 14% (versus 10%) chance at 2 years. Given a 3-way choice where PFS and cost were equal, 49% preferred a monthly IV regimen causing mild memory problems, 47% preferred an oral regimen causing moderate nausea, and 4% preferred a weekly IV regimen causing mild memory and mild neuropathy. CONCLUSIONS: These findings challenge the assumption that oral anti-cancer therapies are universally preferred by patients and demonstrate that there is no "one size fits all" regimen that is preferable to women with ovarian cancer when considering recurrence treatment regimens.

Folic acid supplementation rescues valproic acid-induced developmental neurotoxicity and behavioral alterations in zebrafish embryos.

OBJECTIVE: Fetal exposure to the anticonvulsant drug valproic acid (VPA), used to treat certain types of epilepsy, increases the risk for birth defects, including neural tube defects, as well as learning difficulties and behavioral problems. Here, we investigated neurotoxic effects of VPA exposure using zebrafish as a model organism. The capacity of folic acid (FA) supplementation to rescue the VPA-induced neuronal and behavioral perturbations was also examined. METHODS: Zebrafish embryos of different transgenic lines with neuronal green fluorescent protein expression were exposed to increasing concentrations of VPA with or without FA supplementation. Fluorescence microscopy was used to visualize alterations in brain structures and neural progenitor cells, as well as motor neurons and neurite sprouting. A twitching behavioral assay was used to examine the functional consequences of VPA and FA treatment. RESULTS: In zebrafish embryos, VPA exposure caused a decrease in the midbrain size, an increase in the midline gap of the hindbrain, and perturbed neurite sprouting of secondary motor neurons, in a concentration-dependent manner. VPA exposure also decreased the fluorescence intensity of neuronal progenitor cells in early developmental stages, indicating fewer cells. Furthermore, VPA exposure significantly altered embryonic twitching activity, causing hyperactivity in dark and hypoactivity in light. Supplementation of FA rescued the VPA-induced smaller midbrain size and hindbrain midline gap defects. FA treatment also increased the number of neuronal progenitor cells in VPA-treated embryos and salvaged neurite sprouting of the secondary motor neurons. FA rescued the VPA-induced alterations in twitching activity in light but not in dark. SIGNIFICANCE: We conclude that VPA exposure induces specific neurotoxic perturbations in developing zebrafish embryos, and that FA reversed most of the identified defects. The results demonstrate that zebrafish is a promising model to study VPA-induced teratogenesis and to screen for countermeasures.

Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis.

BACKGROUND: The US Food and Drug Administration warned that exposure of pregnant women to general anaesthetics may impair fetal brain development. This review systematically evaluates the evidence underlying this warning. METHODS: PubMed, EMBASE, and Web of Science were searched from inception until April 3, 2020. Preclinical and clinical studies were eligible. Exclusion criteria included case reports, in vitro models, chronic exposures, and exposure only during delivery. Meta-analyses were performed on standardised mean differences. The primary outcome was overall effect on learning/memory. Secondary outcomes included markers of neuronal injury (apoptosis, synapse formation, neurone density, and proliferation) and subgroup analyses. RESULTS: There were 65 preclinical studies included, whereas no clinical studies could be identified. Anaesthesia during pregnancy impaired learning and memory (standardised mean difference -1.16, 95% confidence interval -1.46 to -0.85) and resulted in neuronal injury in all experimental models, irrespective of the anaesthetic drugs and timing in pregnancy. Risk of bias was high in most studies. Rodents were the most frequently used animal species, although their brain development differs significantly from that in humans. In a minority of studies, anaesthesia was combined with surgery. Monitoring and strict control of physiological homeostasis were below preclinical and clinical standards in many studies. The duration and frequency of exposure and anaesthetic doses were often much higher than in clinical routine. CONCLUSION: Anaesthesia-induced neurotoxicity during pregnancy is a consistent finding in preclinical studies, but translation of these results to the clinical situation is limited by several factors. Clinical observational studies are needed. PROSPERO REGISTRATION NUMBER: CRD42018115194.

Administration of Selenium Nanoparticles Reverses Streptozotocin-Induced Neurotoxicity in the male rats.

