Intrastriatal administration of 3-hydroxyglutaric acid induces convulsionsand striatal lesions in rats

Glutaryl-CoA dehydrogenase deficiency is an inherited neurometabolic diseas e complicated by precipitation of acute encephalopathic crises during a vul nerable period of brain development. These crises result in bilateral stria tal damage and subsequently a dystonic dyskinetic movement disorder. In pre vious in vitro studies neuronal damage in this disease has been linked to a n excitotoxic mechanism mediated in particular by one of the accumulating m etabolites, 3-hydroxyglutaric acid. However, nothing is known about the in vivo effects of this organic acid. In the present study, we used a stereota xic intrastriatal injection technique to investigate the behavioral and neu rotoxic effects of 3-hydroxyglutaric acid exposure in rats. Here, we report that 3-hydroxyglutaric acid induced an increase in convulsion frequency an d duration as determined by open field measurement. Nissl-stained coronal s ections from treated rats revealed a pale lesion in the striatum following 3-hydroxyglutaric acid exposure. N-methyl-D-aspartate (NMDA) receptor block ade by MK-801 and stimulation of GABA, receptors by muscimol prevented the induction of convulsions and striatal damage by 3-hydroxyglutaric acid, whe reas blockade of non-NMDA receptors by 6,7-dinitroquinoxaline-2,3-dione (DN QX) was not protective. We conclude that 3-hydroxyglutaric acid induces con vulsions and striatal damage via initiation of an imbalance in the excitato ry glutamatergic and the inhibitory GABAergic neurotransmission, resulting in an enhanced excitatory input in striatal neurons. These results support the hypothesis of NMDA receptor-mediated excitotoxic cell damage in glutary l-CoA dehydrogenase deficiency and represent the basis for the development of new neuroprotective treatment strategies. (C) 2001 Elsevier Science B.V. All rights reserved.