HCH6-1, an antagonist of formyl peptide receptor-1, exerts anti-neuroinflammatory and neuroprotective effects in cellular and animal models of Parkinson?s disease

Microglial activation-induced neuroinflammation contributes to onset and progression of sporadic and heredi-tary Parkinson's disease (PD). Activated microglia secrete pro-inflammatory and neurotoxic IL-10, IL-6 and TNF-alpha, which subsequently promote neurodegeneration. Formyl peptide receptor-1 (FPR1) of CNS microglia functions as pattern recognition receptor and is activated by N-formylated peptides, leading to microglial activation, in-duction of inflammatory responses and resulting neurotoxicity. In this study, it was hypothesized that FPR1 activation of microglia causes loss of dopaminergic neurons by activating inflammasome and upregulating IL-10, IL-6 or TNF-alpha and that FPR1 antagonist HCH6-1 exerts neuroprotective effect on dopaminergic neurons. FPR1 agonist fMLF induced activation of microglia cells by causing activation of NLRP3 inflammasome and upregu-lation and secretion of IL-10, IL-6 or TNF-alpha. Conditioned medium (CM) of fMLF-treated microglia cells, which contains neurotoxic IL-10, IL-6 and TNF-alpha, caused apoptotic death of differentiated SH-SY5Y dopaminergic neurons by inducing mitochondrial oxidative stress and activating pro-apoptotic signaling. FPR1 antagonist HCH6-1 prevented fMLF-induced activation of inflammasome and upregulation of pro-inflammatory cytokines in microglia cells. HCH6-1 co-treatment reversed CM of fMLF-treated microglia-induced apoptotic death of dopa-minergic neurons. FPR1 antagonist HCH6-1 inhibited rotenone-induced upregulation of microglial marker Iba-1 protein level, cell death of dopaminergic neurons and motor impairment in zebrafish. HCH6-1 ameliorated rotenone-induced microglial activation, upregulation of FPR1 mRNA, activation of NLRP3 inflammasome, cell death of SN dopaminergic neurons and PD motor deficit in mice. Our results suggest that FPR1 antagonist HCH6-1 possesses anti-neuroinflammatory and neuroprotective effects on dopaminergic neurons by inhibiting micro-glial activation and upregulation of inflammasome activity and pro-inflammatory cytokines.

Automated summary

Microglial activation-induced neuroinflammation plays a role in the onset and progression of Parkinson's disease. Activated microglia secrete pro-inflammatory and neurotoxic cytokines, which contribute to neurodegeneration. This study suggests that the activation of microglia through FPR1 leads to loss of dopaminergic neurons by activating inflammasome and upregulating pro-inflammatory cytokines, and that the FPR1 antagonist HCH6-1 has a neuroprotective effect on dopaminergic neurons.