Alzheimer's disease is the most common neurodegenerative disease associated with deposition of amyloid-beta and the increased oxidative stress. High free radical scavenging ability of selenium nanoparticles (SeNPs) has been acknowledged, so in the present study, the effects of treatment with SeNPs on Streptozotocin (STZ)-induced neurotoxicity were evaluated in the male rats. Learning and memory impairment was induced by intraventricular injection of STZ. Following induction of memory impairment, the rats received 0.4 mg/kg of SeNPs daily for one month. Memory function, antioxidant capacity, and deposition of Amyloid ß (Aß) were assessed using the shuttle box task, biochemical methods, and Congo red staining. Injection of STZ caused memory impairment, a decrease in the level of total thiol group (TTG), and an increase in the malondialdehyde (MDA) content and deposition of Aß. Administration of SeNPs reversed the neurotoxicity induced by STZ. It seems that SeNPs likely had neuroprotective effects on the animal model of Alzheimer's disease through increasing antioxidants҆ capacity.

Emerging mechanisms of valproic acid-induced neurotoxic events in autism and its implications for pharmacological treatment.

Autism spectrum disorder (ASD) is a sort of mental disorder marked by deficits in cognitive and communication abilities. To date no effective cure for this pernicious disease has been available. Valproic acid (VPA) is a broad-spectrum, antiepileptic drug, and it is also a potent teratogen. Epidemiological studies have shown that children exposed to VPA are at higher risk for ASD during the first trimester of their gestational development. Several animal and human studies have demonstrated important behavioral impairments and morphological changes in the brain following VPA treatment. However, the mechanism of VPA exposure-induced ASD remains unclear. Several factors are involved in the pathological phase of ASD, including aberrant excitation/inhibition of synaptic transmission, neuroinflammation, diminished neurogenesis, oxidative stress, etc. In this review, we aim to outline the current knowledge of the critical pathophysiological mechanisms underlying VPA exposure-induced ASD. This review will give insight toward understanding the complex nature of VPA-induced neuronal toxicity and exploring a new path toward the development of novel pharmacological treatment against ASD.

Behavioural impairments after exposure of neonatal mice to propofol are accompanied by reductions in neuronal activity in cortical circuitry.

BACKGROUND: Both animal and retrospective human studies have linked extended and repeated general anaesthesia during early development with cognitive and behavioural deficits later in life. However, the neuronal circuit mechanisms underlying this anaesthesia-induced behavioural impairment are poorly understood. METHODS: Neonatal mice were administered one or three doses of propofol, a commonly used i.v. general anaesthetic, over Postnatal days 7-11. Control mice received Intralipid® vehicle injections. At 4 months of age, the mice were subjected to a series of behavioural tests, including motor learning. During the process of motor learning, calcium activity of pyramidal neurones and three classes of inhibitory interneurones in the primary motor cortex were examined in vivo using two-photon microscopy. RESULTS: Repeated, but not a single, exposure of neonatal mice to propofol i.p. caused motor learning impairment in adulthood, which was accompanied by a reduction of pyramidal neurone number and activity in the motor cortex. The activity of local inhibitory interneurone networks was also altered: somatostatin-expressing and parvalbumin-expressing interneurones were hypoactive, whereas vasoactive intestinal peptide-expressing interneurones were hyperactive when the mice were performing a motor learning task. Administration of low-dose pentylenetetrazol to attenuate γ-aminobutyric acid A receptor-mediated inhibition or CX546 to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-subtype glutamate receptor function during emergence from anaesthesia ameliorated neuronal dysfunction in the cortex and prevented long-term behavioural deficits. CONCLUSIONS: Repeated exposure of neonatal mice to propofol anaesthesia during early development causes cortical circuit dysfunction and behavioural impairments in later life. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia.

Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses.

