Taurine, an essential ß-amino acid insulates against ketamine-induced experimental psychosis by enhancement of cholinergic neurotransmission, inhibition of oxidative/nitrergic imbalances, and suppression of COX-2/iNOS immunoreactions in mice.

Cholinergic, oxidative, nitrergic alterations, and neuroinflammation are some key neuropathological features common in schizophrenia disease. They involve complex biological processes that alter normal behavior. The present treatments used in the management of the disorder remain ineffective together with some serious side effects as one of their setbacks. Taurine is a naturally occurring essential ß-amino acid reported to elicit antipsychotic property in first episode psychosis in clinical setting, thus require preclinical investigation. Hence, we set out to investigate the effects of taurine in the prevention and reversal of ketamine-induced psychotic-like behaviors and the associated putative neurobiological mechanisms underlying its effects. Adult male Swiss mice were sheared into three separate cohorts of experiments (n = 7): drug alone, preventive and reversal studies. Treatments consisted of saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) with concomitant ketamine (20 mg/kg/i.p./day) injections between days 8-14, or 14 days entirely. Behavioral hyperactivity, despair, cognitive impairment, and catalepsy were measured. Brain oxidative/nitrergic imbalance, immunoreactivity (COX-2 and iNOS), and cholinergic markers were determined in the striatum, prefrontal-cortex, and hippocampus. Taurine abates ketamine-mediated psychotic-like episodes without cataleptogenic potential. Taurine attenuated ketamine-induced decrease in glutathione, superoxide-dismutase and catalase levels in the striatum, prefrontal-cortex and hippocampus. Also, taurine prevented and reversed ketamine-mediated elevation of malondialdehyde, nitrite contents, acetylcholinesterase activity, and suppressed COX-2 and iNOS expressions in a brain-region dependent manner. Conclusively, taurine insulates against ketamine-mediated psychotic phenotype by normalizing brain central cholinergic neurotransmissions, oxidative, nitrergic and suppression of immunoreactive proteins in mice brains.

Prevention and reversal of ketamine-induced experimental psychosis in mice by the neuroactive flavonoid, hesperidin: The role of oxidative and cholinergic mechanisms.

Currently, prevailing evidence have identified cholinergic and oxidative pathways as important therapeutic targets for abating ketamine-induced schizophrenia-like behavior. Thus, this study evaluated the ability of hesperidin, a naturally occurring antioxidant and neuroprotective flavonoid, to prevent and reverse ketamine-induced schizophrenia-like behaviors and changes in cholinergic, oxidative and nitrergic status in mice. Forty-eight male Swiss mice were allotted into the preventive and reversal studies with 4 groups (n = 6) each. In the preventive study, groups 1 and 2 received vehicle (10 mL/kg/p.o./day), while groups 3 and 4 had hesperidin (100 mg/kg/p.o./day) for 14 days, but ketamine (20 mg/kg/i.p./day) was concurrently given to groups 2 and 4 from days 8-14. In the reversal study, groups 1 and 3 received vehicle, groups 2 and 4 were pretreated with ketamine for 14 days. Nevertheless, groups 3 and 4 additionally received hesperidin from days 8-14. Thereafter, schizophrenia-like behavior from exploratory activity, open-field (positive symptoms), Y-maze (cognitive symptoms) and social interaction (negative symptoms) tests were evaluated. Brain levels of oxidative/nitrergic (glutathione, superoxide-dismutase, malondialdehyde and nitrite levels) and cholinergic (acetylcholinesterase activity) markers were measured in the prefrontal-cortex, striatum and hippocampus. Hesperidin prevents and reverses ketamine-induced hyperactivities, social withdrawal and cognitive impairment. Also, hesperidin prevented and reversed ketamine-induced decrease in glutathione and superoxide-dismutase levels in the prefrontal-cortical, striatal and hippocampal brain regions in mice. Consequently, hesperidin attenuated ketamine-induced increase in malondialdehyde, nitrite levels and acetylcholinesterase activities in the prefrontal-cortex, striatum and hippocampus, respectively. The study showed that hesperidin prevents and reverses ketamine-induced schizophrenia-like behavior through inhibition of oxidative/nitrergic stress and acetylcholinesterase activity in mice brains. Therefore, these findings suggest that hesperidin dietary supplementation could provide natural nutritional intervention to protect against epigenetic-induced mental ill-health like schizophrenia, and thus serve as an important agent for nutritional psychiatry.