Ficus patyphylla STEM BARK EXTRACT REVERSES KETAMINE-INDUCED SCHIZOPHRENIC–LIKE BEHAVIORS IN RATS VIA MODULATION OF CHOLINERGIC, NITRERGIC AND OXIDATIVE PATHWAYS

Ketamine challenge is a suitable animal model for evaluating cognitive, positive and negative symptoms of schizophrenia, besides oxidative stress, cholinergic, dopaminergic, GABAergic and nitrergic dysfunctions observed in the disease. Effects of Ficus platyphylla (FP) methanol extract on behavioral alterations triggered by ketamine were investigated in forced swim, open field, and new object identification tests. To examine the part played by nitrergic, cholinergic, and oxidative pathways in the antipsychotic properties of FP, acetylcholinesterase activity, levels of oxidative stress biomarkers, and nitrite in the brain were also evaluated. In silico molecular docking analysis was conducted to predict the interactions between bioactive compounds from FP and potential drug targets for the treatment of schizophrenia. FP administered alone or in conjunction with risperidone (RIS) significantly reversed ketamine-induced schizophrenic-like behaviors in rats; the increased brain levels of glutathione, catalase and superoxide dismutase activities, the decreased acetylcholinesterase activity, levels of nitrite and malonyladehyde in ketamine-treated rats. The bioactive compounds from FP demonstrated binding affinities for the recognized drug targets for pharmacotherapy of schizophrenia, including dopamine, serotonin and metabotropic glutamate receptors, and phosphodiestrases. Our findings revealed that cholinergic, nitrergic, and oxidative pathways were modulated by FP alone or in conjunction with RIS to reverse symptoms akin to schizophrenia triggered by ketamine. These findings further suggest that co-administration of Ficus platyphylla extracts and risperidone may improve the ameliorative effects of risperidone on cognitive, negative, and positive symptoms of schizophrenia.