For thousands of years, Cannabis sativa has been utilized as a medicine and for recreational and spiritual purposes. Phytocannabinoids are a family of compounds that are found in the cannabis plant, which is known for its psychotogenic and euphoric effects; the main psychotropic constituent of cannabis is Δ9-tetrahydrocannabinol (Δ9-THC). The pharmacological effects of cannabinoids are a result of interactions between those compounds and cannabinoid receptors, CB1 and CB2, located in many parts of the human body. Cannabis is used as a therapeutic agent for treating pain and emesis. Some cannabinoids are clinically applied for treating chronic pain, particularly cancer and multiple sclerosis-associated pain, for appetite stimulation and anti-emesis in HIV/AIDS and cancer patients, and for spasticity treatment in multiple sclerosis and epilepsy patients. Medical cannabis varies from recreational cannabis in the chemical content of THC and cannabidiol (CBD), modes of administration, and safety. Despite the therapeutic effects of cannabis, exposure to high concentrations of THC, the main compound that is responsible for most of the intoxicating effects experienced by users, could lead to psychological events and adverse effects that affect almost all body systems, such as neurological (dizziness, drowsiness, seizures, coma, and others), ophthalmological (mydriasis and conjunctival hyperemia), cardiovascular (tachycardia and arterial hypertension), and gastrointestinal (nausea, vomiting, and thirst), mainly associated with recreational use. Cannabis toxicity in children is more concerning and can cause serious adverse effects such as acute neurological symptoms (stupor), lethargy, seizures, and even coma. More countries are legalizing the commercial production and sale of cannabis for medicinal use, and some for recreational use as well. Liberalization of cannabis laws has led to increased incidence of toxicity, hyperemesis syndrome, lung disease cardiovascular disease, reduced fertility, tolerance, and dependence with chronic prolonged use. This review focuses on the potential therapeutic effects of cannabis and cannabinoids, as well as the acute and chronic toxic effects of cannabis use on various body systems.

Effects of Chemotherapy-Induced Peripheral Neuropathy in Women With Breast Cancer: A Structural Equation Approach With the Theory of Unpleasant Symptoms.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurotoxic effect. Chemotherapy-induced peripheral neuropathy symptoms have multidimensional characteristics that are associated with various physiologic, psychological, and situational factors and affect individual's abilities to effectively function in performing daily tasks. The theory of unpleasant symptoms mediates the relationships among CIPN symptom experience, reduced performance in daily tasks, and causative factors. OBJECTIVES: The aim of this study was to examine how influencing factors (physiologic, psychological, and situational) affect CIPN symptoms and the impact of symptom experience on functional interference in daily activities of chemotherapy-treated breast cancer survivors. METHODS: A cross-sectional survey about causative factors, CIPN symptoms, and functional interference was completed by 190 women treated with adjuvant chemotherapy for nonmetastatic breast cancer. The hypothetical model was tested using structural equation modeling analysis. RESULTS: The proposed model provided a good fit to the data. Physiologic and psychological factors accounted for 25.5% of the variance in CIPN symptom experience and explained 37.1% of the variance interfering with functional performance through CIPN symptom experience. CONCLUSION: Disease- and treatment-related physiologic factors and coexisting psychological distress play crucial roles in explaining CIPN symptom experience and daily function in breast cancer survivors. IMPLICATIONS FOR PRACTICE: The findings help healthcare professionals to improve long-term care for breast cancer survivors in terms of education for self-monitoring, coping, and establishing supportive environment that can contribute to reducing the unmet needs and interference associated with persistent CIPN.

Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis.

BACKGROUND: Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear. METHODS: PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses. RESULTS: Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0-3.7], P=0.001; CBCL externalising: 1.9 [95% CI: 0.7-3.1], P=0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9-3.5], P=0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08-2.02; P=0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23-2.30; P=0.001). CONCLUSIONS: Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence.

Brain biomarkers and neuropsychological outcomes of pediatric posterior fossa brain tumor survivors treated with surgical resection with or without adjuvant chemotherapy.

PURPOSE: Children with brain tumors experience cognitive late effects, often related to cranial radiation. We sought to determine differential effects of surgery and chemotherapy on brain structure and neuropsychological outcomes in children who did not receive cranial radiation therapy (CRT). METHODS: Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery, 11 treated with surgery and chemotherapy) underwent neuroimaging and neuropsychological assessment a mean of 4.5 years (surgery group) to 9 years (surgery + chemotherapy group) posttreatment, along with 18 healthy sibling controls. Psychometric measures assessed IQ, language, executive functions, processing speed, memory, and social-emotional functioning. Group differences and correlations between diffusion tensor imaging findings and psychometric scores were examined. RESULTS: The z-score mapping demonstrated fractional anisotropy (FA) values were ≥2 standard deviations lower in white matter tracts, prefrontal cortex gray matter, hippocampus, thalamus, basal ganglia, and pons between patient groups, indicating microstructural damage associated with chemotherapy. Patients scored lower than controls on visuoconstructional reasoning and memory (P ≤ .02). Lower FA in the uncinate fasciculus (R = -0.82 to -0.91) and higher FA in the thalamus (R = 0.73-0.91) associated with higher IQ scores, and higher FA in the thalamus associated with higher scores on spatial working memory (R = 0.82). CONCLUSIONS: Posterior fossa brain tumor treatment with surgery and chemotherapy affects brain microstructure and neuropsychological functioning years into survivorship, with spatial processes the most vulnerable. Biomarkers indicating cellular changes in the thalamus, hippocampus, pons, prefrontal cortex, and white matter tracts associate with lower psychometric scores.

