Mangiferin ameliorates 6-hydroxydopamine-induced cytotoxicity and oxidative stress in ketamine model of schizophrenia

Background: Accumulating evidence indicates that mangiferin (MGF), a natural xanthone, by virtue of its antioxidant and anti-inflammatory properties is neuroprotective. Here we sought to verify the cytoprotective role of MGF on cultured rat primary mesencephalic cells exposed to 6-hydroxydopamine (6-OHDA) in vitro, and the MGFs anti-inflammatory potential in mouse model of ketamine-induced schizophrenia in vivo. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-assay was performed to measure cell viability in mesencephalic cell cultures exposed to neurotoxin (6-OHDA, 40 mu M). Schizophrenia was induced in mice by ketamine (50 mg/kg, ip, twice a day, for 7 days). The treatment effects of MGF (50 mg/kg,po, for 7 days) were verified on locomotor behavioral changes in open-field test, and on the oxidant stress-related increase in lipid-peroxidation (malondialdehyde) and interleukin-6 (IL-6) levels in brain tissues. Results: MGF (10-100 mu M) produced no per se effect on cell viability as measured by MTT assay, but significantly prevented the 6-OHDA-induced cell death in a concentration-dependent manner. Acridine orange/ethidium bromide (AO/EtBr) staining confirmed the absence of 6-OHDA-induced morphological changes characteristic of apoptosis/necrosis. In open-field test, ketamine-induced impaired locomotor activity and behavioral changes such as grooming and stereotyped but not rearing were effectively ameliorated by MGF pretreatment. Also, ketamine-associated increase in brain tissue levels of IL-6 and MDA were significantly lowered in MGF-pretreated mice. Conclusion: Mangiferin has a neurocytoprotective role related, at least in part, to an antioxidant and anti-inflammatory mechanism, which could be explored for more effective therapies of schizophrenia and other neurodegenerative diseases.