Neurotoxicity Research最新文献

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.

Ferroptosis is an iron-dependent and membrane lipid peroxidation-mediated form of programmed or regulated cell death. A number of recent studies have demonstrated that ferroptosis contributes to Alzheimer's disease (AD)-mediated nerve cell death. Melatonin demonstrates strong antioxidant properties and offers protective benefits for the brain in the context of AD. However, it is not fully known whether melatonin protects against ferroptosis and whether ferroptosis affects amyloid precursor protein (APP) processing. In this study, we studied the effects of melatonin on SH-SY5Y cells-induced ferroptosis using erastin, and ferrostatin-1 was used as a ferroptosis inhibitor. To confirm the occurrence of ferroptosis, we conducted measurements of cell cytotoxicity, intracellular iron, reactive oxygen species (ROS), and 4-hydroxynonenal (4-HNE). The protein expressions that were regulated by either ferroptosis or APP processing were measured. Our results revealed that erastin increased intracellular iron levels, ROS, and 4-HNE lipid peroxidation in SH-SY5Y cells, resulting in an increased percentage of cell death. Erastin disrupted the regulation of proteins involved in ferroptosis and increased the production of amyloid beta (Aβ) through APP proteolysis. Following melatonin treatment, intracellular iron, ROS, and 4-HNE levels were significantly reduced. Additionally, the cystine/glutamate antiporter (system xc^-) and glutathione peroxidase 4 (GPX4) were increased, and acyl-CoA synthetase long chain family member 4 (ACSL4) was diminished. APP, β-site-APP cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and Aβ production were alleviated in erastin-treated SH-SY5Y cells. In conclusion, melatonin effectively inhibits ferroptosis-related cell death and AD-like conditions induced by erastin in SH-SY5Y human neuroblastoma cell lines.

Membrane composition, permeability and fluidity are essential for proper cellular function. According to the membrane aging hypothesis, aging-related diseases, including neurodegenerative disorders, arise from the aging of cell membranes. Membrane proteins, such as the insulin receptor, rely on an optimal membrane environment for proper partitioning and functionality. Our goal was to investigate the effects of streptozotocin (STZ) and L-buthionine-sulfoximine (BSO), two commonly used agents to model aging and neurodegeneration, on membrane composition and permeability, as well as their impact on insulin signaling. Mouse neuroblastoma 2a cell line (neuro-2a) were treated with STZ (6 h) and BSO (24 h). Cell viability was assessed by the MTT assay. Cholesterol and sphingomyelin content were quantified by commercial kits, while membrane polarity was evaluated with the Laurdan probe. Gene expression of Srebf2 and Cyp46a1 was analyzed by qPCR. Proteins from the insulin signaling pathway were examined by immunoblotting. STZ treatment reduced neuronal cholesterol content, downregulated Srebf2 and Cyp46a1 gene expression, and decreased membrane packing. In contrast, BSO-treated cells exhibited increased sphingomyelin content, upregulated Srebf2 and Cyp46a1 gene expression, and decreased membrane packing. Both treatments induced an insulin-resistant state, which we attribute to alterations in the membrane environment.

This study investigates the potential protective role of annexin A1 (ANXA1) in cell models of H₂O₂-induced Alzheimer's disease. PC12 cells exposed to varying concentrations of H₂O₂ exhibited a dose-dependent decrease in cell viability. H₂O₂ exposure led to elevated reactive oxygen species (ROS) levels, reduced superoxide dismutase (SOD) and catalase (CAT) activities, and a decline in ANXA1 protein expression. Under oxidative stress, ANXA1 overexpression increased cell viability, reduced apoptosis rate, enhanced the expression of microtubule-associated protein 3 (LC3) II/I while reducing phosphorylated calcium/calmodulin-dependent protein kinase II (p-CAMK2)/CAMK2 and phosphorylated beclin 1 (p-BECN1)/BECN1. Conversely, ANXA1 knockdown produced contrasting effects. Overexpression of ANXA1, accompanied by administration of KN-93 (a competitive inhibitor of CAMK2), can synergistically diminished p-CAMK2/CAMK2 and p-BECN1/BECN1 levels while significantly increasing LC3 II/I levels, autophagosomes, and autolysosomes. In conclusion, ANXA1 demonstrated a protective role in H₂O₂-induced oxidative stress damage model in PC12 cells by inhibiting the CAMK2/BECN1 signaling pathway and enhancing autophagy.

Increasing evidence of ocular impairments in Alzheimer's disease (AD) has drawn the attention of researchers worldwide towards retinal neurodegeneration in AD. The AD-associated changes observed in the retina include visual discrepancies, pupil size modulations, retinal nerve layer changes, retinal blood flow alterations and histopathological changes. The brain cells that act as pathological triggers for the progression of retinal neurodegeneration associated with AD are microglia, astrocytes and neurons. Various molecular pathways lead to structural and functional abnormalities in the retina, significantly affecting the brain including Aβ accumulation, apoptosis, inflammation and oxidative stress. Therapeutic agents under development that ameliorate disease conditions by targeting retinal anomalies include mesenchymal stem cell-conditioned media, BDNF, glatiramer acetate, salvianolic acid B, Lycium barbarum extract and exosomes. Investigating real-time alterations in the retina in AD may not only affect diagnostic approaches but also help to clarify neuropathological pathways and offer helpful measurements for assessing novel therapeutic approaches for AD.