Redox modulation contributes to the antidepressant-like and neuroprotective effects of 7-chloro-4-(phenylselanyl)quinoline in an Alzheimer’s disease model

OBJECTIVES: Alzheimer's disease (AD) is characterized by cognitive impairment and neuropsychiatric disturbances, including depression, both tightly linked to redox imbalance and neuroinflammatory activation. This study investigated whether the selenium-containing compound 7-chloro-4-(phenylselanyl)quinoline (4-PSQ) mitigates behavioral and biochemical alterations in a β-amyloid (Aβ)-induced mouse model of AD through modulation of redox-regulated pathways. METHODS: Male Swiss mice received intracerebroventricular Aβ (25-35) or saline (3 µL/site) and were treated orally for seven days with 4-PSQ (1 mg/kg), paroxetine (1 mg/kg), or donepezil (1 mg/kg). Depressive-like behavior and memory performance were assessed, followed by determination of plasma corticosterone, reactive species levels, lipid peroxidation, antioxidant enzyme activities, neuroinflammatory mediators, and acetylcholinesterase (AChE) activity in the hippocampus and prefrontal cortex of mice. RESULTS: 4-PSQ significantly reversed Aβ-induced depressive behavior and memory impairment. The compound normalized plasma corticosterone levels, reduced reactive species and lipid peroxidation, and restored antioxidant enzyme activity. It also decreased the expression of inflammatory markers while regulating AChE activity, indicating concomitant modulation of redox, neuroimmune, and cholinergic pathways. CONCLUSION: By restoring redox homeostasis and attenuating neuroinflammatory responses, 4-PSQ effectively counteracted behavioral and biochemical disruptions associated with Aβ toxicity. These findings support 4-PSQ as a promising selenium-based therapeutic candidate targeting redox-driven features of AD, including comorbid depression and cognitive decline.