Potential role of PPAR-γ/MCT1-related mechanisms in INT131-mediated protection against chronic stress-induced...

Chronic unpredictable stress (CUS) is a significant contributor to neurobehavioral changes and cognitive impairment, largely driven by disruptions in cellular homeostasis, elevated corticosterone levels and altered neurotransmitter dynamics. The PPAR-γ/MCT1 pathway plays a crucial role in regulating energy balance, modulating glucose and lipid metabolism, making it a potential target for therapeutic interventions. CUS can alter the expression of PPAR-γ & MCT1 disrupting glucose and lipid metabolism contributing to metabolic dysregulation and stress -related disorders. This study investigates the neuroprotective effects of INT131, a selective PPAR-γ agonist, in mitigating CUS-induced neurobehavioral deficits through modulation of MCT1 signalling. Swiss albino mice were exposed to varied stressors over 56 days to induce CUS. Behavioral assessments including the elevated plus maze (EPM), tail suspension test (TST), sucrose preference test (SPT), and Morris Water Maze (MWM) were used to evaluate anxiety, depression-like behavior, and memory impairment. INT131 was administered orally at 5 and 10 mg/kg doses. Fluoxetine (20 mg/kg, p.o.) served as the positived neuronal architecte control. INT131 significantly alleviated CUS-induced behavioral abnormalities and normalized corticosterone, serotonin, and dopamine levels. It also attenuated oxidative stress and inflammatory cytokines, reduced acetylcholinesterase activity, and preserved neuronal architecture, as confirmed by histological analysis. Importantly, co-treatment with CHCA (100 mg/kg, i.p.), a selective MCT1 inhibitor, abolished the neuroprotective effects of INT131, indicating MCT1's mechanistic involvement. This study demonstrates that INT131 exerts robust neuroprotective effects through the PPAR-γ/MCT1 pathway and supports its potential as a candidate for managing stress-related neurobehavioral and cognitive disorders.