Neurobehavioral Effects Research Articles

Nigella sativa Oil Preserved Anxiety-Like, Motor and Memory Related Behaviours and Neuronal Integrity in Dichlorvos Induced Acetyl Cholinesterase Inhibitions in Rats

Organophosphates are irreversible cholinesterase (ChE) inhibitors with neurological consequences, and there is not yet an effective antidote. Here, we investigated the effects of Nigella sativa oil (NSO) on the ChE inhibition, neurobehavioural and histopathological changes following dichlorvos (DDVP) ingestions in rats. Thirty-two male Wistar rats were randomised into four groups, receiving 1 ml/kg of normal saline, 8.8 mg/kg of DDVP, 8.8 mg/kg of DDVP and 1 ml/kg of NSO, and 1 ml/kg of NSO only respectively, for 14 consecutive days. Locomotor, anxiety-like behaviours and spatial working memory were assessed on the 14th day, using open field (OF), Y-maze and modified elevated plus maze paradigms. The rats were euthanized on the 15th day and the brains excised; three brains were fixed for histopathology, and the other five prepared for biochemical analysis of acetyl cholinesterase (AChE). DDVP exposure caused significant reductions in frontal, amygdala and cerebella AChE activity, spontaneous alternations, line crossing and rearing frequencies and time in centre square, and caused increase in freezing period, transfer latency and necrotic-like cells. NSO intervention was able to reverse DDVP effects on AChE activities, explorative, locomotor, anxiety and spatial memory behaviours in co-exposed rats. It also preserved the histological integrity of the investigated brain regions. It can be concluded that NSO, may be potent against organophosphates induced neurotoxicity and their neurobehavioural consequences through the modulation of AChE activities.

The Activities of the Central Nervous System Following Ethyl Acetate Extract of Mucuna pruriens Seed Administration in Male BALB/c Mice

A number of reports showed the beneficial psychotropic effects of many of the Nigerian medicinal plants, but few scientific studies have been carried out as empirical evidence. This study investigated the possible neurobehavioural effects of ethyl acetate extract of Mucuna pruriens (MP) seed in male BALB/c mice. Male BALB/c mice (2½-3 months old) were grouped into 5 (n=6), treated with normal saline (0.1 mL), n-propanol extract of MP (200, 100, 50 mg/kg) or reference drug haloperidol (HP) or diazepam (DZP); thereafter, subjected to diverse behavioural models to evaluate the central nervous system (CNS) effects of the extract. A bolus of MP (200, 100, and 50 mg/kg) decreased the rectal temperature, exploratory activities (locomotion, rearing and grooming), anxiety-like responses (% open-arms time, open-arm entries, and the total number of enclosed arms times). Additionally, a one-shot of intraperitoneal administration of MP decimated the total score of apomorphine-induced stereotyped behaviours. Latency to hexobarbitone-induced sleep increased significantly in the 200 mg/kg MP, unchanged in the 100 mg/kg MP, and decreased in the 50 mg/kg MP treated groups. There was a marked decrease in the markers of convulsion (tonic flexion, extension, clonic convulsion, stupor, and recovery time) following MP treatment, especially the higher doses (200 mg/kg and 100 mg/kg). In conclusion, the CNS effects of systemic administration of MP seed are not unrelated to its hypothermic, hypnotic, anxiolytic, and anticonvulsant effects.

Morphine Perinatal Exposure Induces Long-Lasting Negative Emotional States in Adult Offspring Rodents.

