Scorpion venom heat-resistant synthesized peptide ameliorates 6-OHDA-induced neurotoxicity and neuroinflammation: likely role of Nav 1.6 inhibition in microglia

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⁺ /CA²⁺ exchange.

Conclusions and implications: SVHRSP might inhibit neuroinflammation and protect dopamine neurons via down-regulating microglial Na_v 1.6 and subsequently suppressing intracellular CA²⁺ accumulation to attenuate the activation of MAPKs signalling pathway in microglia.