Antipsychotic effect of diosgenin in ketamine-induced murine model of schizophrenia: Involvement of oxidative stress and cholinergic transmission

Abstract

A decrease in the levels of antioxidant arsenals exacerbate generation of reactive oxygen/nitrogen species, leading to neurochemical dysfunction, with significant impact on the pathogenesis of psychotic disorders such as schizophrenia. This study examined the preventive and reversal effects of diosgenin, a phyto-steroidal saponin with antioxidant functions in mice treated with ketamine which closely replicates schizophrenia-like symptoms in human and laboratory animals. In the preventive phase, adult mice cohorts were clustered into 5 groups (n = 9). Groups 1 and 2 received saline (10 mL/kg, i.p.), groups 3 and 4 were pretreated with diosgenin (25 and 50 mg/kg), and group 5 received risperidone (0.5 mg/kg) orally for 14 days. Mice in groups 2–5 additionally received a daily dose of ketamine (20 mg/kg, i.p.) or saline (10 mL/kg/day, i.p.). In the reversal phase, mice received intraperitoneal injection of ketamine or saline for 14 consecutive days prior to diosgenin (25 and 50 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) treatment from days 8–14. Mice were assessed for behavioral changes. Oxidative, nitrergic markers, and cholinergic (acetylcholinesterase activity) transmission were examined in the striatum, prefrontal-cortex and hippocampus. Diosgenin prevented and reversed hyperlocomotion, cognitive and social deficits in mice treated with ketamine relative to ketamine groups. The increased acetylcholinesterase, malondialdehyde and nitrite levels produced by ketamine were reduced by diosgenin in the striatum, prefrontal-cortex and hippocampus, but did not reverse striatal nitrite level. Diosgenin increased glutathione, and catalase levels, except for hippocampal catalase activity when compared with ketamine controls. Conclusively, these biochemical changes might be related to the behavioral deficits in ketamine-treated mice, which were prevented and reversed by diosgenin.