Psychoactive substances during pregnancy and lactation is a key problem in contemporary society, causing social, economic, and health disturbance. In 2010, about 30 million people used opioid analgesics for non-therapeutic purposes, and the prevalence of opioids use during pregnancy ranged from 1% to 21%, representing a public health problem. This study aimed to evaluate the long-lasting neurobehavioral and nociceptive consequences in adult offspring rats and mice exposed to morphine during intrauterine/lactation periods. Pregnant rats and mice were exposed subcutaneously to morphine (10 mg/kg/day) during 42 consecutive days (from the first day of pregnancy until the last day of lactation). Offspring were weighed on post-natal days (PND) 1, 5, 10, 15, 20, 30, and 60, and behavioral tasks (experiment 1) or nociceptive responses (experiment 2) were assessed at 75 days of age (adult life). Morphine-exposed female rats displayed increased spontaneous locomotor activity. More importantly, both males and female rats perinatally exposed to morphine displayed anxiety- and depressive-like behaviors. Morphine-exposed mice presented alterations in the nociceptive responses on the writhing test. This study showed that sex difference plays a role in pain threshold and that deleterious effects of morphine during pre/perinatal periods are nonrepairable in adulthood, which highlights the long-lasting clinical consequences related to anxiety, depression, and nociceptive disorders in adulthood followed by intrauterine and lactation morphine exposure.

Phenotypic and transcriptomic effects of developmental exposure to nanomolar levels of pesticides in zebrafish

This study investigates the pesticides atrazine, chlorpyrifos, and dieldrin for endocrine disrupting, phenotypic, and neurobehavioral effects. Zebrafish embryos were exposed to various environmentally relevant concentrations of pesticides during two critical windows, 0-5 days post fertilization (dpf) throughout embryogenesis and 4-5 dpf at early larval development. The toxicity of each chemical and concentration was then determined by evaluating developmental abnormalities, behavioral alterations, and transcriptomic changes. We found the most significant outcomes resulted from dieldrin exposures as low as 1 nM at 0-5 dpf, or 0.1 nM at 4−5 dpf, including abnormalities in skeleton, swim bladder, and yolk sec, as well as hyperactive behavioral phenotypes. Following dieldrin exposures at higher concentrations, 100 nM at 0-5 dpf and 1000 nM at 4−5 dpf, we observed startle movements at the transition between light and dark stimulus. The transcriptomic changes of high-level dieldrin exposures (1000 nM) implicated movement or seizure disorders. Atrazine at concentrations equal or above 100 nM led to underinflated swim bladders following exposure at 0-5 dpf. Both atrazine exposure paradigms showed transcriptomic changes related to neurological disorders and breast cancer. All chlorpyrifos exposures showed no significant morphological abnormalities and the fewest differentially expressed genes, suggesting chlorpyrifos at 0.01-100 nM exhibited the lowest toxicity among these three pesticides.

Neurobehavioral effects of chronic low-dose vanadium administration in young male rats

Exposure to the metal vanadium, in both animals and humans has been linked to various physiological consequences including respiratory and gastrointestinal conditions. Research on the neurobehavioral effects of vanadium exposure is limited. Hence, the purpose of the current study was to examine the effects of chronic low-dose vanadium administration (0.04 mg/week) on the behavior of young male rats. Four weeks following the administration of vanadium, rats were tested on the open field, object recognition, and Morris Water maze tasks. Vanadium did not affect exploration, locomotion, or anxiety-like behavior as measured by the open field task. Vanadium administration affected novel object recognition performance. Intriguingly, rats exposed to vanadium exhibited lower latency times on day 2 of the Morris Water maze. These findings suggest that vanadium’s behavioral effects are complex and warrant further investigation to better understand the potential benefits and consequences of its exposure.

Integrated multi-omics analysis reveals the underlying molecular mechanism for developmental neurotoxicity of perfluorooctanesulfonic acid in zebrafish.

Limited studies on multi-omics have been conducted to comprehensively investigate the molecular mechanism underlying the developmental neurotoxicity of perfluorooctanesulfonic acid (PFOS). In this study, the locomotor behavior of zebrafish larvae was assessed under the exposure to 0.1-20μM PFOS based on its reported neurobehavioral effect. After the number of zebrafish larvae was optimized for proteomics and metabolomics studies, three kinds of omics (i.e., transcriptomics, proteomics, and metabolomics) were carried out with zebrafish larvae exposed to 0.1, 1, 5, and 10μM PFOS. More importantly, a data-driven integration of multi-omics was performed to elucidate the toxicity mechanism involved in developmental neurotoxicity. In a concentration-dependent manner, exposure to PFOS provoked hyperactivity and hypoactivity under light and dark conditions, respectively. Individual omics revealed that PFOS exposure caused perturbations in the pathways of neurological function, oxidative stress, and energy metabolism. Integrated omics implied that there were decisive pathways for axonal deformation, neuroinflammatory stimulation, and dysregulation of calcium ion signaling, which are more clearly specified for neurotoxicity. Overall, our findings broaden the molecular understanding of the developmental neurotoxicity of PFOS, for which multi-omics and integrated omics analyses are efficient for discovering the significant molecular pathways related to developmental neurotoxicity in zebrafish.

