New pharmacological treatment of acute spinal cord trauma.
Numerous experimental studies of blunt spinal cord injury have shown that while a variable degree of immediate mechanical damage occurs to spinal blood vessels and axons in proportion to the magnitude of the injury force, a considerable amount of post-traumatic tissue degeneration is due to a secondary pathophysiological process that may be modifiable by appropriate therapeutic intervention. A growing body of biochemical, physiological, and pharmacological evidence has suggested that oxygen free radical-induced lipid peroxidation, working in concert with aberrant calcium fluxes and eicosanoid generation in particular, plays a key role in progressive post-traumatic spinal cord degeneration. Of particular importance, lipid peroxidation has been linked to microvascular damage and hypoperfusion which, if severe enough, can lead to a secondary ischemic insult to the tissue. The ability of intensive dosing with the glucocorticoid steroid methylprednisolone to beneficially affect post-traumatic ischemia and to promote chronic neurologic recovery in spinal cord injured animals has been correlated not with its glucocorticoid activity, but rather with the ability to inhibit post-traumatic spinal lipid peroxidation. In view of this, a novel series of non-glucocorticoid 21-aminosteroids has been developed which lack glucocorticoid activity but are more effective inhibitors of nervous tissue lipid peroxidation than the glucocorticoid steroids. One of these, U74006F, has now been studied in some detail and appears to be a promising new agent for the acute treatment of spinal cord (and brain) trauma. The background and pre-clinical development of this compound to date is reviewed.
Hall
E D
ED
Central Nervous System Diseases Research Unit, Upjohn Company, Kalamazoo, Michigan.
Braughler
J M
JM
McCall
J M
JM
D006801:Humans; D008775:Methylprednisolone / Q000627:therapeutic use*; D011241:Prednisone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011281:Pregnatrienes / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000188:drug therapy*
D011281:Pregnatrienes; C053319:U 72099E; D011241:Prednisone; D008775:Methylprednisolone; C053355:tirilazad