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

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 Nav 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 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.

CONCLUSIONS AND IMPLICATIONS:

SVHRSP might inhibit neuroinflammation and protect dopamine neurons via down-regulating microglial Nav 1.6 and subsequently suppressing intracellular Ca2+ accumulation to attenuate the activation of MAPKs signalling pathway in microglia.

• Authors: Xiujie Li, Xuefei Wu, Na Li, Donglai Li, Aoran Sui, Khizar Khan, Biying Ge, Sheng Li, Shao Li, Jie Zhao
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 178 Issue 17 Pg. 3553-3569 (09 2021) ISSN: 1476-5381 [Electronic] England
• PMID: 33886140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The British Pharmacological Society.

Chemical References

• Cytokines
• Lipopolysaccharides
• Scorpion Venoms
• Oxidopamine

Topics

• Animals
• Cytokines
• Hot Temperature
• Lipopolysaccharides (toxicity)
• Mice
• Microglia
• Oxidopamine
• Scorpion Venoms (toxicity)