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-CF3-C6H4Se)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-CF3-C6H4Se)2 is effective against GA-induced seizures and oxidative stress in rat pups 21 days of age. Our findings demonstrate that (m-CF3-C6H4Se)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-CF3-C6H4Se)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-CF3-C6H4Se)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 [3H]GABA uptake from striatum slices of rat pups and that (m-CF3-C6H4Se)2 preadministration protected against this increase. A positive correlation between duration of seizures and [3H]GABA uptake levels was demonstrated. The results indicate that (m-CF3-C6H4Se)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 [3H]GABA uptake are possible mechanisms for the potential anticonvulsant action of (m-CF3-C6H4Se)2. © 2012 Wiley Periodicals, Inc.