Neurotoxicity Research最新文献

Inhibition of enzymes responsible for endocannabinoid hydrolysis represents an invaluable emerging tool for the potential treatment of neurodegenerative disorders. Monoacylglycerol lipase (MAGL) is the enzyme responsible for degrading 2-arachydonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system (CNS). Here, we tested the effects of the selective MAGL inhibitor JZL184 on the 3-nitropropinic acid (3-NP)-induced short-term loss of mitochondrial reductive capacity/viability and oxidative damage in rat brain synaptosomal/mitochondrial fractions and cortical slices. In synaptosomes, while 3-NP decreased mitochondrial function and increased lipid peroxidation, JZL184 attenuated both markers. The protective effects evoked by JZL184 on the 3-NP-induced mitochondrial dysfunction were primarily mediated by activation of cannabinoid receptor 2 (CB2R), as evidenced by their inhibition by the selective CB2R inverse agonist JTE907. The cannabinoid receptor 1 (CB1R) also participated in this effect in a lesser extent, as evidenced by the CB1R antagonist/inverse agonist AM281. In contrast, activation of CB1R, but not CB2R, was responsible for the protective effects of JZL184 on the 3-NP-iduced lipid peroxidation. Protective effects of JZL184 were confirmed in other toxic models involving excitotoxicity and oxidative damage as internal controls. In cortical slices, JZL184 ameliorated the 3-NP-induced loss of mitochondrial function, the increase in lipid peroxidation, and the inhibition of succinate dehydrogenase (mitochondrial complex II) activity, and these effects were independent on CB1R and CB2R, as evidenced by the lack of effects of AM281 and JTE907, respectively. Our novel results provide experimental evidence that the differential protective effects exerted by JZL184 on the early toxic effects induced by 3-NP in brain synaptosomes and cortical slices involve MAGL inhibition, and possibly the subsequent accumulation of 2-AG. These effects involve pro-energetic and redox modulatory mechanisms that may be either dependent or independent of cannabinoid receptors' activation.

Perinatal hypoxia is a common risk factor for CNS development. Using bioinformatics databases, a list of 129 genes involved in perinatal hypoxia was selected from the literature and analyzed with respect to proteins important for biological processes influencing the brain development. Functional enrichment analysis using the DAVID database was performed to identify relevant Gene Ontology (GO) biological processes like response to hypoxia, inflammatory response, positive and negative regulation of apoptosis, and positive and negative regulation of cell proliferation. The selected GO processes contain 17-30 proteins and show an enrichment of 6.3-14.3-fold. The STRING protein-protein interaction network and the Cytoscape data analyzer were used to identify interacting proteins playing a significant role in these processes. The two top protein pairs referring to the proteins with highest degrees and the corresponding proteins connected by high score edges exert opposite or regulatory functions and are essential for the balance between damaging, repairing, protective, or epigenetic processes. The GO response to hypoxia is characterized by the high score protein-protein interaction pairs CASP3/FAS promoting apoptosis and by the protective acting BDNF/MECP2 protein pair. Core components of the GO processes positive and negative regulation of apoptosis are the proteins CASP3/FAS/AKT/eNOS/RPS6KB1 involved in several signal pathways. The GO processes cell proliferation are characterized by the high-score protein-protein interaction pairs MYC/ MAPK1, JUN/MAPK1, IL6/IL1B, and JUN/HDAC1. The study provides new insights into the pathophysiology of perinatal hypoxia and is of importance for future investigations, diagnostics, and therapy of perinatal hypoxia.