Abstract P257: Preclinical data identifies bezuclastinib as a differentiated KIT inhibitor with unique selectivity to KIT D816V and minimal evidence of brain penetration

Abstract KIT is a well characterized oncogenic driver of gastro-intestinal stromal tumors (GIST) and systemic mastocytosis (SM), and targeted therapeutics have offered valuable treatment options for these patients. Durable responses in imatinib-resistant GIST are rarely achieved due to secondary mutations that occur in exons 13/14 and 17/18. Exon 13/14 mutations can be addressed with sunitinib treatment, but identifying inhibitors that additionally target exon 17/18 mutations without incurring off-target toxicities related to broad-spectrum kinase inhibition has been challenging. Similarly, agents targeting KIT D816V mutations have shown activity in the treatment of advanced SM, but toxicities such as cognitive effects and intracranial hemorrhage may limit dosing and availability of these therapies. Bezuclastinib (CGT9486) was designed to inhibit exon 17/18 KIT mutations (including KIT D816V) with selectivity versus other closely-related kinases with known liabilities, such as PDGFRα, PDGFRβ, KIT wt, VEGFR2 (KDR), and CSF1R (FMS). Herein, we are presenting results from cell-based kinase profiling assays, which demonstrate that bezuclastinib has a significant and unique selectivity to KIT D816V vs. these aforementioned kinases when tested head-to-head against other clinically relevant compounds in GIST or SM. Additionally, a similar selectivity profile was observed for a broader panel of kinases, ion channels, transporters, and enzymes, which will be presented here. Importantly, we also show that bezuclastinib has minimal brain penetration. In a tissue distribution study performed in rats, bezuclastinib shows a brain:plasma ratio <0.1 following 3 day administration at 25 mg/kg, a dose that closely correlates with clinical exposure. This was supported functionally by assessing neurobehavioral effects of bezuclastinib at dose levels up to 100 mg/kg which showed no CNS related effects. Minimal brain penetration is a preferred feature of an anti-Kit molecule due to CNS-related adverse events observed in these indications. This attractive selectivity and nonclinical safety profile, combined with early clinical data (1) in advanced solid tumors, supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM with additional clinical studies planned in non-advanced SM and imatinib-resistant GIST. 1. Jonathan Trent, William D. Tap, Rashmi Chugh, Gabriel Tinoco, Athanasios Tsiatis, Paul Severson, Kerry Inokuchi, Chao Zhang, Glenn Michelson, Andrew J. Wagner. The Potent and Selective KIT Inhibitor PLX9486 Dosed in Combination With Sunitinib Demonstrates Promising Progression Free Survival (PFS) in Patients With Advanced Gastrointestinal Stromal Tumor (GIST): Final Results of a Phase 1/2 Study. Abstract Presented at the Connective Tissue Oncology Society Virtual Meeting; November 20, 2020. Citation Format: Anna Guarnieri, Mark Chicarelli, LouAnn Cable, Francis Sullivan, Howard Ball, Shannon Winski, John Robinson. Preclinical data identifies bezuclastinib as a differentiated KIT inhibitor with unique selectivity to KIT D816V and minimal evidence of brain penetration [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P257.

Treatment Considerations for Obstructive Sleep Apnea in Pediatric Down Syndrome.

