Neuropharmacology NeuroReport 0959-4965 # Lippincott Williams & Wilkins Ascorbic acid and á- tocopherol attenuate methylmalonic acid- induced convulsions Michele Rechia Fighera, Cla  udio Marcos Queiroz, 1 Marcelo Paulo Stracke, Martin Cla  udio Nin Brauer, Larissa Linnette Gonza  lez-Rodrõ Âguez, Roberto Frussa-Filho, 1 Moacir Wajner 2 and Carlos Fernando de Mello CA Departamento de Quõ Âmica, Centro de Cie à ncias Naturais e Exatas, Universidade Federal de Santa Maria, 97105-900 Santa Maria; 1 Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de Sa Ä o Paulo, 04023-062 Sa Äo Paulo; 2 Departamento de Bioquõ Âmica, Instituto de Cie Ãncias Ba Âsicas da Sau  de, Universidade Federal do Rio Grande do Sul, 90050-170 Porto Alegre, RS, Brasil CA Corresponding Author THE effects of chronic administration of á-tocopherol or melatonin, or acute ascorbic acid administration on the convulsant action of methylmalonic acid (MMA) were investigated in adult male rats. Animals were chronically injected with á-tocopherol (40 mg kg 1 , i.p.), melatonin (5 mg kg 1 , i.p.) or vehicle for 7 days. Buffered MMA (6 ìmol/2 ìl) or NaCl (9 ìmol/2 ìl) was injected intrastriatally and the animals were observed for the appearance of clonic or tonic-clonic convulsions and rotational behavior. Ascorbic acid (100 mg kg 1 , s.c.) was administered 30 min before MMA injection. á- Tocopherol and ascorbic acid pretreatment decreased the duration of the convulsive episodes and the rota- tional behavior elicited by MMA. This study provides evidence that free radical generation may participate in the convulsant effects of methylmalonic acid. Neuro- Report 10:2039±2043 # 1999 Lippincott Williams & Wilkins. Key words: Antioxidants; Ascorbic acid; Convulsion; Excitotoxicity; Glutamate; Melatonin; Methylmalonic acid; Succinate dehydrogenase; á-Tocopherol Introduction Methylmalonic acidemias comprise a group of in- herited metabolic disorders biochemically character- ized by tissue accumulation of methylmalonyl-CoA and its free acid methylmalonic acid. They are caused by a severe de®ciency or lack of activity of the enzyme methylmalonyl-CoA mutase (EC 5.4.99.2) and are characterized by neonatal or infan- tile ketoacidosis, failure to thrive and neurological dysfunction, including convulsions [1]. We have previously reported that methylmalonic acid inhibits succinate dehydrogenase (SDH) and â- hydroxybutyrate dehydrogenase activity in vitro [2]. In addition, we have demonstrated that the acute intrastriatal administration of methylmalonic acid (MMA) induces convulsions through glutamatergic mechanisms [3], probably involving Krebs cycle inhibition and ATP depletion, since MMA does not seem to interact directly with glutamate receptors [4]. Recently, it has been reported that MMA induces neuronal depolarization in vitro [5], con- ®rming our behavioral observations. These results have suggested that MMA accumulation, depolariza- tion and activation of NMDA receptors may play a critical role in the genesis of the convulsions ob- served in methylmalonicacidemic patients. A signi®cant amount of work has suggested that free radical generation may underlie the neurotoxic effects of succinate dehydrogenase inhibitors [6±12]. Malonate- and 3-nitropropionate-induced neuro- toxicity is diminished by coenzyme Q administra- tion [7] and attenuated in transgenic mice, with a three-fold increase in copper/zinc superoxide dismu- tase (SOD) activity [8], respectively. Moreover, SOD over-expression protects from 3-nitropropio- nate-induced increases in the striatal concentrations of 3-nitrotyrosine and 2,3 and 2,5 dihydroxybenzoic acids [8]. A similar protection against the neurotoxic effects of malonate was observed in neuronal nitric oxide synthase knockout mice [12], and after nitric oxide synthase inhibitor administration [10], supporting the view that SDH inhibitors induce free radical generation and cellular death through NeuroReport 10, 2039±2043 (1999) Vol 10 No 10 13 July 1999 2039