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.
Keywords: Microglia; NOX2; Neuroinflammation; Parkinson's disease; SVHRSP.
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