Children with Down syndrome (DS) are at high risk for developing obstructive sleep apnea (OSA) compared to children without DS. The negative impact of OSA on health, behavior, and cognitive development in children with DS highlights the importance of timely and effective treatment. Due to the higher prevalence of craniofacial and airway abnormalities, obesity, and hypotonia in patients with DS, residual OSA can still occur after exhausting first-line options. While treatment commonly includes adenotonsillectomy (AT) and continuous positive airway pressure (CPAP) therapy, additional therapy such as medical management and/or adjuvant surgical procedures need to be considered in refractory OSA. Given the significant comorbidities secondary to untreated OSA in children with DS, such as cardiovascular and neurobehavioral consequences, more robust randomized trials in this patient population are needed to produce treatment guidelines separate from those for the general pediatric population of otherwise healthy children with OSA. Further studies are also needed to look at desensitization and optimization of CPAP use in patients with DS and OSA.

Predictors of interindividual differences in vulnerability to neurobehavioral consequences of chronic partial sleep restriction.

Interindividual differences in the neurobehavioral response to sleep loss are largely unexplained and phenotypic in nature. Numerous factors have been examined as predictors of differential response to sleep loss, but none have yielded a comprehensive view of the phenomenon. The present study examines the impact of baseline factors, habitual sleep-wake patterns, and homeostatic response to sleep loss on accrued deficits in psychomotor vigilance during chronic partial sleep restriction (SR), in a total of 306 healthy adults that participated in one of three independent laboratory studies. Findings indicate no significant impact of personality, academic intelligence, subjective reports of chronotype, sleepiness and fatigue, performance on working memory, and demographic factors such as sex, ethnicity, and body mass index, on neurobehavioral vulnerability to the negative effects of sleep loss. Only superior baseline performance on the psychomotor vigilance test and ability to sustain wakefulness on the maintenance of wakefulness test were associated with relative resilience to decrements in vigilant attention during SR. Interindividual differences in vulnerability to the effects of sleep loss were not accounted for by prior sleep history, habitual sleep patterns outside of the laboratory, baseline sleep architecture, or homeostatic sleep response during chronic partial SR. A recent theoretical model proposed that sleep-wake modulation may be influenced by competing internal and external demands which may promote wakefulness despite homeostatic and circadian signals for sleep under the right circumstances. Further research is warranted to examine the possibility of interindividual differences in the ability to prioritize external demands for wakefulness in the face of mounting pressure to sleep.

Molecular mechanisms of action of stimulant novel psychoactive substances that target the high-affinity transporter for dopamine.

Drug misuse is a significant social and public health problem worldwide. Misused substances exert their neurobehavioural effects through changing neural signalling within the brain, many of them leading to substance dependence and addiction in the longer term. Among drugs with addictive liability, there are illicit classical stimulants such as cocaine and amphetamine, and their more recently available counterparts known as novel psychoactive substances (NPS). Stimulants normally increase dopamine availability in the brain, including the pathway implicated in reward-related behaviour. This pattern is observed in both animal and human brain. The main biological target of stimulants, both classical and NPS, is the dopamine transporter (DAT) implicated in the dopamine-enhancing effects of these drugs. This article aims at reviewing research on the molecular mechanisms underpinning the interactions between stimulant NPS, such as benzofurans, cathinones or piperidine derivatives and DAT, to achieve a greater understanding of the core phenomena that decide about the addictive potential of stimulant NPS. As the methodology is essential in the process of experimental research in this area, we review the applications of in vitro, in vivo and in silico approaches. The latter, including molecular dynamics, attracts the focus of the present review as the method of choice in molecular and atomistic investigations of the mechanisms of addiction of stimulant NPS. Research of this kind is of interest to not only scientists but also health professionals as updated knowledge of NPS, their modes of action and health risks, is needed to tackle the challenges posed by NPS misuse.

Lipidomics Reveals Dysregulated Glycerophospholipid Metabolism in the Corpus Striatum of Mice Treated with Cefepime.

