Xiujie Li1, Xuefei Wu2, Na Li1, Donglai Li1, Aoran Sui2, Khizar Khan2, Biying Ge1, Sheng Li1, Shao Li1,2, Jie Zhao1. 1. National-Local Joint Engineering Research Center for Drug Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, No 9 Western Section, Lvshun South Road, Dalian City, P.R. China, 116044. 2. Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, Dalian Medical University, No 9 Western Section, Lvshun South Road, Dalian City, P.R. China, 116044.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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. This article is protected by copyright. All rights reserved.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: Unilateral brain injection of 6-OHDA was performed to establish PDmouse 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. KEY RESULTS: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. CONCLUSION AND IMPLICATIONS: 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. This article is protected by copyright. All rights reserved.