4-aminopyridine exerts anxiolytic and pro-cognitive effects in mice model of medial prefrontal cortex ischemia.

Abstract

Brain ischemia is a major global cause of disability, frequently leading to psychoneurological issues. This study investigates the effects of 4-aminopyridine (4-AP) on anxiety, cognitive impairment, and potential underlying mechanisms in a mouse model of medial prefrontal cortex (mPFC) ischemia. Mice with mPFC ischemia were treated with normal saline (NS) or different doses of 4-AP (250, 500, and 1000 µg/kg) for 14 consecutive days. The open field test, elevated plus maze, Barnes maze, and novel object recognition test were used to perform a series of behavioral assessments to evaluate anxiety as well as spatial and episodic memory. Serum corticosterone levels and changes in oxidative stress markers (MDA, SOD, GPx, and TAC) were measured by ELISA. Inflammatory and apoptotic markers (p-P38, NF-κB, IL-1β, TNF-α, p-PI3K, p-AKT, Caspase-3, BAX, and BCL2) were analyzed via western blotting. Results showed that mPFC ischemia induced anxiety-like behavior and disrupted both recognition and spatial memory at the behavioral level. Additionally, ischemia increased serum corticosterone levels, elevated oxidative stress, and upregulated inflammatory and apoptotic markers. However, 4-AP at the highest dose significantly mitigated these behavioral and molecular deficits. These findings suggest that 4-AP alleviates anxiety-like behavior and cognitive impairment associated with mPFC ischemia, possibly through modulation of corticosterone, oxidative stress, inflammation, and apoptotic signaling pathways.