Neurotoxicity Research最新文献

Lethal organophosphate (OP) exposure leads to status epilepticus (SE), which, despite standard-of-care (SOC) therapy, is associated with acute mortality and long-term morbidities. Neuronal injury and inflammation are reported following OP-SE, and drugs targeted at these processes have produced beneficial outcomes. Verapamil (VPM) is a calcium-channel blocker used as an antihypertensive drug and has been shown to exhibit neuroprotective and anti-inflammatory actions in experimental models of CNS injuries. Here, we investigated the feasibility of an adjunctive intramuscular (i.m.) VPM therapy in OP Diisopropyl Fluorophosphate (DFP)-induced SE. We also investigated the safety and toxicity of i.m. VPM and compared its pharmacokinetic (PK) profile to oral (p.o.) administration. Rats were injected with DFP (4 mg/kg, s.c.). One minute later, SOC treatment consisting of atropine (0.5 mg/kg, i.m.) and pralidoxime chloride (2-PAM; 25 mg/kg, i.m.) were administered, and at 1-hour post-SE, midazolam (1.78 mg/kg, i.m.) was given. Rats that met the behavioral SE severity criteria (Racine 4-5) were randomized into two treatment groups: those receiving saline (SAL) or VPM (10 mg/kg, i.m. bid, 3 days). Histological analysis was conducted to assess neuronal injury and injection-site pathology. In a separate group of rats, PK studies were conducted on blood and brain homogenates treated once with saline or VPM (10 mg/kg, p.o. or i.m.). Our data demonstrated that following DFP-SE, i.m. VPM achieved higher blood and brain levels and exhibited a favorable PK profile compared to p.o. route. VPM therapy did not cause significant muscle pathology and produced a robust neuroprotective response. Neuroinflammatory markers and long-term behavioral outcomes were not included in this study. Our studies provide evidence that the i.m. route is an effective method for delivering VPM following SE, producing significant neuroprotective outcomes compared to treatment with the standard-of-care alone in OP-SE.

Novelty-seeking (NS) refers to the tendency of humans and animals to explore novel and unfamiliar stimuli and environments. It is a core feature of Attention Deficit Hyperactivity Disorder (ADHD) and associated with multiple psychiatric disorders. Recent researches indicated that NS behavior has an effect on reward-related learning. The hippocampus is a core brain region linked to reward-related learning and memory. However, how the hippocampal proteome modulates NS behavior remain largely elusive. In current study, we identified 165 differentially expressed proteins in the hippocampus between high and low novelty response mice with mass-spectrometry-based proteomics. Among these proteins, the over-expression of Tenascin-R (TNR) in high novelty response mice was verified with Western Blot and Immunofluorescence imaging. Moreover, systematic genetic analysis based on the BXD strains showed the expression of TNR is genetically cis-regulation. Further, gene co-expression analysis revealed that TNR has a negative connection with the expression of dopamine receptor D2 (DRD2) (P = 0.003, r = -0.298). And the knockdown of TNR enhanced the expression of DRD2 in vitro. Finally, we constructed a correlation network to exhibit the links among TNR gene variant, expression of TNR and DRD2, and NS related behaviors. Our study provides a novel hippocampal biomarker with preliminary insights into its association with the dopaminergic synaptic pathway. ROC analysis further confirms TNR's robust discriminatory power for distinguishing novel open field behavior, a key NS - related phenotype, which may be a new strategy for diagnosis of NS-related traits.

