title: Intracerebroventricular metformin decreases body weight but has pro-oxidant effects and decreases survival.
abstract: Metformin (Met), which is an insulin-sensitizer, decreases insulin resistance and fasting insulin levels. The precise molecular target of Met is unknown; however, several reports have shown an inhibitory effect on mitochondrial complex I of the electron transport chain (ETC), which is a related site for reactive oxygen species production. In addition to peripheral effects, Met is capable of crossing the blood-brain barrier, thus regulating the central mechanism involved in appetite control. The present study explores the effects of intracerebroventricular (i.c.v.) infusion of Met on ROS production on brain, insulin sensitivity and metabolic and oxidative stress outcomes in CF1 mice. Metformin (Met 50 and 100 µg) was injected i.c.v. in mice daily for 7 days; the brain mitochondrial H2O2 production, food intake, body weight and fat pads were evaluated. The basal production of H2O2 of isolated mitochondria from the hippocampus and hypothalamus was significantly increased by Met (100 µg). There was increased peripheral sensitivity to insulin (Met 100 µg) and glucose tolerance tests (Met 50 and 100 µg). Moreover, Met decreased food intake, body weight, body temperature, fat pads and survival rates. Additionally, Met (1, 4 or 10 mM) decreased mitochondrial viability and increased the production of H2O2 in neuronal cell cultures. In summary, our data indicate that a high dose of Met injected directly into the brain has remarkable neurotoxic effects, as evidenced by hypothermia, hypoglycemia, disrupted mitochondrial ETC flux and decreased survival rate.
authors.affiliation: Departamento de Bioquímica, Programa de Pós Graduação em Ciências Biológicas-Bioquímica, ICBS, UFRGS, Rua: Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, CEP 90035-003, Brazil.
authors.forename: Luis Valmor
authors.initials: LV
authors.lastname: Portela
authors.forename: Jussania
authors.initials: J
authors.lastname: Gnoatto
authors.forename: Andressa Wigner
authors.initials: AW
authors.lastname: Brochier
authors.forename: Clarissa Branco
authors.initials: CB
authors.lastname: Haas
authors.forename: Adriano Martimbianco
authors.initials: AM
authors.lastname: de Assis
authors.forename: Afonso Kopczynski
authors.initials: AK
authors.lastname: de Carvalho
authors.forename: Gisele
authors.initials: G
authors.lastname: Hansel
authors.forename: Eduardo Rigon
authors.initials: ER
authors.lastname: Zimmer
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Oses
authors.forename: Alexandre Pastoris
authors.initials: AP
authors.lastname: Muller
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism / Q000401:mortality*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000633:toxicity; D057967:Infusions, Intraventricular; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000633:toxicity*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015996:Survival Rate / Q000639:trends
chemical_list: D007004:Hypoglycemic Agents; D017382:Reactive Oxygen Species; D008687:Metformin