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Involvement of GABAergic, BDNF and Nox-2 mechanisms in the prevention and reversal of ketamine-induced schizophrenia-like behavior by morin in mice.
- Source :
-
Brain research bulletin [Brain Res Bull] 2018 May; Vol. 139, pp. 292-306. Date of Electronic Publication: 2018 Mar 13. - Publication Year :
- 2018
-
Abstract
- 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/day), haloperidol (1 mg/kg/day), risperidone (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 8th to 14th days mice were additionally treated with morin, haloperidol, risperidone or saline. Schizophrenic-like behaviors consisting of positive (stereotypy test), negative (behavioral despair in forced swim test) and cognitive (novel-object recognition test) symptoms were evaluated. Afterwards, brain levels of biomarkers of GABAergic (Glutamic acid decarboxylase-67, GAD <subscript>67</subscript> ), 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 significantly (p < 0.05) prevented and reversed KET-induced increased stereotypy, behavioral despair and deficit in cognitive functions when compared with KET-treated mice respectively. Also, morin and risperidone but not haloperidol, significantly (p < 0.05) prevented and reversed the decreases in expressions of GAD <subscript>67</subscript> and BDNF immunoreactivity in the striatum, PFC and hippocampus caused by KET. Moreover, morin and risperidone significantly (p < 0.05) decreased regional brain expressions of NADPH-oxidase immunopositive cells and increased endogenous anti-oxidant enzymes (SOD and CAT) in the striatum, PFC and hippocampus relative to KET controls respectively. Taken together, these findings further suggest that the antipsychotic-like activity of morin may be mediated via mechanisms related to enhancement of GABAergic neurotransmission and neurotrophic factor, and suppression of NADPH-oxidase induced oxidative damage in mice.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antioxidants metabolism
Brain drug effects
Brain metabolism
Catalase metabolism
Disease Models, Animal
Dopamine Antagonists pharmacology
Excitatory Amino Acid Antagonists toxicity
Haloperidol pharmacology
Ketamine toxicity
Male
Memory, Short-Term drug effects
Mice
Risperidone pharmacology
Schizophrenia chemically induced
Stereotyped Behavior drug effects
Superoxide Dismutase metabolism
Swimming psychology
Antioxidants therapeutic use
Behavioral Symptoms etiology
Behavioral Symptoms prevention & control
Brain-Derived Neurotrophic Factor metabolism
Flavonoids therapeutic use
NADPH Oxidases metabolism
Schizophrenia complications
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2747
- Volume :
- 139
- Database :
- MEDLINE
- Journal :
- Brain research bulletin
- Publication Type :
- Academic Journal
- Accession number :
- 29548911
- Full Text :
- https://doi.org/10.1016/j.brainresbull.2018.03.006