Involvement of GABAergic, BDNF and Nox-2 mechanisms in the prevention and reversal of ketamine-induced schizophrenia-like behavior by morin in mice

Publication date: Available online 13 March 2018
Source:Brain Research Bulletin
Author(s): Benneth Ben-Azu, Adegbuyi Oladele Aderibigbe, Abayomi Mayowa Ajayi, Aya-Ebi Okubo Eneni, Solomon Umukoro, Ezekiel O. Iwalewa
GABAergic (Gamma-aminobutyric acid) and neurotrophic derangements have important implication in schizophrenia, a neuropsychiatric disease. Previous studies have shown that nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) alters GABAergic and neurotrophic activities via inflammatory and oxidative pathways. Thus, it has been proposed that agents with anti-oxidant and anti-inflammatory properties might be beneficial for the treatment of the disease. Morin is neuroactive bioflavonoid compound, which has been reported to demonstrate antipsychotic and anti-oxidant/anti-inflammatory activities. In this study, we further evaluated its effects on the brain markers of GABAergic, neurotrophic and oxidative alterations in the preventive and reversal of schizophrenia-like behavior induced by ketamine (KET). In the prevention protocol, adult mice were treated intraperitoneally with morin (100 mg/kg), haloperidol (1 mg/kg/day), risperidol (0.5 mg/kg/day), or saline (10 mL/kg/day) for 14 consecutive days. In addition, the animals were administered KET (20 mg/kg/day) from the 8th to the 14th day. In the reversal protocol, the animals received KET or saline for 14 days. From 8thto 14th days mice were additionally treated with morin, haloperidol, risperidone or saline. Schizophrenic-like behaviors consisting of positive (stereotypy test), negative (despair test) and cognitive (novel-object recognition test) symptoms were evaluated. Afterwards, brain levels of biomarkers of GABAergic (Glutamic acid decarboxylase-67, GAD67), neurotrophic (Brain-derived neurotrophic factor, BDNF) and oxidative [NADPH-oxidase, superoxide dismutase, (SOD) and catalase (CAT)] alterations were determined in the striatum, prefrontal cortex (PFC) and hippocampus, respectively. Morin prevented and reversed KET-induced increased stereotypy, behavioral despair in forced-swim test and deficit in cognitive functions. Also, morin and risperidone but not haloperidol, prevented and reversed the decreases in expressions of GAD67 and BDNF immunoreactivity in the striatum, PFC and hippocampus caused by KET. Moreover, morin and risperidone decreased regional brain expressions of NADPH-oxidase immunopositive cells and increased endogenous anti-oxidant enzymes (SOD and CAT) in the striatum, PFC and hippocampus, respectively. Taken together, these findings further suggest that the antipsychotic-like activity of morin maybe mediated via mechanisms related to enhancement of GABAergic neurotransmission and neurotrophic factor, and suppression of NADPH-oxidase induced oxidative damage in mice.

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