Neurotoxicity Research最新文献

This study elucidates the molecular mechanisms by which FABP3 regulates neuronal apoptosis via mitochondrial autophagy in the context of cerebral ischemia-reperfusion (I/R). Employing a transient mouse model of middle cerebral artery occlusion (MCAO) established using the filament method, brain tissue samples were procured from I/R mice. High-throughput transcriptome sequencing on the Illumina CN500 platform was performed to identify differentially expressed mRNAs. Critical genes were selected by intersecting I/R-related genes from the GeneCards database with the differentially expressed mRNAs. The in vivo mechanism was explored by infecting I/R mice with lentivirus. Brain tissue injury, infarct volume ratio in the ischemic penumbra, neurologic deficits, behavioral abilities, neuronal apoptosis, apoptotic factors, inflammatory factors, and lipid peroxidation markers were assessed using H&E staining, TTC staining, Longa scoring, rotation experiments, immunofluorescence staining, and Western blot. For in vitro validation, an OGD/R model was established using primary neuron cells. Cell viability, apoptosis rate, mitochondrial oxidative stress, morphology, autophagosome formation, membrane potential, LC3 protein levels, and colocalization of autophagosomes and mitochondria were evaluated using MTT assay, LDH release assay, flow cytometry, ROS/MDA/GSH-Px measurement, transmission electron microscopy, MitoTracker staining, JC-1 method, Western blot, and immunofluorescence staining. FABP3 was identified as a critical gene in I/R through integrated transcriptome sequencing and bioinformatics analysis. In vivo experiments revealed that FABP3 silencing mitigated brain tissue damage, reduced infarct volume ratio, improved neurologic deficits, restored behavioral abilities, and attenuated neuronal apoptosis, inflammation, and mitochondrial oxidative stress in I/R mice. In vitro experiments demonstrated that FABP3 silencing restored OGD/R cell viability, reduced neuronal apoptosis, and decreased mitochondrial oxidative stress. Moreover, FABP3 induced mitochondrial autophagy through ROS, which was inhibited by the free radical scavenger NAC. Blocking mitochondrial autophagy with sh-ATG5 lentivirus confirmed that FABP3 induces mitochondrial dysfunction and neuronal apoptosis by activating mitochondrial autophagy. In conclusion, FABP3 activates mitochondrial autophagy through ROS, leading to mitochondrial dysfunction and neuronal apoptosis, thereby promoting cerebral ischemia-reperfusion injury.

The white matter is an important constituent of the central nervous system, containing axons, oligodendrocytes, and its progenitor cells, astrocytes, and microglial cells. Oligodendrocytes are central for myelin synthesis, the insulating envelope that protects axons and allows normal neural conduction. Both, oligodendrocytes and myelin, are highly vulnerable to toxic factors in many neurodevelopmental and neurodegenerative disorders associated with disturbances of myelination. Here we review the main alterations in oligodendrocytes and myelin observed in some organic acidurias/acidemias, which correspond to inherited neurometabolic disorders biochemically characterized by accumulation of potentially neurotoxic organic acids and their derivatives. The yet incompletely understood mechanisms underlying the high vulnerability of OLs and/or myelin in glutaric acidemia type I, the most prototypical cerebral organic aciduria, are particularly discussed.

Nonketotic hyperglycinemia (NKH) is an inherited disorder of amino acid metabolism biochemically characterized by the accumulation of glycine (Gly) predominantly in the brain. Affected patients usually manifest with neurological symptoms including hypotonia, seizures, epilepsy, lethargy, and coma, the pathophysiology of which is still not completely understood. Treatment is limited and based on lowering Gly levels aiming to reduce overstimulation of N-methyl-D-aspartate (NMDA) receptors. Mounting in vitro and in vivo animal and human evidence have recently suggested that excitotoxicity, oxidative stress, and bioenergetics disruption induced by Gly are relevant mechanisms involved in the neuropathology of NKH. This brief review gives emphasis to the deleterious effects of Gly in the brain of patients and animal models of NKH that may offer perspectives for the development of novel adjuvant treatments for this disorder.

Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in pathological conditions including Parkinson's disease (PD). This study investigates the role of anti-oxidant protein paraoxonase 2 (PON2) in ER stress and OS in PD, along with its regulatory molecule. PD was induced in C57BL/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and in SH-SY5Y cells using 1-methyl-4-phenylpyridinium. PON2 was found to be poorly expressed in the substantia nigra pars compacta (SNc) of PD mice, and its overexpression improved motor coordination of mice. Through the evaluation of tyrosine hydroxylase, dopamine transporter, reactive oxygen species (ROS), and C/EBP homologous protein (CHOP) levels and neuronal loss in mice, as well as the examination of CHOP, glucose-regulated protein 94 (GRP94), GRP78, caspase-12, sarco/endoplasmic reticulum calcium ATPase 2, malondialdehyde, and superoxide dismutase levels in SH-SY5Y cells, we observed that PON2 overexpression mitigated ER stress, OS, and neuronal apoptosis both in vivo and in vitro. Forkhead box A1 (FOXA1) was identified as a transcription factor binding to the PON2 promoter to activate its transcription. Upregulation of FOXA1 similarly protected against neuronal loss by alleviating ER stress and OS, while the protective roles were abrogated by additional PON2 silencing. In conclusion, this study demonstrates that FOXA1-mediated transcription of PON2 alleviates ER stress and OS, ultimately reducing neuronal apoptosis in PD.