Evaluation of the dentate gyrus in adult mice exposed to acetaminophen (paracetamol) on postnatal day 10.

Acetaminophen (AAP; or paracetamol) is a widely used nonprescription drug with antipyretic and analgesic properties. Alarmingly, there is an increasing body of evidence showing that developmental exposure to AAP is associated with adverse behavioural outcomes later in life. We have previously shown that relevant doses of AAP in 10-day-old mice affected memory, learning and locomotor activity in the adult animals. Interestingly, the neurons of the dentate gyrus (DG) have a relatively late time of origin as they are generated during the first two weeks of postnatal life in rodents. Since the generation of these cells, which are important for memory processing, coincides with our AAP exposure, we aim to investigate if the cytoarchitecture of the DG is affected by postnatal day 10 AAP treatment. In addition, we investigate if markers for differentiation and migration in the hippocampus were affected by the same treatment. We did not observe any visual effects in adult DG cytoarchitecture, nor any changes of markers for differentiation/migration in the hippocampus in 24 hr after exposure. Even though a large effect size was estimated on adult DG thickness following AAP exposure, the estimated 95% CIs around the differences of the means reveal no significant effect. Hence, larger sample sizes are warranted to clarify if neonatal AAP exposure affects adult DG thickness in mice.

Infant isoflurane exposure affects social behaviours, but does not impair specific cognitive domains in juvenile non-human primates.

BACKGROUND: Clinical studies show that children exposed to anaesthetics for short times at young age perform normally on intelligence tests, but display altered social behaviours. In non-human primates (NHPs), infant anaesthesia exposure for several hours causes neurobehavioural impairments, including delayed motor reflex development and increased anxiety-related behaviours assessed by provoked response testing. However, the effects of anaesthesia on spontaneous social behaviours in juvenile NHPs have not been investigated. We hypothesised that multiple, but not single, 5 h isoflurane exposures in infant NHPs are associated with impairments in specific cognitive domains and altered social behaviours at juvenile age. METHODS: Eight Rhesus macaques per group were anaesthetised for 5 h using isoflurane one (1×) or three (3×) times between postnatal days 6 and 12 or were exposed to room air (control). Cognitive testing, behavioural assessments in the home environment, and provoked response testing were performed during the first 2 yr of life. RESULTS: The cognitive functions tested did not differ amongst groups. However, compared to controls, NHPs in the 3× group showed less close social behaviour (P=0.016), and NHPs in the 1× group displayed increased anxiety-related behaviours (P=0.038) and were more inhibited towards novel objects (P<0.001). CONCLUSIONS: 5 h exposures of NHPs to isoflurane during infancy are associated with decreased close social behaviour after multiple exposures and more anxiety-related behaviours and increased behavioural inhibition after single exposure, but they do not affect the cognitive domains tested. Our findings are consistent with behavioural alterations in social settings reported in clinical studies, which may guide future research.

Phosphodiesterase 2 inhibitor Hcyb1 reverses corticosterone-induced neurotoxicity and depression-like behavior.

RATIONALE: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 inhibitor Bay 60-7550. OBJECTIVES: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice. METHODS: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice. RESULTS: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA inhibitor H89 or the PKG inhibitor KT5823. Moreover, Hcyb1 reversed acute stress-induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823. CONCLUSION: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling.

Associations of the Behavioral Assessment and Research System (BARS) neurobehavioral outcomes with attention problems in children living near coal ash storage sites.