The coronavirus disease 2019 (COVID-19) pandemic has brought significant challenges to global health, not only due to respiratory symptoms but also due to its impact on psychiatric disorders. Understanding the biological mechanisms underlying psychiatric manifestations in individuals with COVID-19 is crucial. This study aimed to investigate potential alterations in caspase 3 and 8 levels, as well as brain-derived neurotrophic factor (BDNF) levels, in individuals with COVID-19. The association of these markers with mental health was also assessed. A cross-sectional study was conducted, including individuals with COVID-19 and those without the disease. The stress levels were higher in individuals with COVID-19. Caspase 3 and 8 and BDNF levels were increased in individuals with COVID-19 compared to individuals without COVID-19. No significant differences were found in caspase 3 and 8 and BDNF levels between moderate/severe and asymptomatic/mild symptoms of COVID-19. The results indicate that no significant differences were observed between the diagnosis of anxiety disorders and the levels of markers. However, higher caspase 3 levels in individuals without anxiety and COVID-19 were found. No significant associations between the diagnosis of major depressive disorder or psychiatric symptoms and caspase 3, caspase 8, and BDNF levels were found. The results indicate that, although caspase 3, caspase 8, and BDNF levels are increased in individuals with COVID-19, these elevations are not associated with the severity of COVID-19 symptoms or psychiatric conditions and symptoms in post-COVID-19. These findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may influence cellular activity and neurotrophic markers, but that other factors likely contribute to psychiatric disorders.

Arsenic (As) contamination of groundwater in some parts of Bangladesh has become a major threat to human health. Chronic exposure to As leads to anxiety development, memory impairment, and muscle weakness in humans and experimental animals. Panax ginseng (PG) is an herb utilized for multiple health-related applications. Furthermore, regular exercise (Ex) can reduce the risk of various diseases, and is also effective against heavy metal-associated neurotoxicity. Swiss albino mice were divided into five groups (n = 6) to evaluate the protective effects of Ex and PG (50 mg/kg body weight) supplementation against As-induced (10 mg/kg body weight) muscular weakness and neurobehavioral Changes for 60 days. Mice exposed to As showed weaker muscular strength, impaired memory and increased anxiety-like behavior along with the alteration of biochemical parameters related muscular weakness and neurobehavioral changes compared to control mice. However, As + Ex + PG-exposed mice showed significantly (p < 0.05) better performances in all behavioral tests compared to mice exposed to As alone. Additionally, compared to As-exposed mice, As + Ex + PG-exposed mice showed significantly improved (p < 0.05) activity of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), superoxide dismutase (SOD), and reduced glutathione reductase (rGR) in brain, while serum levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were reduced. Furthermore, levels of nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and interleukin-10 (IL-10) levels were increased, while interleukin-6 (IL-6) levels were decreased in brain tissue of As + Ex + PG-exposed mice compared to As-exposed mice. The results of this study suggest that Ex with PG supplementation can attenuate As-induced muscle weakness, cognitive disorder and anxiety development, possibly through the up-regulation of the Nrf2-HO-1 pathway in the As-exposure mice.

Elevated hydrogen sulfide (sulfide) levels are observed in tissues, including the brain, of patients with ethylmalonic encephalopathy. Clinical manifestations of this disorder involve severe neurological symptoms and abnormalities such as developmental delay, pyramidal and extrapyramidal signs, cortical atrophy and basal ganglia lesions. To elucidate the pathophysiology of basal ganglia alterations, we investigated the effects of sulfide on bioenergetics, redox status and mitochondrial quality control in the striatum of Wistar rats. After placing the rat in a stereotaxic apparatus, a single intrastriatal administration of sulfide (NaHS; 2 or 4 µmol) or PBS (control) was performed. Thirty minutes after the administration, the rats were euthanized, and the striatum was used for the determination of biochemical parameters. Sulfide administration, at both doses, altered the activities of antioxidant enzymes. At the lowest dose, sulfide showed a strong tendency toward increased activity of citrate synthase. Furthermore, the highest dose of sulfide also reduced respiratory chain complex IV activity and mitochondrial respiration with NADH- and FADH₂-linked substrates. Levels of Nrf2, the main factor that regulates the expression of antioxidant defenses, were also reduced by 4 µmol of sulfide. The metabolite further increased the content of MFN1, suggesting mitochondrial fusion. Additionally, sulfide elevated Parkin and TBC1D15 and reduced LC3 levels, indicative of mitophagy dysregulation. The content of markers of mitochondrial mass and fission were not changed. Our study shows that high levels of sulfide in the striatum of rats affect bioenergetics, redox status and mitochondrial quality control. We suggest that these pathomechanisms are involved in the pathophysiology of basal ganglia alterations verified in ethylmalonic encephalopathy.