Cefepime exhibits a broad spectrum of antimicrobial activity and thus is a widely used treatment for severe bacterial infections. Adverse effects on the central nervous system (CNS) have been reported in patients treated with cefepime. Current explanation for the adverse neurobehavioral effect of cefepime is mainly attributed to its ability to cross the blood-brain barrier and competitively bind to the GABAergic receptor; however, the underlying mechanism is largely unknown. In this study, mice were intraperitoneally administered 80 mg/kg cefepime for different periods, followed by neurobehavioral tests and a brain lipidomic analysis. LC/MS-MS-based metabolomics was used to investigate the effect of cefepime on the brain lipidomic profile and metabolic pathways. Repeated cefepime treatment time-dependently caused anxiety-like behaviors, which were accompanied by reduced locomotor activity in the open field test. Cefepime profoundly altered the lipid profile, acyl chain length, and unsaturation of fatty acids in the corpus striatum, and glycerophospholipids accounted for a large proportion of those significantly modified lipids. In addition, cefepime treatment caused obvious alteration in the lipid-enriched membrane structure, neurites, mitochondria, and synaptic vesicles of primary cultured striatal neurons; moreover, the spontaneous electrical activity of striatal neurons was significantly reduced. Collectively, cefepime reprograms glycerophospholipid metabolism in the corpus striatum, which may interfere with neuronal structure and activity, eventually leading to aberrant neurobehaviors in mice.

Preclinical Data with KIT D816V Inhibitor Bezuclastinib (CGT9486) Demonstrates High Selectivity and Minimal Brain Penetrance

The molecular pathogenesis of Systemic Mastocytosis (SM) is driven by mutations in the KIT gene, with 95% of patients having a mutation in exon 17, D816V, leading to constant proliferation of mast cells (Garcia-Montero et al, 2006; Jara-Acevedo et al, 2015; Vaes et al, 2017). Targeted therapeutics have revealed clinical activity in these patients, but toxicities such as cognitive effects, intracranial hemorrhage, hypertension, and edema may limit dosing and availability of these therapies. While the exact cause of these effects is difficult to determine, numerous closely related kinases, such as wild type PDGFRα, PDGFRβ, KIT, VEGFR2 (KDR), and CSF1R (FMS), are considered to be anti-targets, with previous evidence of their inhibition linked to observed clinical toxicities (Liu & Kurzrock, 2015; Giles et al., 2009; Jayson et al., 2005). Bezuclastinib (CGT9486) was designed to selectively inhibit KIT D816V versus these other closely related kinase anti-targets. Additionally, we demonstrate that bezuclastinib has minimal brain penetration, together with no observed CNS-related toxicities in nonclinical studies. Herein, we present results from cell-based kinase profiling assays, which demonstrate that bezuclastinib has a significant and unique selectivity to KIT D816V relative to the aforementioned kinases when tested head-to-head against other clinically relevant compounds in SM. Additionally, a similar selectivity profile was observed for a broader panel of kinases, ion channels, transporters, and enzymes, which will be presented here, including drug concentrations and target engagement achieved with recent in vivo studies. Importantly, we also show that bezuclastinib has minimal brain penetration, a preferred feature of an anti-Kit molecule due to CNS-related adverse events observed in these indications. In a tissue distribution study performed in rats, bezuclastinib shows a brain:plasma ratio <0.1 following 3 day administration at 25 mg/kg, a dose that closely correlates with clinical plasma exposure. This was supported functionally by assessing neurobehavioral effects of bezuclastinib at dose levels up to 100 mg/kg in rats which showed no CNS related effects. This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors (Trent et al, 2020), supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM with additional clinical studies planned in non-advanced SM and imatinib-resistant GIST. DisclosuresGuarnieri: Cogent Biosciences: Current Employment. Cable: Cogent Biosciences: Current Employment. Bouhana: Cogent Biosciences: Current Employment. Sullivan: Cogent Biosciences: Current Employment. Ball: Cogent Biosciences: Current Employment. Sachs: Cogent Biosciences: Current Employment. Winski: Cogent Biosciences: Current Employment. Robinson: Cogent Biosciences: Current Employment.

