Small neurons in the lower spinal cord are selectively damaged in the spastic rat by acromelic acid

Abstract

A single systemic injection of acromelic acid, one of kainoids, caused semipermanent severe spastic paraparesis in the rat. One week after the injection, routine histological examination disclosed chromatoly-sis of small neurons with marked reactive gliosis in the spinal cord, particularly the lumbar and sacral segments. These changes were observed throughout the gray matter except the most dorsal margin of the posterior horn (I and II layers of Rexed). Glial processes were intensely stained by immunohistochemistry against glial fibrillary acidic protein (GFAP) which was maximal at the ventral part of the dorsal horn at the sacral and lumbar segment. Mild glial proliferation was visualized only by the immunohistochemistry of GFAP in the hippocampal CA4, but pyramidal cells appeared intact by ordinary staining. The remaining structures were not affected including large anterior horn cells and the white matter of the spinal cord. The following points are deduced from these results; 1) The selective loss of small neurons in the lower spinal cord is responsible for the marked spastic paraparesis produced by the injection of acromelic acid. Destroyed neurons may belong to a group of inhibitory intemeurons of spinal reflex arcs. 2) By analogy to the excitotoxic action of kainic acid, acromelic acid may have caused neural degeneration through excessive depolarization. This suggests that degenerated neurons might bear receptors with great affinity to acromelic acid. 3) Acromelic acid conceivably acts through a different glutamate receptor subtype from the kainate receptor in the rat central nervous system because of the different pattern of cell vulnerability from that following systemic kainic acid injection. 4) Selective destruction of small neurons of the spinal cord, possibly by extrinsic neurotoxin, might give a clue to the pathophysiology of human spastic paraparesis such as the ‘stiff-man syndrome’.