National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, 116044, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China.
Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
Free Radic Biol Med. 2022 Aug 1;188:363-374. doi: 10.1016/j.freeradbiomed.2022.06.241. Epub 2022 Jun 24.
Current treatment of Parkinson's disease (PD) ameliorates symptoms but fails to block disease progression. This study was conducted to explore the protective effects of SVHRSP, a synthetic heat-resistant peptide derived from scorpion venom, against dopaminergic neurodegeneration in experimental models of PD. Results showed that SVHRSP dose-dependently reduced the loss of dopaminergic neuron in the nigrostriatal pathway and motor impairments in both rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse PD models. Microglial activation and imbalance of M1/M2 polarization were also abrogated by SVHRSP in both models. In rotenone-treated primary midbrain neuron-glial cultures, loss of dopaminergic neuron and microglial activation were mitigated by SVHRSP. Furthermore, lipopolysaccharide (LPS)-elicited microglial activation, M1 polarization and related dopaminergic neurodegeneration in primary cultures were also abrogated by SVHRSP, suggesting that inhibition of microglial activation contributed to SVHRSP-afforded neuroprotection. Mechanistic studies revealed that SVHRSP blocked both LPS- and rotenone-induced microglial NADPH oxidase (NOX2) activation by preventing membrane translocation of cytosolic subunit p47phox. NOX2 knockdown by siRNA markedly attenuated the inhibitory effects of SVHRSP against LPS- and rotenone-induced gene expressions of proinflammatory factors and related neurotoxicity. Altogether, SVHRSP protects dopaminergic neurons by blocking NOX2-mediated microglial activation in experimental PD models, providing experimental basis for the screening of clinical therapeutic drugs for PD.
目前治疗帕金森病（PD）的方法虽然可以改善症状，但无法阻止疾病的进展。本研究旨在探索源自蝎子毒液的耐热合成肽 SVHRSP 对 PD 实验模型中多巴胺能神经元退行性变的保护作用。结果表明，SVHRSP 呈剂量依赖性地减少了鱼藤酮和 1-甲基-4-苯基-1,2,3,6-四氢吡啶/丙磺舒（MPTP/p）诱导的 PD 小鼠模型中黑质纹状体通路中多巴胺能神经元的丢失和运动障碍。SVHRSP 还可阻断两种模型中小胶质细胞的激活和 M1/M2 极化失衡。在鱼藤酮处理的原代中脑神经元-神经胶质培养物中，SVHRSP 减轻了多巴胺能神经元的丢失和小胶质细胞的激活。此外，SVHRSP 还阻断了脂多糖（LPS）诱导的原代培养物中小胶质细胞的激活、M1 极化和相关的多巴胺能神经退行性变，表明抑制小胶质细胞激活是 SVHRSP 发挥神经保护作用的机制之一。机制研究表明，SVHRSP 通过阻止胞质亚基 p47phox 的膜易位来阻断 LPS 和鱼藤酮诱导的小胶质细胞 NADPH 氧化酶（NOX2）的激活。用 siRNA 敲低 NOX2 可显著减弱 SVHRSP 对 LPS 和鱼藤酮诱导的促炎因子基因表达和相关神经毒性的抑制作用。总之，SVHRSP 通过阻断 NOX2 介导的小胶质细胞激活来保护多巴胺能神经元，为筛选 PD 的临床治疗药物提供了实验依据。