Neural and behavioral effects of theta burst stimulation priming on processing of affective and neutral information in working memory

Abstract Theta-burst stimulation (TBS) has been increasingly used to target prefrontal brain regions, such as the dorsolateral prefrontal cortex (DLPFC), to improve neurocognitive and emotional functioning. However, despite the promising outcomes, there is still a lot of variability in responses and the clinical efficacy remains rather modest. Interestingly, fundamental research targeting the motor cortex has suggested the use of priming techniques to enhance TBS-related changes in cortical excitability. Hence, TBS priming - using a prime TBS protocol to enhance the effects of a subsequent test TBS protocol - can yield improved TBS efficacy when applied over the prefrontal cortex. Moreover, recent developments in the field indicate that stimulation priming can be highly efficacious in reducing depressive symptoms. In this within-subjects, sham-controlled study, we investigated how different TBS priming protocols over the left DLPFC affect cognitive performance and task-related brain activity in a sample of fifty healthy adults. Participants performed a verbal working memory task, consisting of affective and neutral word stimuli, during functional magnetic resonance imaging (fMRI) after receiving one of four TBS priming combinations (i.e., a prime followed by a test protocol); (1) sham TBS + sham TBS, (2) sham TBS + intermittent TBS, (3) intermittent TBS + intermittent TBS, (4) continuous TBS + intermittent TBS. Each prime and test protocol was separated by a 15-minute break and there was one week in between each experimental session. Task performance and participants’ activation patterns elicited by the task following the different TBS priming conditions were assessed. During this talk, the behavioral and neural findings will be presented. Moreover, implications of the study findings for further studies evaluating the neurobehavioral effects of TBS priming on emotional working memory, in healthy and neuropsychiatric samples, will be discussed. Keywords: Theta Burst Stimulation (TBS), functional magnetic resonance imaging (fMRI), Stimulation Priming, Working Memory

Teratogenic of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) on Eye Diameters and Body Weight in Chicken Embryo

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a chemical compound resulting from the burning effect that is very dangerous for humans, plants, or animals which can cause skin damage, immunotoxic, hepatotoxic, carcinogenic, teratogenic, effects on reproduction, growth processes, neurobehavioral, and endocrine effects that are specific In addition, this compound can also reduce embryo weight and increase embryo mortality. This study aimed to determine the teratogenic of TCDD administration on eye diameters and body weight of chicken embryo. In this study there were 2 treatment groups, i.e: 1) P1 as a normal group without the addition of TCDD, and 2) P2 as a group with the addition of TCDD of 5 ng / egg with dissolved in 5 µL corn oil. The treatment was carried out for 7 days. The measurement data of eye diameters and body weight of chicken embryo were analyzed by the unpaired sample T test. The analysis showed that the teratogenic of TCDD had a significant effect on eye diameters and body weight of chicken embryos, where the teratogenic of TCDD caused a decrease in eye diameters and body weight loss in chicken embryos.

Sex differences in long-term behavioral alterations, especially anxiety, following prenatal fluoxetine exposure in C57BL/6 mice

Evidence demonstrates that psychiatric disorders during pregnancy are detrimental to the offspring. Many disorders are treated with SSRIs and increasing numbers of pregnant women now receive these drugs during gestation. The long-term neurobehavioral consequences of prenatal SSRI exposure require further evaluation. This study examined the effects of prenatal fluoxetine exposure in mice in an extensive battery of behaviors related to neurodevelopment, mood, social, and repetitive behaviors. C57BL/6J dams were administered fluoxetine at a low (0.6 mg/kg/day) or high (6 mg/kg/day) dose or saline from embryonic days 8 to 18. Juvenile mice were tested for changes in ultrasonic vocalizations and neuromotor development. In adulthood, offspring were tested for changes in behaviors related to anxiety, depression, social, and repetitive behaviors. Prenatal exposure to fluoxetine impaired surface righting reflex at P5, and sex-dependently reduced the frequency of ultrasonic vocalizations in juvenile males but not females. In adulthood, both males and females prenatally exposed to high, but not low, doses of fluoxetine exhibited an increase in repetitive behaviors in the marble burying task and a decrease in sucrose preference. Males, but not females, exposed to fluoxetine exhibited increased anxiety-related behaviors in the elevated plus maze. Prenatal fluoxetine exposure did not affect other adult behaviors including social preference, self-grooming, passive avoidance and open field activity. These findings suggest males are more sensitive than females to disruptions in serotonin balance during prenatal development and highlight the need for additional systematic and mechanistic studies to evaluate the impact of fluoxetine exposure during other periods of gestation.