Glutamate in monosodium glutamate (MSG), which is widely used in the food industry, has an important role in major brain functions such as memory, learning, synapse formation, and stabilization. However, extensive use of MSG has been linked with neurotoxicity. Therefore, in addition to clarifying the underlying mechanisms of MSG-induced neurotoxicity, it is also important to determine safe agents that can diminish the damage caused by MSG. Tannic acid (TA) is a naturally occurring plant polyphenol that exhibits versatile physiological effects such as anti-inflammatory, anti-carcinogenic, antioxidant, and radical scavenging. This study was conducted to assess the neurotoxic and neuroprotective effects of these two dietary components in the rat cerebral cortex. Twenty-four Sprague Dawley rats were divided into 4 equal groups and were treated with MSG (2 g/kg) and TA (50 mg/kg) alone and in combination for 3 weeks. Alterations in oxidative stress indicators (MDA and GSH) were measured in the cortex tissues. In addition, changes in enzymatic activities and gene expression patterns of antioxidant system components (GST, GPx, CAT, and SOD) were investigated. Furthermore, mRNA expressions of FoxO transcription factors (Foxo1 and Foxo3) and apoptotic markers (Casp3 and Casp9) were assessed. Results revealed that dietary TA intake significantly rehabilitated MSG-induced dysregulation in cortical tissue by regulating redox balance, cellular homeostasis, and apoptosis. The present study proposes that MSG-induced detrimental effects on cortical tissue are potentially mitigated by TA via modulation of oxidative stress, cell metabolism, and programmed cell death.

Anthracyclines, a class of drugs considered as most effective anticancer drugs, used in the various regimens of cancer chemotherapy, induce long-term impairment of mitochondrial respiration, increase reactive oxygen species, and induce other mechanisms potentially leading to neurotoxicity. According to literature findings, one drug of this class - doxorubicin used to treat e.g. breast cancer, bladder cancer, lymphoma, and acute lymphocytic leukemia may induce such effects in the nervous system. Doxorubicin has poor penetration into the brain due to the lack of drug penetration through the blood-brain barrier, thus the toxicity of this agent is the result of its peripheral action. This action is manifested by cognitive impairment and anatomical changes in the brain and peripheral nervous system found in both preclinical and clinical studies in adult patients. Furthermore, more than 50% of children with cancer are treated with anthracyclines including doxorubicin, which may affect their nervous system, and lead to lifelong damage in many areas of their life. Despite ongoing research into the side effects of this drug, the mechanism of its neurotoxicity action on the central and peripheral nervous system is still not well understood. This review aims to summarize the neurotoxic effects of doxorubicin in preclinical (in vitro and in vivo) research and in clinical studies. Furthermore, it discusses the possible mechanisms of the toxic action of this agent on the nervous system.

Memory impairment is a result of multiple factors including amyloid-beta (Aβ) accumulation. Several receptors are mediated for Aβ transport and signaling. Moreover, blood lipids are involved in Aβ signaling pathway through these receptors. Mediated blood lipid level by statins aims to regulate Aβ signaling cascade. First, the structure of receptors was taken from the RCSB PDB database and prepared with MGLTools and AutoDock tool 4. Second, the ligand was prepared for docking through AutoDock Vina. The binding affinity was calculated, and the binding sites were determined through LigPlot+ software. Besides, pharmacokinetic properties were calculated through multiple software. Finally, a molecular dynamics (MD) simulation was conducted to evaluate ligands stability along with clustering analysis to evaluate proteins connection. Our molecular docking and dynamic analyses revealed silymarin as a potential inhibitor of acetylcholinesterase (AChE), P-glycoprotein, and angiotensin-converting enzyme 2 (ACE2) with 0.704, 0.85, and 0.83 Å for RMSD along with -114.27, -107.44, and -122.51 kcal/mol for free binding energy, respectively. Moreover, rosuvastatin and quercetin have more stability compared to silymarin and donepezil in complex with P-glycoprotein and ACE2, respectively. Eventually, based on clustering and pharmacokinetics analysis, silymarin, rosuvastatin, and quercetin are suggested to be involved in peripheral clearance of Aβ. The bioactivity effects of mentioned statins and antioxidants are predicted to be helpful in treating memory impairment in Alzheimer's disease (AD). Nevertheless, mentioned drug effect could be improved by nanoparticles to facilitate penetration of the blood-brain barrier (BBB).

