A pharmacological analysis of the pathophysiological mechanisms of posttraumatic spinal cord ischemia

Abstract

A pharmacological analysis was carried out to determine the possible role of aberrant calcium fluxes, vasoactive arachidonic acid metabolites, and microvascular lipid peroxidation in the development of posttraumatic spinal cord white matter ischemia. Pentobarbital-anesthetized cats were treated intravenously 30 minutes before a 500-gm-cm contusion injury to the lumbar spinal cord with one of the following test drugs: the Ca++ channel antagonists verapamil, diltiazem, or nifedipine; the cyclo-oxygenase inhibitors ibuprofen or meclofenamate; the thromboxane A2 (TXA2) synthetase inhibitor furegrelate sodium; or the stable epoprostenol (prostacyclin, or PGI2) analogue ciprostene calcium alone or in combination with furegrelate sodium. Another group of animals was pretreated for 5 days before spinal injury with a combination of the antioxidants vitamin E and selenium in high doses. The hydrogen clearance technique was used to make repeated measurements of spinal cord blood flow (SCBF) in the dorsolateral funiculus of the injured segment before and for 4 hours after injury. In 11 untreated uninjured cats, the mean preinjury SCBF was 12.7 +/- 1.5 ml/100 gm/min. Following contusion, there was a progressive decline in SCBF to 6.8 +/- 0.4 ml/100 gm/min, or 53.5% of the preinjury level at 4 hours. In comparison, the Ca++ antagonists diltiazem and nifedipine (but not verapamil) prevented a significant posttraumatic decrease in SCBF. Similarly, both cyclo-oxygenase inhibitors (ibuprofen and meclofenamate) maintained SCBF within normal limits (10 ml/100 gm/min or greater). However, neither TXA2 synthetase inhibition nor the stable PGI2 analogue alone had a significant effect in preventing ischemia, whereas a combination of the two agents did serve to support SCBF. The most impressive preservation of posttraumatic SCBF, however, was observed in the antioxidant-treated animals. Based upon these results, a hypothesis is presented concerning the pathogenesis of posttraumatic central nervous system ischemia which integrates an injury-induced rise in intracellular Ca++, the increased synthesis of vasoactive prostanoids (such as prostaglandin F2 alpha and TXA2), and progressive microvascular lipid peroxidation.

Oxidative stress in spinal cord injury and antioxidant-based intervention

“…Pretreatment with vitamin E has been shown to be protective in animal models of SCI. 2,53 Iwasa et al systemically studied the effects of vitamin E on injury of the spinal cord associated with ischemia in rats. 54,55 The results showed that the motor disturbance induced by SCI was greatly reduced and spinal cord blood flow was promptly restored and remained normal after injury in the vitamin E-supplemented group.…”

Oxidative stress and antioxidative parameters in patients with spinal cord injury: implications in the pathogenesis of disease

“…On the other hand, high-dose oral vit E supplementation for 5 days before SCI acts to attenuate the progressive posttraumatic decrease in white matter spinal cord blood flow together with a significant enhancement in hind-limb motor function compared with non-vit E supplemented animals, this effect has been replicated in a rat compression SCI model. 29 In contrast, vit E deficiency has been shown to increase post-SCI LP and to attenuate motor functional recovery. 30 However, despite these effects, the value of vit E as an acute treatment for SCI is limited by the fact that it requires weeks to achieve a significant increase in parenchymal CNS tissue levels.…”

Intrathecal bupivacaine protects against extension of lesions in an acute photochemical spinal cord injury model

“…The main cause was observed to be ischemia of the gray matter, a consequence of the intracellular entry of calcium, and edema of the perilesional white matter. 2,3 Experimentally, the photochemical model of a secondary lesion was described by Watson et al 4 in rats. The resultant photochemical reaction leads to vascular stasis and congestion, hemorrhagic necrosis of the central gray matter and edematous pale-staining white matter tracts.…”

“…Another important element of the cascade of events leading to cell ischemia is phospholipase activation in cell membranes. 3 Bupivacaine is an inhibitor of A2 phospholipase. 21 However, this inhibition was demonstrated in vitro with high doses of bupivacaine, larger than those used in clinical investigations and reaching cardiotoxic levels.…”

“…Neurologic recovery is in general partial, related to the injury level but not to age. 1 Cat models of lesions by impaction 2,3 have been used to clarify the pathophysiology of secondary extension of traumatic injury. The main cause was observed to be ischemia of the gray matter, a consequence of the intracellular entry of calcium, and edema of the perilesional white matter.…”