Environmental exposures have been linked to childhood problems with overactivity, attention, and impulse control, and an increased risk of attention deficit hyperactivity disorder (ADHD) diagnosis. Two approaches to identify these types of exposure-related neurobehavioral problems include the use of computerized tests, such as the Behavioral Assessment and Research System (BARS), as well as the use of behavior rating scales. To assess comparability of these two types of measures, we analyzed data from 281 children aged 6 to 14 years enrolled in a 5-year research study investigating coal ash exposure and neurobehavioral health. All children lived in proximity of coal ash storage sites. We administered six computer tests from the BARS and obtained behavior measures from the parent-completed Child Behavior Checklist (CBCL) ADHD DSM oriented scale. BARS test performance was associated with age indicating that the tests could be used to evaluate neurodevelopmental changes over time or across a wide age range. Tests within the BARS including Continuous Performance (CPT) false alarm (standardized estimate 1.57, 95% confidence interval (CI) (0.67, 2.48), adjusted p = 0.006), Selective Attention (SAT) wrong count (standardized estimate 2.8, 95% CI (1.17, 4.44), adjusted p = 0.006), and SAT proportion correct (standardized estimate -2.45, 95% CI (-4.01, -0.88), adjusted p = 0.01) were associated with attention and impulse control problems on the CBCL after adjustment for multiple comparisons. Findings support that the BARS can contribute to research on environmental exposures by assessing subclinical behaviors related to ADHD such as sustained attention, impulse control, response inhibition, associative learning, and short-term memory. Future research can examine relationships of these BARS measures with biomarkers of neurotoxic exposures related to living near coal ash storage sites to better identify the potential risk for ADHD-related behaviors among children living near coal ash storage sites.

The neuroprotective effect of curcumin against Cd-induced neurotoxicity and hippocampal neurogenesis promotion through CREB-BDNF signaling pathway.

Heavy metal neurotoxicity is one of the major challenges in today's era due to the large scale and widespread mechanisation of the production. However, the causative factors responsible for neurotoxicity are neither known nor do we have the availability of therapeutic approaches to deal with it. One of the major causative agents of neurotoxicity is a non-essential transition heavy metal, Cadmium (Cd), that reaches the central nervous system (CNS) through the nasal mucosa and olfactory pathway causing adverse structural and functional effects. In this study, we explored the neuroprotective efficacy of plant derived Curcumin which is reported to have pleiotropic biological activity including anti-oxidant, anti-inflammatory, anti-apoptotic, anti-carcinogenic and anti-angiogenic effects. Four different concentrations of curcumin (20, 40, 80 and 160 mg/kg of the body weight) were used to assess the behavioural, biochemical, hippocampal proteins (BDNF, CREB, DCX and Synapsin II) and histological changes in Swiss Albino mice that were pre-treated with Cd (2.5 mg/kg). The findings showed that Cd exposure led to the behavioural impairment through oxidative stress, reduction of hippocampal neurogenesis associated proteins, and degeneration of CA3 and cortical neurons. However, treatment of different curcumin concentrations had effectively restored the behavioural changes in Cd-exposed mice through regulation of oxidative stress and up-regulation of hippocampal proteins in a dose-dependent manner. Significantly, a dose of 160 mg/kg body weight was found to be glaringly effective. From this study, we infer that curcumin reverses the adverse effects of neurotoxicity induced by Cd and promotes neurogenesis.

Ertapenem-induced encephalopathy.

Neurotoxicity is an unusual side effect of carbapenems, and it has been reported most commonly presenting as seizures, encephalopathy and hallucinations. Ertapenem neurotoxicity most classically presents as seizures in patients with end-stage renal disease (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2). We present a patient with a baseline eGFR of 30-59 mL/min/1.73 m2 with acute kidney injury who developed non-seizure neurotoxicity after ertapenem exposure. This patient is a middle-aged Caucasian man who received intravenous ertapenem for treatment of empyema. Although the empyema improved, he developed delirium beginning on day 7 of ertapenem. The delirium progressed to constant agitation and visual hallucinations requiring transfer to the intensive care unit with eventual intubation for airway protection. No improvement in mental status was observed with cessation of other medications. Ertapenem was discontinued and within 24 hours, he was extubated, and his mental status returned to baseline. He was discharged from the hospital the following day. The timely resolution after ertapenem discontinuation makes ertapenem-induced encephalopathy the most likely explanation for this patient's course.