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Abstract
Nuclear receptor related-1 (Nurr1) orphan receptor has emerged as a promising contender in ameliorating Parkinson{u2019}s disease, thus finding a suitable activator of Nurr1 receptor is an attracting target for treating PD. Meanwhile, the deregulation of autophagy, along with other processes such as; inflammation, apoptosis and mitochondrial dysfunction is believed to contribute to the pathogenesis of the disease. The aim of this study is to explore the neuroprotective effect of cilostazol and hydroxychloroquine in rotenone-induced PD model in rats. Both drugs managed to enhance the dopaminergic neurons functionality and integrity as depicted by the increase in the striatal tyrosine hydroxylase content, as well as the improved locomotion and muscle coordination in rotarod and open field. However, this improvement was opposed by hydroxychloroquine induced autophagic inhibition as manifested by enhancing both LC3-II and P62 levels possibly through the prominent decline in sirtuin 1 level and enhanced apoptosis evidenced by cytochrome C and caspase-3 elevation. In conclusion, cilostazol could be a promising candidate for PD treatment through modulating Nurr1 expression, as well as SIRT-1/autophagy, and GSK-3Ý/apoptosis cross-regulation. Where, hydroxychloroquine successfully ameliorated PD motor dysfunction in spite of the fact that both autophagy and apoptosis were deregulated through Nurr1 modulation