Scorpion venom peptide SVHRSP ameliorates 6-OHDA-induced neurotoxicity and neuroinflammation: potential role of Nav 1.6 inhibition in microglia.

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Microglia-related inflammation is associated with the pathology of Parkinson’s disease (PD). Functional voltage-gated sodium channels (VGSCS) are involved in regulating microglial function. Here, we aim to investigate the effects of SVHRSP (scorpion venom heat-resistant synthesized peptide) on 6-OHDA-induced PD-like mouse model and reveal its underlying mechanism.Unilateral brain injection of 6-OHDA was performed to establish PD mouse model. After behavior test, brain tissuses were collected for morphological analysis and protein/gene expression examination. Primary microglia culture was used to investigate the role of sodium channel Nav 1.6 in the regulation of microglia inflammation by SVHRSP.SVHRSP treatment attenuated motor deficits, dopaminergic neurodegeneration, activation of glial cells as well expression of pro-inflammatory cytokines induced by 6-OHDA lesion. Primary microglia activation and the production of pro-inflammatory cytokines induced by lipopolysaccharide (LPS) were also suppressed by SVHRSP treatment. In addition, SVHRSP could inhibit mitogen-activated protein kinases (MAPKs) pathway which plays pivotal roles in the pro-inflammatory response. Notably, SVHRSP treatment suppressed the over-expression of microglial Nav 1.6 induced by 6-OHDA and LPS. Finally, it was shown that the anti-inflammatory effect of SVHRSP in microglia was Nav 1.6 dependent and was related to suppression of sodium current and probably the consequent Na+ /Ca2+ exchange.SVHRSP might inhibit neuroinflammation and protect dopaminergic neurons via down-regulating microglial Nav 1.6 and subsequently suppressing intracellular Ca2+ accumulation to attenuate the activation of MAPKs signaling pathway in microglia.

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Authors: Xiujie Li, Xuefei Wu, Na Li, Donglai Li, Aoran Sui, Khizar Khan, Biying Ge, Sheng Li, Shao Li, Jie Zhao