Dexmedetomidine (Dex) is reported to play a neuroprotective role in Alzheimer's disease (AD). However, the specific mechanism remains unclear. Figure out the underlying molecular mechanism of Dex regulating nerve cell apoptosis in the AD model. The AD model in vitro was established after SH-SY5Y cells were treated with Aβ1 - 42 at (10 μM) for 24 h. The interaction among UPF1, lncRNA SNHG14, and HSPB8 was verified by RIP assay. Cell viability, apoptosis, the level of genes, and proteins were detected by CCK-8 assay, flow cytometry, Western blot, and qRT-PCR, respectively. Dex downregulated lncRNA SNHG14 level and inhibited apoptosis of nerve cells. LncRNA SNHG14 overexpression reversed the inhibitory effect of Dex on nerve cell apoptosis in the AD model. LncRNA SNHG14 attenuated HSPB8 mRNA stability by recruiting UPF1. HSPB8 overexpression inhibited apoptosis of nerve cells in the AD model. Moreover, HSPB8 knockdown reversed the inhibitory effect of Dex on nerve cell apoptosis in the AD model. Our study demonstrated that Dex promoted HSPB8 expression via inhibiting the lncRNA SNHG14/UPF1 axis to inhibit nerve cell apoptosis in AD.

Methamphetamine (METH) and HIV-1 lead to oxidative stress and their combined effect increases the risk of HIV-associated neurocognitive disorder (HAND), which may be related to the synergistic ferroptotic impairment in microglia. Ferroptosis is a redox imbalance cell damage associated with iron overload that is linked to the pathogenic processes of METH and HIV-1. NRF2 is an antioxidant transcription factor that plays a protective role in METH and HIV-1-induced neurotoxicity, but its mechanism has not been fully elucidated. To explore the role of ferroptosis in METH abuse and HIV-1 infection and the potential role of NRF2 in this process, we conducted METH and HIV-1 Tat exposure models using the BV2 microglia cells. We found that METH and HIV-1 Tat reduced the expression of ferroptotic protein GPX4 and the cell viability and enhanced the expression of P53 and the level of ferrous iron, while the above indices were significantly improved with pretreatment of ferrostatin-1. In addition, NRF2 knockdown accelerated METH and HIV-1 Tat-induced BV2 cell ferroptosis accompanied by decreased expression of SLC7A11. On the contrary, NRF2 stimulation significantly increased the expression of SLC7A11 and attenuated ferroptosis in cells. In summary, our study indicates that METH and HIV-1 Tat synergistically cause BV2 cell ferroptosis, while NRF2 antagonizes BV2 cell ferroptotic damage induced by METH and HIV-1 Tat through regulation of SLC7A11. Overall, this study provides potential therapeutic strategies for the treatment of neurotoxicity caused by METH and HIV-1 Tat, providing a theoretical basis and new targets for the treatment of HIV-infected drug abusers.

Spinal cord injury (SCI) is a critical medical condition during which sensorimotor function is lost. Current treatments are still unable to effectively improve these conditions, so it is important to pay attention to other effective approaches. Currently, we investigated the combined effects of human placenta mesenchymal stem cells (hPMSCs)-derived exosomes along with hyperbaric oxygen (HBO) in the recovery of SCI in rats. Ninety male mature Sprague-Dawley (SD) rats were allocated into five equal groups, including; sham group, SCI group, Exo group (underwent SCI and received hPMSCs-derived exosomes), HBO group (underwent SCI and received HBO), and Exo+HBO group (underwent SCI and received hPMSCs-derived exosomes plus HBO). Tissue samples at the lesion site were obtained for the evaluation of stereological, immunohistochemical, biochemical, molecular, and behavioral characteristics. Findings showed a significant increase in stereological parameters, biochemical factors (GSH, SOD, and CAT), IL-10 gene expression and behavioral functions (BBB and EMG Latency) in treatment groups, especially Exo+HBO group, compared to SCI group. In addition, MDA levels, the density of apoptotic cells and gliosis, as well as expression of inflammatory genes (TNF-α and IL-1β) were considerably reduced in treatment groups, especially Exo+HBO group, compared to SCI group. We conclude that co-administration of hPMSCs-derived exosomes and HBO has synergistic neuroprotective effects in animals undergoing SCI.