Sinapic acid attenuates PERK-dependent ER stress signaling and resolves α-synuclein pathology in rotenone-induced Parkinson's disease rat model

Abstract

The current study aimed to evaluate the neuroprotective potential of sinapic acid (SA) administration in alleviating Parkinson's disease (PD) features, focusing on its effects in amelioration of endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) signaling, oxidative stress, and alpha-synucleinopathy in chronic ROT-induced PD rats. PD was induced using 11 ROT injections (1.5 mg/kg/48h; s.c.). One day following the fifth ROT dose, rats started treatment with SA (10 mg/kg), SA (20 mg/kg), SA (40 mg/kg), or L-dopa/carbidopa (100/10 mg/kg) daily via oral gavage for 21 consecutive days, followed by assessment of neurobehavioral parameters and subsequent histopathological and neurochemical analyses. Treatment with a high dose of SA amended ROT-induced locomotor deficits with significantly improved open-field ambulation, grooming, and rearing behavior, as well as increased cylinder wall forelimb placements, and prolonged rotarod fall-off latency. Additionally, SA treatment protected nigral dopaminergic neurons from ROT-induced neurodegeneration and dose-dependently preserved nigral tyrosine hydroxylase (TH) immunoexpression. Furthermore, SA treated rats showed markedly improved striatal dopamine (DA) content and diminished striatal alpha synuclein (α-Syn) overexpression. Additionally, SA treatment provided antioxidant properties as evidenced by improved striatal GSH/SOD/Catalase and suppressed MDA levels. Notably, SA administration resulted in significant, dose-dependent attenuation of ER stress sensors PERK, eIF2α, CHOP/GADD135, IRE1α, and ATF6 signaling. These findings provide novel in vivo insights into SA's beneficial neuroprotective properties in amelioration of ROT-induced ER stress via modulation of all three UPR branches, particularly the PERK/eIF2α/CHOP signaling axis, and establishes SA as a promising neurotherapeutic candidate for possible management of PD.