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Functional voltage\u2010gated sodium channels (VGSCs) are involved in regulating microglial function. Here, we aim to investigate the effects of scorpion venom heat\u2010resistant synthesized peptide (SVHRSP) on 6\u2010hydroxydopamine (6\u2010OHDA)\u2010induced Parkinson's disease\u2010like mouse model and reveal its underlying mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Unilateral brain injection of 6\u2010OHDA 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<jats:sub>v<\/jats:sub>1.6 in the regulation of microglia inflammation by SVHRSP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>SVHRSP treatment attenuated motor deficits, dopamine neuron degeneration, activation of glial cells and expression of pro\u2010inflammatory cytokines induced by 6\u2010OHDA lesion. Primary microglia activation and the production of pro\u2010inflammatory cytokines induced by lipopolysaccharide (LPS) were also suppressed by SVHRSP treatment. In addition, SVHRSP could inhibit mitogen\u2010activated protein kinases (MAPKs) pathway, which plays pivotal roles in the pro\u2010inflammatory response. Notably, SVHRSP treatment suppressed the overexpression of microglial Na<jats:sub>v<\/jats:sub>1.6 induced by 6\u2010OHDA and LPS. Finally, it was shown that the anti\u2010inflammatory effect of SVHRSP in microglia was Na<jats:sub>v<\/jats:sub>1.6 dependent and was related to suppression of sodium current and probably the consequent Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> exchange.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>SVHRSP might inhibit neuroinflammation and protect dopamine neurons via down\u2010regulating microglial Na<jats:sub>v<\/jats:sub>1.6 and subsequently suppressing intracellular Ca<jats:sup>2+<\/jats:sup> accumulation to attenuate the activation of MAPKs signalling pathway in microglia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15502","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T21:06:42Z","timestamp":1619125602000},"page":"3553-3569","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Scorpion venom heat\u2010resistant synthesized peptide ameliorates 6\u2010OHDA\u2010induced neurotoxicity and neuroinflammation: likely role of Na<sub>v<\/sub>1.6 inhibition in microglia"],"prefix":"10.1111","volume":"178","author":[{"given":"Xiujie","family":"Li","sequence":"first","affiliation":[{"name":"National\u2010Local Joint Engineering Research Center for Drug Research and Development (R&amp;D) of Neurodegenerative Diseases Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Wu","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology College of Basic Medical Sciences, Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"National\u2010Local Joint Engineering Research Center for Drug Research and Development (R&amp;D) of Neurodegenerative Diseases Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donglai","family":"Li","sequence":"additional","affiliation":[{"name":"National\u2010Local Joint Engineering Research Center for Drug Research and Development (R&amp;D) of Neurodegenerative Diseases Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoran","family":"Sui","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology College of Basic Medical Sciences, Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khizar","family":"Khan","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology College of Basic Medical Sciences, Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biying","family":"Ge","sequence":"additional","affiliation":[{"name":"National\u2010Local Joint Engineering Research Center for Drug Research and Development (R&amp;D) of Neurodegenerative Diseases Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Li","sequence":"additional","affiliation":[{"name":"National\u2010Local Joint Engineering Research Center for Drug Research and Development (R&amp;D) of Neurodegenerative Diseases Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4889-8636","authenticated-orcid":false,"given":"Shao","family":"Li","sequence":"additional","affiliation":[{"name":"National\u2010Local Joint Engineering Research Center for Drug Research and Development (R&amp;D) of Neurodegenerative Diseases Dalian Medical University  Dalian China"},{"name":"Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology College of Basic Medical Sciences, Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhao","sequence":"additional","affiliation":[{"name":"National\u2010Local Joint Engineering Research Center for Drug Research and Development (R&amp;D) of Neurodegenerative Diseases Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,18]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612822666151125000300"},{"issue":"1","key":"e_1_2_14_3_1","first-page":"S21","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: G protein\u2010coupled receptors","volume":"176","author":"Alexander S. 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