Neuroprotective role of lipoic acid against acute toxicity of N-acetylaspartic acid.
N-Acetylaspartic acid (NAA) accumulates in Canavan disease, a severe inherited neurometabolic disorder clinically characterized by mental retardation, hypotonia, macrocephaly, and seizures. The mechanisms of brain damage in this disease remain poorly understood. Recent studies developed by our research group showed that NAA induces oxidative stress in vitro and in vivo in cerebral cortex of rats. Lipoic acid is considered as an efficient antioxidant which can easily cross the blood-brain barrier. Considering the absence of specific treatment to Canavan disease, this study evaluates the possible prevention of the oxidative stress promoted by NAA in vivo by the antioxidant lipoic acid to preliminarily evaluate lipoic acid efficacy against pro-oxidative effects of NAA. Fourteen-day-old Wistar rats received an acute administration of 0.6 mmol NAA/g body weight with or without lipoic acid (40 mg/kg body weight). Catalase (CAT), glutathione peroxidase (GPx), and glucose 6-phosphate dehydrogenase activities, hydrogen peroxide content, thiobarbituric acid-reactive substances (TBA-RS), spontaneous chemiluminescence, protein carbonyl content, total antioxidant potential, and DNA-protein cross-links were assayed in the cerebral cortex of rats. CAT, GPx activities, and total antioxidant potential were significantly reduced, while hydrogen peroxide content, TBA-RS, spontaneous chemiluminescence, and protein carbonyl content were significantly enhanced by acute administration of NAA. Those effects were all prevented by lipoic acid pretreatment. Our results clearly show that lipoic acid may protect against the oxidative stress promoted by NAA. This could represent a new therapeutic approach to the patients affected by Canavan disease.
Pederzolli
Carolina Didonet
CD
Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Rosa
Andrea Pereira
AP
de Oliveira
Amanda Szekir
AS
Coelho
Juliana G
JG
Becker
Débora da Luz
Dda L
Dalazen
Giovana Reche
GR
Moraes
Tarsila Barros
TB
Dutra-Filho
Carlos S
CS
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D002374:Catalase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*
D018696:Neuroprotective Agents; D017392:Thiobarbituric Acid Reactive Substances; D001224:Aspartic Acid; D008063:Thioctic Acid; C000179:N-acetylaspartate; D002374:Catalase; D005979:Glutathione Peroxidase