Clozapine Mitigates Lipopolysaccharide-Induced Cognitive Dysfunction by Modulating Cholinergic Function, Oxidative Stress, and Apoptotic Signaling in Rats

BACKGROUND: Clozapine (CLZ) is an atypical antipsychotic mainly prescribed for treatment-resistant schizophrenia. Beyond psychotic symptoms, patients often exhibit persistent cognitive impairments across domains such as attention, learning, and memory. The mechanisms by which CLZ may influence cognition and provide neuroprotection are not fully elucidated. Accordingly, this study examined how CLZ modulates lipopolysaccharide (LPS)-induced neurotoxicity in rats. METHOD: Rats were administered LPS to induce cognitive impairment and subsequently treated with CLZ. Behavioral assessments were performed using maze tests (elevated plus-maze (EPM), novel object recognition (NOR), and Y-maze). Biochemical analyses included cholinergic function (acetylcholine (ACh)), neurodegeneration-associated enzymes (glycogen synthase kinase-3 beta (GSK-3β), β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), and dipeptidyl peptidase-4 (DPP-4)), oxidative stress markers (lipid Peroxidation (LPO), catalase, and reduced glutathione (GSH)), and apoptotic proteins (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved Caspase-3 (c-Caspase-3)). RESULTS: CLZ treatment markedly improved performance in EPM, NOR, and Y-maze tasks, indicating recovery of cognitive function in LPS-exposed rats. At the molecular level, CLZ enhanced ACh levels, upregulated the anti-apoptotic protein Bcl-2, and restored antioxidant defenses (catalase and GSH). Conversely, CLZ reduced LPS-induced neurotoxicity by lowering GSK-3β activity, LPO, and pro-apoptotic markers (Bax and c-Caspase-3). CONCLUSION: The findings demonstrate that CLZ exerts neuroprotective effects in an LPS-induced rat model, improving cognition through modulation of cholinergic transmission, oxidative stress, and apoptosis pathways. These results clarify key mechanistic pathways through which CLZ may exert cognitive benefits and highlight its potential relevance for improving schizophrenia-related cognitive dysfunction. Further molecular studies are warranted to confirm and extend these observations toward clinical translation.