LIMITING ISCHEMIC SPINAL-CORD INJURY USING A FREE-RADICAL SCAVENGER 21-AMINOSTEROID AND OR CEREBROSPINAL-FLUID DRAINAGE

Traumatic spinal cord injury occurs in two phases: biomechanical injur y, followed by ischemia and reperfusion injury. Biomechanical injury t o the spinal cord, preceded or followed by various pharmaceutical mani pulations or interventions, has been studied, but the ischemia/reperfu sion aspect of spinal cord injury isolated from the biomechanical inju ry has not been previously evaluated. In the current study, ischemia t o the lumbar spinal cord was induced in albino rabbits via infrarenal aortic occlusion, and two interventions were analyzed: the use of U740 06F (Tirilazad mesylate), a 21-aminosteroid, and cerebrospinal fluid ( CSF) drainage. These treatment modalities were tested alone or in comb ination. In Phase 1 of this study, the rabbits received 1.0 mg/kg of T irilazad or an equal volume of vehicle (controls) prior to the actual occlusion, three doses of Tirilazad (1 mg/kg each) during the occlusio n, then several doses after the occlusion. Of the Tirilazad-treated an imals, 30% became paraplegic while 70% of the control animals became p araplegic. Phase 2 involved the same doses of Tirilazad as in Phase 1 and, in addition, CSF pressure monitoring and drainage were performed. The paraplegia rate was 79% in the control animals, 36% in the group receiving Tirilazad alone, 25% in the group with CSF drainage alone, a nd 20% in the Tirilazad plus CSF drainage group. This rate also correl ated with changes noted in CSF pressure; both Tirilazad administration alone and CSF drainage alone induced a decrease in CSF pressure and t he two combined produced a further decrease. There was marked improvem ent in the perfusion pressure when using Tirilazad alone, CSF drainage alone, and Tirilazad therapy in combination with CSF drainage, with t he last group producing the largest increase. This change in CSF press ure and perfusion pressure correlated with improved functional neurolo gical outcome. Pathological examination revealed that Tirilazad therap y reduced the extensive and diffuse neuronal, glial, and endothelial d amage to (in its most severe form) a more patchy focal region of damag e in the gray matter. Cerebrospinal fluid drainage resulted in pyknosi s of some motor neurons, and some eosinophilia. The combination of CSF drainage and Tirilazad administration resulted in the least abnormali ty, with either normal or near-normal spinal cords. It is concluded th at Tirilazad administration decreased CSF pressure during spinal cord ischemia and reperfusion and, like CSF drainage, increased and improve d the perfusion pressure to the spinal cord, decreased spinal cord dam age, and improved functional outcome. These effects may be related to the role has on free radical scavenging during ischemia and reperfusio n, and it is possible that Tirilazad or in combination with CSF draina ge is an effective adjunct to other neural protective measures injury.