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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS015590-15
Application #
2262850
Study Section
Neurology A Study Section (NEUA)
Project Start
1979-07-01
Project End
1996-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
15
Fiscal Year
1994
Total Cost
Indirect Cost
Name
New York University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Saruhashi, Y; Young, W; Sugimori, M et al. (1999) GABA increases refractoriness of adult rat dorsal column axons. Neuroscience 94:1207-12
Saruhashi, Y; Young, W; Hassan, A Z (1997) Calcium-mediated intracellular messengers modulate the serotonergic effects on axonal excitability. Neuroscience 81:959-65
Saruhashi, Y; Young, W; Sugimori, M et al. (1997) Evidence for serotonin sensitivity of adult rat spinal axons: studies using randomized double pulse stimulation. Neuroscience 80:559-66
Saruhashi, Y; Young, W; Perkins, R (1996) The recovery of 5-HT immunoreactivity in lumbosacral spinal cord and locomotor function after thoracic hemisection. Exp Neurol 139:203-13
Sakuma, J; Ciporen, J; Abrahams, J et al. (1996) Independent depressive mechanisms of GABA and (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide on young rat spinal axons. Neuroscience 75:927-38
Ferris, D C; Kume-Kick, J; Russo-Menna, I et al. (1995) Gender differences in cerebral ascorbate levels and ascorbate loss in ischemia. Neuroreport 6:1485-9
Honmou, O; Young, W (1995) Norepinephrine modulates excitability of neonatal rat optic nerves through calcium-mediated mechanisms. Neuroscience 65:241-51
Young, W; Kume-Kick, J; Constantini, S (1994) Glucocorticoid therapy of spinal cord injury. Ann N Y Acad Sci 743:241-63;discussion 263-5
Saruhashi, Y; Young, W; Hassan, A Z et al. (1994) Excitatory and inhibitory effects of serotonin on spinal axons. Neuroscience 61:645-53
Constantini, S; Young, W (1994) The effects of methylprednisolone and the ganglioside GM1 on acute spinal cord injury in rats. J Neurosurg 80:97-111

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