In 1990, the Second National Acute Spinal Cord Injury Study (NASCIS 2) demonstrated that a 24-hour (24h) course of high dose methylprednisolone (MP), a synthetic glucocorticoid, significantly improved motor and sensory recovery in human spinal cord injury (SCI). This was the first demonstration of any effective treatment for this devastating condition which afflicts mostly young males and causes more years of paralysis and handicap than any other disease (due to the tendency of spinal-injured people to live nearly normal lifespans). Unexpectedly, NASCIS 2 showed that MP not only must be given within 8 hours to be effective but may be deleterious if started later. We investigated this in a rat model of spinal cord injury and found that a single bolus dose of the drug shortly after injury is as or more effective than a 24h course of treatment. Although the 24h MP regimen is now widely used clinically, little is known about the optimal initiation time or duration of treatment and the relationship of this time window to injury severity. In addition, the mechanisms underlying the time window or MP-mediated neuroprotection are not well understood. Finally, we recently discovered that monosialic ganglioside (GM1), a drug that was recently reported to be useful in human spinal cord injury, strongly antagonizes the effects of MP in our SCI model. We propose a systematic study to establish therapeutic time window for MP in a rat model of graded spinal cord injury, to correlate the time window to extracellular calcium changes in injured spinal cords, and to determine the mechanisms by which GM1 antagonizes MP. The experiments will test the hypotheses that (1) delayed or continuation of MP treatment beyond a short time after injury is ineffective or deleterious, (2) the therapeutic window duration increases with injury severity, (3) the window corresponds to the period of extracellular calcium depression that occurs in injured spinal cords, (4) secondary tissue damage occurs when extracellular calcium recovers and drug must be given before this time, (5) the protective effects of MP are due to induction and release of anti-inflammatory proteins which inhibit phospholipase, (6) GM1-stimulated protein kinases phosphorylate and down-regulate these proteins and thereby antagonize the effects of MP in acute SCI, (7) dexamethasone, a more potent glucocorticoid, has similar neuroprotective effects as MP and is strongly antagonized by GM1. Our overall goal is to establish a rational basis for design of effective drug treatment protocols for acute SCI.
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