Central nervous system oxygen toxicity (CNS-OT) is a complication of hyperbaric oxygen (HBO) treatment, with limited prevention and treatment options available. In this study, we aimed to explore the effect of polyethylene glycol 300 (PEG300) on CNS-OT and underlying mechanisms. Motor and cognitive functions of mice in normobaric conditions were evaluated by Morris water maze, passive active avoidance, and rotarod tests. HBO was applied at 6 atmospheres absolute (ATA) for 30 min after drug administration. The latency period of convulsion in mice was recorded, and hippocampal tissues were extracted for biochemical experiments. Our experimental results showed that PEG300 extended the convulsion latencies in CNS-OT mice, reduced oxidative stress and inflammation levels in hippocampal tissues. Furthermore, PEG300 preserved mitochondrial integrity and maintained mitochondrial membrane potential in hippocampal tissue by upregulating Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α). This protective effect was enhanced following the administration of ZLN005, an agonist of PGC-1a. Hence, our study suggests that PEG300 might exert protective effects by upregulating PGC-1α expression and preserving mitochondrial health, offering promising prospects for CNS-OT treatment.

Ethanol (EtOH) intake and noise exposure are particularly concerning among human adolescents because the potential to harm brain. Unfortunately, putative underlying mechanisms remain to be elucidated. Moreover, implementing non-pharmacological strategies, such as enriched environments (EE), would be pertinent in the field of neuroprotection. This study aims to explore possible underlying triggering mechanism of hippocampus-dependent behaviors in adolescent animals of both sexes following ethanol intake, noise exposure, or a combination of both, as well as the impact of EE. Adolescent Wistar rats of both sexes were subjected to an intermittent voluntary EtOH intake paradigm for one week. A subgroup of animals was exposed to white noise for two hours after the last session of EtOH intake. Some animals of both groups were housed in EE cages. Hippocampal-dependent behavioral assessment and hippocampal oxidative state evaluation were performed. Results show that different hippocampal-dependent behavioral alterations might be induced in animals of both sexes after EtOH intake and sequential noise exposure, that in some cases are sex-specific. Moreover, hippocampal oxidative imbalance seems to be one of the potential underlying mechanisms. Additionally, most behavioral and oxidative alterations were prevented by EE. These findings suggest that two frequently found environmental agents may impact behavior and oxidative pathways in both sexes in an animal model. In addition, EE resulted a partially effective neuroprotective strategy. Therefore, it could be suggested that the implementation of a non-pharmacological approach might also potentially provide neuroprotective advantages against other challenges. Finally, considering its potential for translational human benefit might be worth.

Parkinson's disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson's disease (PD) and Alzheimer's disease (AD). Although it is assumed that alpha-synuclein ( $\alpha$ -Syn), amyloid beta (A $\beta$ ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10 $\mu$ M) for 24 h. ROT provokes loss of $\Delta \Psi m$ , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser⁹³⁵) concomitantly with phosphorylation of $\alpha$ -synuclein ( $\alpha$ -Syn, Ser¹²⁹), induces accumulation of intracellular A $\beta$ (iA $\beta$ ), oxidized DJ-1 (Cys¹⁰⁶), as well as phosphorylation of TAU (Ser²⁰²/Thr²⁰⁵), increases the phosphorylation of c-JUN (Ser⁶³/Ser⁷³), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- $\alpha$ (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p- $\alpha$ -Syn, iA $\beta$ , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.

Early and prolonged exposure to anesthetic agents could cause neurodevelopmental disorders in children. Astrocytes, heavily outnumber neurons in the brain, are crucial regulators of synaptic formation and function during development. However, how general anesthetics act on astrocytes and the impact on cognition are still unclear. In this study, we investigated the role of ferroptosis and GPX4, a major hydroperoxide scavenger playing a pivotal role in suppressing the process of ferroptosis, and their underlying mechanism in isoflurane-induced cytotoxicity in astrocytes and cognitive impairment. Our results showed that early 6 h isoflurane anesthesia induced cognitive impairment in mice. Ferroptosis-relative genes and metabolic changes were involved in the pathological process of isoflurane-induced cytotoxicity in astrocytes. The level of GPX4 was decreased while the expression of 4-HNE and generation of ROS were elevated after isoflurane exposure. Selectively blocking ferroptosis with Fer-1 attenuated the abovementioned cytotoxicity in astrocytes, paralleling with the reverse of the changes in GPX4, ROS and 4-HNE secondary to isoflurane anesthesia. Fer-1 attenuated the cognitive impairment induced by prolonged isoflurane exposure. Thus, ferroptosis conduced towards isoflurane-induced cytotoxicity in astrocytes via suppressing GPX4 and promoting lipid peroxidation. Fer-1 was expected to be an underlying intervention for the neurotoxicity induced by isoflurane in the developing brain, and to alleviate cognitive impairment in neonates.

Oxygen (O₂) supplementation is commonly used to treat hypoxia in patients with respiratory failure. However, indiscriminate use can lead to hyperoxia, a condition detrimental to living tissues, particularly the brain. The brain is sensitive to reactive oxygen species (ROS) and inflammation caused by high concentrations of O₂, which can result in brain damage and mitochondrial dysfunction, common features of neurodegenerative disorders. Hyperoxia leads to increased production of ROS, causing oxidative stress, an imbalance between oxidants and antioxidants, which can damage tissues. The brain is particularly vulnerable to oxidative stress due to its lipid composition, high O₂ consumption rate, and low levels of antioxidant enzymes. Moreover, hyperoxia can cause vasoconstriction and decreased O₂ supply to the brain, posing a challenge to redox balance and neurodegenerative processes. Studies have shown that the severity of hyperoxia-induced brain damage varies with inspired O₂ concentration and duration of exposure. Therefore, careful evaluation of the balance between benefits and risks of O₂ supplementation, especially in clinical settings, is crucial.