Acromelic acid, a novel kainate analogue, induces long-lasting paraparesis with selective degeneration of interneurons in the rat spinal cord.
A single systemic administration of acromelic acid, a novel kainate analogue (kainoid), induces a series of characteristic behavioral changes in association with selective damage of interneurons in the caudal spinal cord in adult rats. When an effective dose of acromelic acid (5 mg/kg) was systemically administered, forced extension of hindlimbs with or without cramps appeared in all rats. In the course of the intensified hindlimb extension, 10 of 16 rats suffered from generalized convulsive seizures during which 6 rats died without apparent neuropathological change. Of 4 surviving rats that experienced seizures, two developed long-lasting spastic paraparesis which remained unchanged for at least 3 months, whereas the other two were normal in behavior on the days following the administration. In lower doses (less than 4 mg/kg), the rats transiently displayed forced extension of hindlimbs, and in a higher dose (5.5 mg/kg), all rats died during an attack of severe generalized convulsion. Neuropathological changes were observed only in the rats with persistent paraparesis, in which neuron damage was identified selectively in small interneurons in the lumbosacral cord. The morphological change of the degenerated spinal interneurons resembles that of degenerated hippocampal CA1 pyramidal cells seen after systemic administration of kainate. Large motoneurons, spinal roots, and white matter of the spinal cord were well preserved. Unlike the case of systemic administration of kainate, other structures in the central and peripheral nervous system and muscles were morphologically intact except the hippocampal CA4 and the stratum moleculare-lacnosum in which there were reactive astrocytes. The regional difference between kainate-induced and acromelate-induced neuron damage suggests that systemically administered acromelic acid, a kainoid, induces selective neuron damage through activating a particular kainate receptor subtype. The clinicopathological feature of the paraparetic rats resembles closely that of stiffman syndrome, a progressive human neurological disorder with selective loss of interneurons in the spinal cord.
Shin
K
K
National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
Hitoshi
A
A
Michiko
I
I
Haruhiko
S
S
D000818:Animals; D001522:Behavior, Animal; D002908:Chronic Disease; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007395:Interneurons / Q000473:pathology*; D007608:Kainic Acid / Q000031:analogs & derivatives*; D008297:Male; D009410:Nerve Degeneration; D010264:Paraplegia / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*
D005904:Glial Fibrillary Acidic Protein; C051743:acromelic acid A; D007608:Kainic Acid