Scorpion venom heat‐resistant synthesized peptide ameliorates 6‐OHDA‐induced neurotoxicity and neuroinflammation: likely role of Na<sub>v</sub>1.6 inhibition in microglia
Xiujie Li, Xuefei Wu, Na Li, Donglai Li, Ao‐Ran Sui, Khizar Khan, Bi-Ying Ge, Sheng Li, Shao Li, Jie Zhao
Abstract
Background and Purpose Microglia‐related inflammation is associated with the pathology of Parkinson's disease. Functional voltage‐gated sodium channels (VGSCs) are involved in regulating microglial function. Here, we aim to investigate the effects of scorpion venom heat‐resistant synthesized peptide (SVHRSP) on 6‐hydroxydopamine (6‐OHDA)‐induced Parkinson's disease‐like mouse model and reveal its underlying mechanism. Experimental Approach Unilateral brain injection of 6‐OHDA was performed to establish Parkinson's disease mouse model. After behaviour test, brain tissues were collected for morphological analysis and protein/gene expression examination. Primary microglia culture was used to investigate the role of sodium channel Na v 1.6 in the regulation of microglia inflammation by SVHRSP. Key Results SVHRSP treatment attenuated motor deficits, dopamine neuron degeneration, activation of glial cells and 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 overexpression of microglial Na v 1.6 induced by 6‐OHDA and LPS. Finally, it was shown that the anti‐inflammatory effect of SVHRSP in microglia was Na v 1.6 dependent and was related to suppression of sodium current and probably the consequent Na + /Ca 2+ exchange. Conclusions and Implications SVHRSP might inhibit neuroinflammation and protect dopamine neurons via down‐regulating microglial Na v 1.6 and subsequently suppressing intracellular Ca 2+ accumulation to attenuate the activation of MAPKs signalling pathway in microglia.