Anti‐oxidative and anti‐neuroinflammatory role of Necrostatin‐1s and docosahexaenoic acid in RIP‐1‐mediated neurotoxicity in MPTP‐induced Parkinson's disease model

Abstract Parkinson's disease (PD) is a neuromuscular ailment that affects people in their later years and causes both motor and non‐motor deficits. Receptor‐interacting protein‐1 (RIP‐1) is a critical participant in necroptotic cell death, possibly through an oxidant–antioxidant imbalance and cytokine cascade activation in PD pathogenesis. The present study examined the role of RIP‐1‐mediated necroptosis and neuroinflammation in the MPTP‐induced PD mouse model, as well as their protection by Necrostatin‐1s (an RIP signalling inhibitor), antioxidant DHA and their functional interaction. BALB/c mice were given acute MPTP therapy (4 injections of 15 mg/kg i.p. at 2‐h intervals) on day 1. After MPTP intoxication, Necrostatin‐1s (Nec‐1s; 8 mg/kg/day, i.p.) and DHA (300 mg/kg/day, p.o.) treatments were given once daily for 7 days. The Nec‐1s treatment prevented MPTP‐induced behavioural, biochemical and neurochemical alterations, and the addition of DHA increases Nec‐1s' neuroprotective impact. In addition, Nec‐1s and DHA significantly improve the survival of TH‐positive dopaminergic neurons and lower expression levels of the inflammatory cytokines, IL‐1β and TNF‐α. Furthermore, Nec‐1s dramatically reduced RIP‐1 expression, whereas DHA had little effect. Our research raises the possibility that neuroinflammatory signalling and acute MPTP‐induced necroptosis are both mediated by TNFR1‐driven RIP‐1 activity. In this study, RIP‐1 ablation through Nec‐1s and the addition of DHA showed a reduction in the levels of pro‐inflammatory and oxidative markers, as well as protection from MPTP‐driven dopaminergic degeneration and neurobehavioural changes, suggesting potential therapeutic applications. For a better understanding, additional research about the mechanism(s) behind Nec‐1s and DHA is required.