Neuroscience
-
Review
The Roles of Oxidative Stress in Regulating Autophagy in Methylmercury-induced Neurotoxicity.
Methylmercury (MeHg) is a potential neurotoxin that is highly toxic to the human central nervous system. Although MeHg neurotoxicity has been widely studied, the mechanism of MeHg neurotoxicity has not yet been fully elucidated. Some research evidence suggests that oxidative stress and autophagy are important molecular mechanisms of MeHg-induced neurotoxicity. ⋯ The current study reviews the activation of Nuclear factor-erythroid-2-related factor (Nrf2)-related oxidative stress pathways and autophagy signaling pathways in the case of MeHg neurotoxicity. In addition, autophagy mainly plays a role in the neurotoxicity of MeHg through mTOR-dependent and mTOR-independent autophagy signaling pathways. Finally, the regulation of autophagy by reactive oxygen species (ROS) and Nrf2 in MeHg neurotoxicity was explored in this review, providing a new concept for the study of the neurotoxicity mechanism of MeHg.
-
The transport mechanism of intestinal α-synuclein to the central nervous system has become a new hot topic in Parkinson's disease (PD) research. It is worth noting that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been reported to be involved in the pathogenesis of PD. After silencing GAPDH expression by GAPDH siRNA, the normal human intestinal epithelial crypt-like (HIEC) and human SH-SY5Y neuroblastoma cell lines were co-cultured with Escherichia coli cells which were transfected with an α-synuclein overexpression plasmid. ⋯ Oxidative stress was assessed by measuring the levels of reactive oxygen species (ROS) using 2',7'-dichlorofluorescein diacetate (DCFH-DA), thiobarbituric acid-reactive substances (TBARS), and antioxidant capacity was assessed by measuring the glutathione (GSH) levels and superoxide dismutase (SOD) activity. The silencing of the expression of GAPDH pre-knockdown was found to reduce the intracellular levels of ROS and lipid peroxidation, enhance autophagy activity, thereby reducing the cell injury, apoptosis and necrosis induced by exogenous α-synuclein protein in SH-SY5Y cells. This study identifies a new therapeutic target of exogenous α-synuclein protein induced SH-SY5Y cell injury and improves our understanding of the pathophysiological role of GAPDH in vitro.
-
α-Synuclein (α-syn), especially its abnormal oligomeric and phosphorylated form, plays a critical role in the pathogenesis of Parkinson's disease (PD). Plasma exosomal α-syn species have been shown to be a promising PD biomarker. However, whether different α-syn species in plasma exosomes (the oligomeric α-syn and the Ser129 phosphorylated α-syn (p-α-syn)) which represent the PD pathogenesis in the brain could be specific peripheral PD biomarker haven't been well elucidated. ⋯ Aggregated α-syn and p-α-syn existed both inside and on the membrane surface of plasma exosomes. The Receiver operating characteristic (ROC) performance of α-syn oligomer/total α-syn in exosomes was moderately helpful in PD diagnosis (AUC = 0.71, sensitivity = 60.5%, specificity = 59.4%), and the ratio of p-α-syn oligomer/total p-α-syn showed similar result (AUC = 0.69, sensitivity = 60.0%, specificity = 59.5%). This study indicates that the oligomeric α-syn/total α-syn and oligomeric p-α-syn/total p-α-syn ratio in plasma exosomes may be applied to assist the PD diagnosis, which needs further research.
-
Clinical trials of new drugs for Alzheimer's disease (AD) have ended with disappointing results, with tremendous resources and time. Repositioning of existing anti-cancer epidermal growth factor receptors (EGFR) inhibitors in various preclinical AD models has gained growing attention in recent years because hyperactivation of EGFR has been implicated in many neurodegenerative disorders, including AD. Many recent studies have established that EGFR inhibition suppresses reactive astrocytes, enhances autophagy, ameliorates Aβ toxicity, neuroinflammation, and regenerates axonal degradation. ⋯ In this perspective article, we recap recent studies to merge data on the neuroprotective effects of EGFR inhibition. By consequent analysis of previous data, we notably find the under-investigated neuroprotective pathways that highlight the importance of additional research of EGFR inhibitors in attempts to be repurposed as burgeoning therapeutic strategies for AD. Finally, we will discuss future prospective challenges in the repositioning of EGFR inhibitors in AD.
-
Alcohol use disorder is one of the most prevalent addictions, strongly influenced by environmental factors. Voluntary physical activity (VPA) has proven to be intrinsically reinforcing and we hypothesized that, as a non-drug reinforcer, VPA could mitigate ethanol-induced rewarding effects. The transcriptional factor cAMP response element binding protein (CREB), and deacetylases isozymes sirtuins 1 and 2 (SIRT-1 and SIRT-2) have a complex interplay and both play a role in the rewarding effects of ethanol. ⋯ Both VPA groups presented lower SIRT-1 levels in the NAc compared to the Sedentary groups. Thus, exposure to running wheels prevented ethanol-rewarding effects and ethanol-induced increases in CREB in the NAc. The molecular alterations underlying CPP prevention may be related to a lower expression of CREB in the NAc of Ethanol-VPA compared to the respective Sedentary group, given the positive correlation between CPP and CREB levels in the Ethanol-Sedentary group.