PERK activation mediates neuroprotection against chronic unpredictable stress-induced neurobehavioral changes via the TFEB pathway

Abstract

Chronic unpredictable stress (CUS) is a significant contributor to neurobehavioral changes, via disrupted cellular homeostasis, corticosterone and altered neurotransmitter dynamics. The PERK (Protein Kinase RNA-like Endoplasmic Reticulum Kinase)-TFEB (Transcription factor EB) pathway integrates stress responses with autophagy and lysosomal biogenesis to maintain cellular resilience, influencing oxidative stress, neuroinflammation and neurodegeneration. Hence, this study was intended to explore the possible involvement of PERK-TFEB pathway in mediating the neuroprotective effects of SB202190 (a PERK activator) in mitigating neurobehavioral changes induced by CUS. For evaluating the impact pharmacological interventions on neurobehavioral alterations, the Swiss albino either sex mice were subjected to different stressors for 8 weeks. The parameters for anxiety-like behaviour, depressive-like behaviour and memory impairment were assessed by elevated plus maze, sucrose preference test, tail suspension test, forced swim test, Morris water maze and passive avoidance task. The levels of corticosterone, dopamine, serotonin, biochemical parameters of oxidative stress, inflammatory mediators, and acetylcholinesterase (AChE) activity along with the histological changes were also examined. Administration of SB202190 (5 and 10 mg/kg) improved anxiety-like behaviour, depression-like behaviour, spatial learning and memory retention, histological changes; restored corticosterone, dopamine levels, AChE activity, oxidative stress and inflammatory markers and serotonin levels in CUS-exposed mice compared to controls. Molecular docking studies were carried out to reveal the binding interaction of SB202190 with TFEB, suggesting that it may modulate TFEB activity. It was also observed that these neuroprotective effects of SB202190 were significantly abolished by pre-treatment with eltrombopag (50 mg/kg, p.o.), a TFEB inhibitor, which signifies the involvement of TFEB signalling in protective mechanism of SB202190 that may have resulted in enhancement of TFEB-mediated autophagy. Therefore, this study highlights the critical role of PERK- TFEB pathway in neuroprotection as well as highlights mechanism and therapeutic potential of SB202190 in alleviating neurobehavioral changes and memory dysfunction associated with chronic unpredictable stress.