Selective degeneration of inhibitory interneurons in the rat spinal cord induced by intrathecal infusion of acromelic acid.

We investigated the characteristics of the neurotoxicity mediated by non-N-methyl-D-aspartic acid (NMDA)-type glutamate receptors in the spinal cord by infusing rats intrathecally with three specific agonists (acromelic acid A (ACRO), kainic acid and 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)). When ACRO was infused intrathecally continuously for 2 h, the rats developed dose-dependent flaccid paraplegia during the infusion, followed by pure motor, rigid-spastic, long-lasting paraparesis (ED50: 220 pmol/h). The paraparetic rats showed selective degeneration of interneurons in the spinal cord with about 50% loss of their contents of glycine and aspartic and glutamic acids. The alpha-motoneurons in the ventral horns were largely free from permanent damage. These changes were selectively ameliorated by concomitant administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist at non-NMDA receptors. Kainate induced long-lasting paraplegia with neuronal damage at doses about 40-times higher than those of ACRO that caused paraplegia. When examined 30 days after kainate infusion, the neurotransmitter markers had decreased markedly in the lumbar cords of the rats with long-lasting paraplegia. Intrathecal infusion of large doses of AMPA caused long-lasting flaccid paraplegia, which were accompanied by extensive necrosis in the caudal spinal cord. It seems that ACRO exerts its unique pharmacological actions by activating a subclass of non-NMDA receptors distinct from those activated by kainate and AMPA, and may become a useful tool for investigating the biological roles of glutamate receptors.