Using High-Throughput Screening to Evaluate Perturbations Potentially Linked to Neurobehavioral Outcomes: A Case Study Using Publicly Available Tools on FDA Batch-Certified Synthetic Food Dyes.

There is growing evidence from human and animal studies indicating an association between exposure to synthetic food dyes and adverse neurobehavioral outcomes in children. However, data gaps persist for potential mechanisms by which the synthetic food dyes could elicit neurobehavioral impacts. We developed an approach to evaluate seven US FDA-batch-certified food dyes using publicly available high-throughput screening (HTS) data from the US EPA's Toxicity Forecaster to assess potential underlying molecular mechanisms that may be linked to neurological pathway perturbations. The dyes were screened through 270 assays identified based on whether they had a neurological-related gene target and/or were mapped to neurodevelopmental processes or neurobehavioral outcomes, and were conducted in brain tissue, targeted specific hormone receptors, or targeted oxidative stress and inflammation. Some results provided support for neurological impacts found in human and animal studies, while other results showed a lack of correlation with in vivo findings. The azo dyes had a range of activity in assays mapped to G-protein-coupled receptors and were active in assays targeting dopaminergic, serotonergic, and opioid receptors. Assays mapped to nuclear receptors (androgen, estrogen, and thyroid hormone) also exhibited activity with the food dyes. Other molecular targets included the aryl hydrocarbon receptor, acetylcholinesterase, and monoamine oxidase. The Toxicological Prioritization Index tool was used to visualize the results of the Novascreen assays. Our results highlight certain limitations of HTS assays but provide insight into potential underlying mechanisms of neurobehavioral effects observed in in vivo animal toxicology studies and human clinical studies.

Undesired Effects of Bioinsecticides Molecules in Wistar Rats: Case of Spirotetramat, Citrulus Colocynthis and Cleome Arabica Extracts

The use of pesticides is becoming an indispensable technique in most agricultural practices, regardless of the level of development of the country. Currently, the pesticides used are often less toxic and more specific and are based on insect physiology. Recent studies indicate that pesticide intoxication induces oxidative stress. This work aims to study the neurobehavioral consequences of the administration of two insecticides currently widely used in agriculture: spirotetramat (an inhibitor of lipid synthesis in insects) and the ethanolic extract of Citrullus colocynthis (a plant endemic to the Algerian Sahara) and the ethanolic extract of Cleome arabica (Capparidaceae) The different behavioral tests (elevated cross maze, open fields and forced swimming) show that the have a significant impact on the degree of anxiety of rodents.These products significantly influence the biochemical parameters (blood sugar, cholesterol, triglycerides, urea, creatinine), the hormone Adreno CorticoTropic Hormone, acetylcholine esterase,

The Neurobehavioral Effects of Buprenorphine and Meloxicam on a Blast-Induced Traumatic Brain Injury Model in the Rat.

