Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model

Nuclear receptor related 1 (Nurr1) orphan receptor has emerged as a promising contender in ameliorating Parkinson's disease; thus, finding a suitable activator of Nurr1 receptor is an attracting target for treating PD. Cilostazol, a phosphodiesterase-3 inhibitor, recently showed a favorable neuroprotective activity in multiple devastating central disorders, yet the possible antiparkinsonian activity of the drug has not been fully elucidated. Thus, the aim of this study is to explore the neuroprotective effect of cilostazol in rotenone-induced PD model in rats. Cilostazol successfully upregulated Nurr1 expression in PD rats, which resulted in successful preservation of the dopaminergic neuron functionality and integrity as verified by the marked improvement of motor performance in rotarod and open field tests, as well as the increased striatal tyrosine hydroxylase content. Moreover, cilostazol revealed an anti-inflammatory activity as manifested by hampering the global controller of inflammatory signaling pathway, nuclear factor-kappa B, together with its downstream pro-inflammatory cytokines, namely tumor necrosis factor-alpha and interleukin-1 beta, via Nurr-1 upregulation and glycogen synthase kinase 3 beta GSK-3β inhibition. In turn, the increase in GSK-3β inhibited form suppressed the measured downstream apoptotic biomarkers, viz. cytochrome C and caspase-3. Remarkably, cilostazol enhanced autophagy as depicted by hampering both LC3-II and P62 levels possibly through the prominent rise in sirtuin 1 level. In conclusion, cilostazol could be a promising candidate for PD treatment through modulating Nurr1 expression, as well as SIRT-1/autophagy, and GSK-3β/apoptosis cross-regulation. Graphical Abstract In the rat rotenone model of Parkinson's disease (PD), Nurr1 expression was downregulated, GSK-3β was activated, and autophagic flux was inhibited. Those deleterious effects were associated with deteriorated motor functions, striatal TH content, enhanced inflammatory state, and apoptotic cascade. Cilostazol, a phosphodiesterase-3 inhibitor, exerted a potential protective effect against PD through Nurr1 enhancement, GSK-3β/apoptosis modulation, and SIRT-1/autophagy enhancement. Nurr1 nuclear receptor related 1, TH tyrosine hydroxylase, NF-κB nuclear factor κB, TNFα tumor necrosis factor alpha, ILs interleukins, GSK-3β glycogen synthase kinase 3 beta, SIRT-1 sirtuin 1.