New Pharmacological Treatment of Acute Spinal Cord Trauma

Abstract

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.

Antioxidant therapies in traumatic brain and spinal cord injury

“…Thus emerged the 21-aminosteroids or “lazaroids,” a novel group of LP inhibitors designed to be devoid of glucocorticoid receptor interactions, which limited the clinical use of high-dose MP. Of these, tirilazad (U-74006F) was selected for further studies based on positive results in animal SCI models [63–65]. …”

Correlation Between Attenuation of Posttraumatic Spinal Cord Ischemia and Preservation of Tissue Vitamin E by the 21-Aminosteroid U74006F: Evidence for anIn VivoAntioxidant Mechanism

“…INTRODUCTION U 74006F is a NONGLUcocoRTicoiD 21-aminosteroid that has been shown to be a potent inhibitor of iron-catalyzed CNS tissue lipid peroxidation (Braughler et al, 1987;Hall et al, 1988). Previous studies have demonstrated that intensive treatment of cats beginning 30 min after a moderately severe compression spinal cord injury (L3) and extending for 48 h postinjury enhances 4 week neurologic recovery over a broad range of total 48 h i.v.…”

Effect of superoxide dismutase, allopurinol and glucocorticoids on liver and lung metallothionein induction by endotoxin in the rat

“…The glucocorticoid PRED, similarly, did not reduce the effect of endotoxin on liver TBARS levels and even potentiated it in some cases. These hormones are potent antioxidants in a number of pathological processes (Baud & Ardaillou 1986, Hall et al 1988), but their effects on liver TBARs in different situations remain conflicting (Hidalgo et al 1991). Although we have no explanation for these unexpected effects of SOD, ALLO and PRED on liver TBARs, the conclusion is clear that liver MT and TBARs levels are not directly correlated.…”

“…Therefore, the aim of the present work was to study the effect of the antioxidants (Halliwell & Gutteridge 1989) superoxide dismutase (SOD) and allopurinol (ALLO) on the MT response to endotoxin. The effect of glucocorticoids was also studied, because these hormones can act as antioxidants (Baud & Ardaillou 1986, Hall et al 1988) in addition to their well known antiinflammatory activity. While this manuscript was in preparation, a report from Min et al (1992a) demonstrated that glucocorticoids decrease the liver MT response to endotoxin in mice, which is relevant for the present results.…”