Previous findings have indicated that pain relieving medications such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs) may be neuroprotective after traumatic brain injury in rodents, but only limited studies have been performed in a blast-induced traumatic brain injury (bTBI) model. In addition, many pre-clinical TBI studies performed in rodents did not use analgesics due to the possibility of neuroprotection or other changes in cognitive, behavioral, and pathology outcomes. To examine this in a pre-clinical setting, we examined the neurobehavioral changes in rats given a single pre-blast dose of meloxicam, buprenorphine, or no pain relieving medication and exposed to tightly-coupled repeated blasts in an advanced blast simulator and evaluated neurobehavioral functions up to 28 days post-blast. A 16.7% mortality rate was recorded in the rats treated with buprenorphine, which might be attributed to the physiologically depressive side effects of buprenorphine in combination with isoflurane anesthesia and acute brain injury. Rats given buprenorphine, but not meloxicam, took more time to recover from the isoflurane anesthesia given just before blast. We found that treatment with meloxicam protected repeated blast-exposed rats from vestibulomotor dysfunctions up to day 14, but by day 28 the protective effects had receded. Both pain relieving medications seemed to promote short-term memory deficits in blast-exposed animals, whereas vehicle-treated blast-exposed animals showed only a non-significant trend toward worsening short-term memory by day 27. Open field exploratory behavior results showed that blast exposed rats treated with meloxicam engaged in significantly more locomotor activities and possibly a lesser degree of responses thought to reflect anxiety and depressive-like behaviors than any of the other groups. Rats treated with analgesics to alleviate possible pain from the blast ate more than their counterparts that were not treated with analgesics, which supports that both analgesics were effective in alleviating some of the discomfort that these rats potentially experienced post-blast injury. These results suggest that meloxicam and, to a lesser extent buprenorphine alter a variety of neurobehavioral functions in a rat bTBI model and, because of their impact on these neurobehavioral changes, may be less than ideal analgesic agents for pre-clinical studies evaluating these neurobehavioral responses after TBI.

IFNγ-Producing γ/δ T Cells Accumulate in the Fetal Brain Following Intrauterine Inflammation.

Intrauterine inflammation impacts prenatal neurodevelopment and is linked to adverse neurobehavioral outcomes ranging from cerebral palsy to autism spectrum disorder. However, the mechanism by which a prenatal exposure to intrauterine inflammation contributes to life-long neurobehavioral consequences is unknown. To address this gap in knowledge, this study investigates how inflammation transverses across multiple anatomic compartments from the maternal reproductive tract to the fetal brain and what specific cell types in the fetal brain may cause long-term neuronal injury. Utilizing a well-established mouse model, we found that mid-gestation intrauterine inflammation resulted in a lasting neutrophil influx to the decidua in the absence of maternal systemic inflammation. Fetal immunologic changes were observed at 72-hours post-intrauterine inflammation, including elevated neutrophils and macrophages in the fetal liver, and increased granulocytes and activated microglia in the fetal brain. Through unbiased clustering, a population of Gr-1+ γ/δ T cells was identified as the earliest immune cell shift in the fetal brain of fetuses exposed to intrauterine inflammation and determined to be producing high levels of IFNγ when compared to γ/δ T cells in other compartments. In a case-control study of term infants, IFNγ was found to be elevated in the cord blood of term infants exposed to intrauterine inflammation compared to those without this exposure. Collectively, these data identify a novel cellular immune mechanism for fetal brain injury in the setting of intrauterine inflammation.

Review On Arsenic Toxicity: Effect On Human Health And Biochemical Aspects

Looking at the global scenario, it has been found that a huge perccntage of population around the globe consider groundwater as their main source for drinking. But unfortunately, this main source is being heavily exposed to various heavy metals like mercury, cadmium, arsenic making it unfit for consumption, ultimately posing threat to human health out there. Although groundwater is considered as safe, but high concentrations of heavy metals like arsenic (As) (above the permissible limit) in ground water can pose risk to human health. Toxicity level of inorganic arsenic is more than the organic one. Arsenic contamination is having a worldwide effect. Arsenic is found to be carcinogcnic in nature, genotoxic as well as cytotoxic. Prolonged exposure to arsenic causes various health hazards like arsenicosis, skin cancer, pigmentation, neurobehavioral effects, impaired intellect and various other chronic illness. Creating awareness and providing proper medical care still remains a big challenge. The biomarkers of arsenic exposure include nails, hair, urine and blood sample. This paper provides an overall overview of ground water arsenic contamination, its health hazards, its toxicity and metabolism in human body. The paper also reviews various analytical techniques that are being used to detect arsenic, the collective steps required to eradicate this global problem and provide high quality safe drinking water for the future generations to come.