Excitotoxicity mediated by overactivation of
glutamate receptors, particularly the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (
AMPA) type, has been implicated in motoneuron degeneration.
AMPA receptors lacking the GluR2 subunit are permeable to Ca(2+) and the entrance of this
cation might be responsible for the selective vulnerability of spinal motoneurons in
amyotrophic lateral sclerosis (ALS). To evaluate this hypothesis in vivo, we have used a model of motoneuron death in which
AMPA, perfused by microdialysis in the rat lumbar spinal cord, produces ipsilateral
paralysis and a remarkable loss of spinal motoneurons. Perfusion of
1-naphthyl acetyl spermine, a selective blocker of the Ca(2+)-permeable
AMPA receptors, and of the intracellular Ca(2+)
chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl
ester) (
BAPTA-AM), prevented the
AMPA-induced
paralysis and reduced by about 50% the loss of motoneurons. In addition, perfusion of
pyruvate, an energy metabolic substrate, similarly prevented the
paralysis and the motoneuron death. These results suggest that functional
AMPA receptors lacking the GluR2 subunit are present in the rat spinal cord, and that motoneuron death is triggered by an increase of intracellular Ca(2+) via such Ca(2+)-permeable
AMPA receptors. Our finding that
pyruvate also protected against the excitotoxic effects of
AMPA suggests that the increased intracellular Ca(2+) probably interferes with the mitochondrial energetic metabolism.