Neurotoxicity Research最新文献

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.

Rotenone, often used to experimentally induce Parkinson's disease in rodents, is a well-known neurotoxic pesticide. One of the most common non-motor symptoms in Parkinson's patients is gastrointestinal dysfunction. Therefore, protecting the gastrointestinal system plays an important role in the onset and progression of the disease. In this study, both the effects of Rotenone on the stomach and small intestine and the possible protective role of Alpha Pinene against Rotenone toxicity, were investigated. Sixty adult male Sprague-Dawley rats were randomly divided into five groups as Control, Vehicle, Alpha Pinene (50 mg/kg/day), Rotenone (2 mg/kg/day) and Rotenone + Alpha Pinene. At the end of the 28-day experimental period, the stomach and jejunum tissues were examined using histological (haematoxylin-eosin and alcian blue-PAS stainings), biochemical (malondialdehyde, zonulin and Fatty Acid Binding Protein-2 levels) and molecular (Keap1, Nrf2 and HO-1 mRNA levels) techniques. While the data showed the presence of oxidative stress and impaired intestinal permeability in the stomach and jejunum tissues in the Rotenone group, these symptoms were observed to be alleviated in the Rotenone + Alpha Pinene group. This study reveals that Alpha Pinene may be a valuable herbal organic compound for the protection of the stomach and intestine and the reduction of complaints in diseases affecting the gastrointestinal system such as Parkinson's disease.

This study investigates the effects of an acute 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) treatment, a known inducer of parkinsonism, on oxidative stress and epigenetic changes in the mouse ventral midbrain (VM) and striatum. Key markers were analyzed at 4, 8, 24, and 48 h post-injections: the hydroxylated form of the purine guanine (8-hydroxy-2'-deoxyguanosine; 8-OHdG), a marker of oxidative stress; the methylated form of cytosine (5-methylcytosine; 5-mC), associated with gene silencing; the hydroxy methylated form of cytosine (5-hydroxymethylcytosine; 5-hmC), involved in demethylation and gene regulation. The results showed a pronounced decrease in 8-OHdG levels in the VM, suggesting a rapid oxidative stress response, whereas the striatum exhibited a less pronounced response, reflecting regional differences in oxidative stress vulnerability DNA methylation patterns revealed complex and biphasic changes in 5-mC levels in the VM, contrasted with a less pronounced response in the striatum, suggesting disrupted methylation homeostasis and regional epigenetic variability. MPTP treatment also significantly reduced in 5-hmC levels in the VM, pointing to impaired active DNA demethylation and compromised epigenetic flexibility. In contrast, the striatum maintained consistently high 5-hmC levels, reflecting compensatory hydroxymethylation mechanisms specific to this region. These findings highlight pronounced regional differences in oxidative stress vulnerability and epigenetic regulation, with the VM showing heightened sensitivity to oxidative damage and impaired epigenetic flexibility. This underscores the importance of understanding the role of oxidative and epigenetic mechanisms in Parkinson's disease pathophysiology, The changes pave the way for novel therapeutic strategies targeting oxidative DNA damage and epigenetic homeostasis.

Ketamine is an anesthetic drug that has been illegally used due to its hallucinogenic effects. Its use is often concomitant with drugs such as ethanol, which can cause irreversible damage to the central nervous system. This study investigates the neurotoxicity of ketamine-ethanol combination in human neuroblastoma SH-SY5Y cell line, exploring the mechanisms preceding cell death. Cell viability, oxidative stress parameters, and apoptosis pathways were assessed after 3 and 6 h of drug exposure. A concentration-response curve using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay determined the lowest observed adverse effect levels for ketamine (1 mM; K1) and ethanol (100 mM; E100). After 12, 24 and 48 h, MTT assay revealed a decrease in cell viability, with a possible synergistic effect in K1E100 at 48 h, confirmed by annexin-V/7-aminoactinomycin D flow cytometry analysis, which showed a higher proportion of late apoptotic cells. Mechanisms preceding cell death were assessed by measuring reduced glutathione (GSH) levels, glutathione-related enzymes activities, and apoptosis markers (caspase-8, Bax, Bcl-2, and caspase-3). GSH levels decreased after 6 h in E100 and K1E100. Glutathione peroxidase activity increased for all groups after 3 h and in K1 and K1E100 after 6 h. Glutathione reductase and glutathione S-transferase activities increased only for K1E100 after 3 h. K1E100 also showed increased caspase-8 and Bax expression after 3 and 6 h, respectively, indicating activation of both extrinsic and intrinsic apoptotic pathways. These results suggest that ketamine-ethanol combination induces neurotoxicity by triggering oxidative stress and apoptosis in a time-dependent manner prior to cell death, increasing the risk for neuronal damage compared to individual drug exposure. While these findings are promising, they should be interpreted with caution due to certain limitations, such as variability in enzyme activity measurements, reduced sample size for some markers, and the use of an immortalized, proliferative cell line. Further studies using differentiated neuronal cells are needed to validate and expand these observations.

Memory decline is a common hallmark signal of neurodegenerative diseases marked by elevated neuroinflammatory cytokines, oxidative damage and cholinergic insufficiency in cortical regions. Studies indicate that inhibiting these cytokines and associated markers may enhance memory and provide neuroprotection. This study investigates the effects of sabinene, a neuroprotective monoterpene found in essential oils with neuroprotective and antioxidant properties, on lipopolysaccharide (LPS)-induced neuroinflammation, oxidative stress and learning/memory impairment in mice. In this study, mice in groups 1 and 2 received normal saline, while groups 3-5 were pretreated with sabinene (5, 10, and 20 mg/kg). Group 6 received donepezil (1 mg/kg) orally. Groups 2-6 were additionally injected with LPS (0.5 mg/kg, i.p.) 30 min post-treatment for 7 days. Behavioral consequences indicating spatial and non-spatial deficits were assessed through Y-maze and novel-object recognition tests, along with locomotor functions conducted. Biochemical markers of neuroinflammation (TNF-α, IL-6), oxidative stress (glutathione, peroxidase, malondialdehyde, nitrite), cholinergic function, and molybdenum enzymes were analyzed in the prefrontal-cortex (PFC) and hippocampus. Sabinene treatment mitigated LPS-induced memory impairments and reduced motor activity. It also significantly decreased acetylcholinesterase activity and malondialdehyde levels in the hippocampus and PFC while increasing glutathione and glutathione peroxidase levels, respectively. Moreover, sabinene reduced LPS-induced molybdenum enzyme elevation in the PFC. Compared to LPS, sabinene significantly lowered TNF-α and IL-6 levels in the PFC and hippocampus while protecting neuronal cell damage in the PFC. Overall, sabinene enhances memory function in LPS-treated mice by reducing oxidative stress and neuroinflammation while improving cholinergic activity and molybdenum enzymes in the cortical regions of mice brains.