Repaglinide, a meglitinide insulinotropic antidiabetic, was unraveled as a promising therapeutic agent for Huntington's disease by targeting the neuronal calcium sensor downstream regulatory element antagonist modulator (DREAM). However, its mechanistic profile in Parkinson's disease (PD) especially its impact on endoplasmic reticulum (ER) stress, mitophagy, and their interconnections is poorly elucidated. This study is the first to examine the neuroprotective potential of repaglinide in rotenone-induced PD in rats by exploring its effects on DREAM, BiP/ATF6/CHOP ER stress pathway, apoptosis, mitophagy/ autophagy, oxidative stress, astrogliosis/microgliosis, and neuroinflammation. Male Wistar rats were randomly assigned to four groups: groups 1 and 2 received the vehicle or repaglinide (0.5 mg/kg/day p.o). Groups 3 and 4 received rotenone (1.5 mg/kg/48 h s.c) for 21 days; meanwhile, group 4 additionally received repaglinide (0.5 mg/kg/day p.o) for 15 days starting from day 11. Interestingly, repaglinide lessened striatal ER stress and apoptosis as evidenced by reduced BiP/ATF6/CHOP and caspase-3 levels; however, it augmented striatal DREAM mRNA expression. Repaglinide triggered the expression of the mitophagy marker PINK1 and the autophagy protein beclin1 and alleviated striatal oxidative stress through escalating catalase activity. In addition, repaglinide halted astrocyte/microglial activation and neuroinflammation in the striatum as expressed by reducing glial fibrillary acidic protein (GFAP) and ionized calciumbinding adaptor protein 1 (Iba1) immunostaining and decreasing interleukin (IL)-6 and IL-1β levels. Repaglinide restored striatum morphological alterations, intact neuron count, and neurobehavioral motor performance in rats examined by an open field, grip strength, and footprint gait analysis. Conclusively, repaglinide modulates the DREAM-ER stress BiP/ATF6/CHOP cascade, increases mitophagy/autophagy, inhibits apoptosis, and lessens oxidative stress, astrocyte/microglial activation, and neuroinflammation in PD.
