Sabinene's neuroprotective effect reverses ketamine-induced experimental schizophrenia in mice through enhancement of cholinergic, antioxidant, and anti-inflammatory mechanisms.

Abstract

Schizophrenia is a serious neuropsychiatric disorder marked by oxidative stress, immune system changes, and neurochemical imbalances. Current treatments are constrained by inconsistent effectiveness and side effects. This study evaluates the neuroprotective effects of sabinene, a monoterpene, in a mouse model of ketamine-induced schizophrenia. Male mice received ketamine (20 mg/kg/day, i.p.) for 14 days to induce schizophrenia-like deficits, followed by treatment with sabinene (5 or 10 mg/kg, p.o.) or risperidone (0.5 mg/kg, p.o.) from days 8-14. Neurochemical analyses assessed oxidative stress markers, including superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione (GSH), thiobarbituric acid-reactive substance (TBARS), and nitrite. This was followed by assays of acetylcholinesterase activity and levels of cytokines (IL-6 and IL-10) in the prefrontal cortex, striatum, and hippocampus. Ketamine-induced hyperactivity, social withdrawal and memory impairment compared to the ketamine group, which were reversed by sabinene. Sabinene (10 mg/kg) and risperidone restored SOD, GST, and CAT activities, GSH concentration, and reduced TBARS and nitrite concentrations across regions. The increased IL6 and reduced IL-10 levels by ketamine were reversed by sabinene in the prefrontal cortex, striatum, and hippocampus compared to the ketamine groups. Sabinene (10 mg/kg) also attenuated acetylcholinesterase activity in the prefrontal cortex and hippocampus. The 5 mg/kg dose showed limited efficacy, indicating dose-dependency. Sabinene's efficacy, comparable to risperidone, involves enhancement of the cholinergic system and inhibition of oxidative/nitrergic stress and brain inflammation, suggesting its potential as a therapeutic agent for schizophrenia by improving cholinergic transmission deficits. Further mechanistic and clinical studies are warranted to optimize sabinene's therapeutic benefits and antipsychotic-like potential.