Neuroscience
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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.
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The present study aimed to investigate the association between the serum SIRT1 protein and the severity of spinal cord injury (SCI) as well as the neurological recovery in mice. In this study, the wild-type (WT), Mx1-Cre+ SIRT1loxP/loxP (Mx1), and LCK-Cre+SIRT1loxP/loxP (LCK) mice were subjected to sham surgery, mild, moderate, or severe SCI, respectively. The serum was collected at intervals of 12 h, 1 day (d), 3 d, 5 d, 7 d, 10 d, 14 d, and 21 d after the injury. ⋯ The results demonstrated that about 7-10 d after SCI, the levels of SIRT1 protein in the serum correlated significantly with the severity of the injury and at 28 d post-injury, there was a distant neurological recovery (BMS score). The serum SIRT1 concentration in both the Mx1 and LCK mice in the sham group was significantly reduced compared to that in the WT mice, and there was a delayed increase in the serum SIRT1 levels after injury. These findings indicate that the SIRT1 concentrations in the serum of the SCI mice closely correlated with the acute severity and neurological outcome.
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The progression of neurodegenerative disorders is mainly characterized by immense neuron loss and death of glial cells. The mechanisms which are active and regulate neuronal cell death are namely necrosis, necroptosis, autophagy and apoptosis. These death paradigms are governed by a set of molecular determinants that are pivotal in their performance and also exhibit remarkable overlapping functional pathways. ⋯ In addition, the review also focuses on the exorbitant number of newer molecules with the potential to cross communicate between death pathways and create a complex cell death scenario. This review highlights recent studies on the inter-dependent regulation of cell death paradigms in neurodegeneration, mediated by cross-communication between pathways. This will help in identifying potential targets for therapeutic intervention in neurodegenerative diseases.
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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.
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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.