Drug Development

Chronic Unpredictable Stress (CUS) is a widely used model to induce cognitive impairments and neurodegeneration through the activation of the kynurenine (KYN) pathway. Long-term stress causes the production of more cortisol, which activates microglia and raises quinolinic acid (QA). This lowers levels of brain-derived neurotrophic factor (BDNF), which causes neurodegeneration. Avicularin, recognized for its antioxidant and antidepressant properties, was evaluated for its neuroprotective effects against CUS-induced cognitive impairments.

Mice (Swiss albino) exposed to CUS for five weeks were administered avicularin at doses of 50, 100, and 200 mg/kg from 4^th week four to 7^th week. Behavioral assessments, including the forced swim test, sucrose preference test, Morris Water Maze, and Passive Avoidance Test, were conducted in the 6^th th and 7^th weeks. Biochemical analyses evaluated corticosterone, oxidative stress markers, and neurotransmitter levels (serotonin and norepinephrine). The proinflammatory indicators TNF-α, IL-6, IL-1β, and acetylcholinesterase (AChE) activity were measured, and immunohistochemistry evaluated BDNF and amyloid-beta levels.

Avicularin treatment significantly improved cognitive performance, reduced corticosterone levels, and mitigated oxidative stress. Mice treated with 100 and 200 mg/kg doses showed elevated serotonin, norepinephrine, and BDNF levels, with concomitant reductions in amyloid-beta levels, inflammatory cytokines, and AChE activity.

Avicularin demonstrates significant neuroprotective effects against CUS-induced cognitive impairments, reducing neuroinflammation, and enhancing neurotrophic support. These findings underscore its potential as a therapeutic agent for stress-related cognitive dysfunctions.