title: m-Trifluoromethyl diphenyl diselenide attenuates glutaric acid-induced seizures and oxidative stress in rat pups: involvement of the γ-aminobutyric acidergic system.
abstract: Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and seizures. The intrastriatal GA administration in rats has been used as an animal model to mimic seizures presented by glutaric acidemic patients. m-Trifluoromethyl diphenyl diselenide, (m-CF(3) -C(6) H(4) Se)(2) , is an organoselenium compound that protects against seizures induced by pentylenetetrazole in mice. Thus, the aim of this study was to investigate whether (m-CF(3) -C(6) H(4) Se)(2) is effective against GA-induced seizures and oxidative stress in rat pups 21 days of age. Our findings demonstrate that (m-CF(3) -C(6) H(4) Se)(2) preadministration (50 mg/kg; p.o.) protected against the reduction in latency and the increased duration of GA (1.3 μmol/right striatum)-induced seizures in rat pups. In addition, (m-CF(3) -C(6) H(4) Se)(2) protected against the increase in reactive species generation and the reduction in antioxidant defenses glutathione peroxidase and glutathione S-transferase activities induced by GA. By contrast, no change in glutathione reductase or catalase activities was found. In addition, (m-CF(3) -C(6) H(4) Se)(2) was effective in protecting against inhibition of Na(+) ,K(+) -ATPase activity caused by GA in striatum of rat pups. This study showed for the first time that GA administration caused an increase in [(3) H]GABA uptake from striatum slices of rat pups and that (m-CF(3) -C(6) H(4) Se)(2) preadministration protected against this increase. A positive correlation between duration of seizures and [(3) H]GABA uptake levels was demonstrated. The results indicate that (m-CF(3) -C(6) H(4) Se)(2) protected against GA-induced seizures. Moreover, these findings suggest that the protection against oxidative stress, the inhibition of Na(+) ,K(+) -ATPase activity, and the increase in [(3) H]GABA uptake are possible mechanisms for the potential anticonvulsant action of (m-CF(3) -C(6) H(4) Se)(2).
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, Brasil. danielimagni@gmail.com
authors.forename: Danieli Valnes
authors.initials: DV
authors.lastname: Magni
authors.forename: César Augusto
authors.initials: CA
authors.lastname: Brüning
authors.forename: Bibiana Mozzaquatro
authors.initials: BM
authors.lastname: Gai
authors.forename: Caroline Brandão
authors.initials: CB
authors.lastname: Quines
authors.forename: Suzan Gonçalves
authors.initials: SG
authors.lastname: Rosa
authors.forename: Michele Rechia
authors.initials: MR
authors.lastname: Fighera
authors.forename: Cristina Wayne
authors.initials: CW
authors.lastname: Nogueira
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001928:Brain Diseases, Metabolic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D005977:Glutarates / Q000633:toxicity*; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency / Q000378:metabolism; D008297:Male; D017646:Organosilicon Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid
chemical_list: D000927:Anticonvulsants; D005977:Glutarates; D017646:Organosilicon Compounds; C546861:m-trifluoromethyl-diphenyl diselenide; D005680:gamma-Aminobutyric Acid; D050770:Glutaryl-CoA Dehydrogenase; C035736:glutaric acid