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

Abstract

Mangiferin ameliorates 6-hydroxydopamine- induced cytotoxicity and oxidative stress in ketamine model of schizophrenia Vietla S. Rao 1 , Ana C. Carvalho 1 , Maria Teresa S. Trevisan 2 , Geanne M. Andrade 1 , Helio V. Nobre Júnior 1 , Manoel O. Moraes 1 , Hemerson I. Magalhães H. Iury 1 , Talita C. Morais 1 , Flavia A. Santos 1 1 Department of Physiology and Pharmacology, Federal University of Ceará, Cel Nunes de Melo-1127, Caixa Postal-3157, 60430-270 Fortaleza, CE, Brazil 2 Department of Organic and Inorganic Chemistry, Federal University of Ceara, Fortaleza, CE, Brazil Correspondence: Vietla S. Rao, e-mail: vietrao@ufc.br ; viet_rao@yahoo.com.br Abstract: 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 mesen- cephalic 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-diphenyltetrazoliu m bromide (MTT)-assay was performed to measure cell viabili ty in mesen- cephalic cell cultures exposed to neurotoxin (6-OHDA, 40 μM ). 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 i n open-field test, and on the oxidant stress-related increase in lipid-peroxi dation (malondialdehyde) and interleukin-6 (IL-6) levels in brain tissues. Results: MGF (10–100 μM) 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 con - firmed 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 ame - liorated 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.