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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Traumatic spinal cord injury occurs in two phases: biomechanical injury, followed by ischemia and reperfusion injury. Biomechanical injury to the spinal cord, preceded or followed by various pharmaceutical manipulations or interventions, has been studied, but the ischemia/reperfusion aspect of spinal cord injury isolated from the biomechanical injury has not been previously evaluated. In the current study, ischemia to the lumbar spinal cord was induced in albino rabbits via infrarenal aortic occlusion, and two interventions were analyzed: the use of U74006F (Tirilazad mesylate), a 21-aminosteroid, and cerebrospinal fluid (CSF) drainage. These treatment modalities were tested alone or in combination. In Phase 1 of this study, the rabbits received 1.0 mg/kg of Tirilazad or an equal volume of vehicle (controls) prior to the actual occlusion, three doses of Tirilazad (1 mg/kg each) during the occlusion, then several doses after the occlusion. Of the Tirilazad-treated animals, 30% became paraplegic while 70% of the control animals became paraplegic. 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, and 20% in the Tirilazad plus CSF drainage group. This rate also correlated with changes noted in CSF pressure; both Tirilazad administration alone and CSF drainage alone induced a decrease in CSF pressure and the two combined produced a further decrease. There was marked improvement in the perfusion pressure when using Tirilazad alone, CSF drainage alone, and Tirilazad therapy in combination with CSF drainage, with the last group producing the largest increase. This change in CSF pressure and perfusion pressure correlated with improved functional neurological outcome. Pathological examination revealed that Tirilazad therapy reduced the extensive and diffuse neuronal, glial, and endothelial damage to (in its most severe form) a more patchy focal region of damage in the gray matter. Cerebrospinal fluid drainage resulted in pyknosis of some motor neurons, and some eosinophilia. The combination of CSF drainage and Tirilazad administration resulted in the least abnormality, with either normal or near-normal spinal cords. It is concluded that Tirilazad administration decreased CSF pressure during spinal cord ischemia and reperfusion and, like CSF drainage, increased and improved the perfusion pressure to the spinal cord, decreased spinal cord damage, and improved functional outcome.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Limiting ischemic spinal cord injury using a free radical scavenger 21-aminosteroid and/or cerebrospinal fluid drainage. 841 Feb 54

Cardiac arrest and resuscitation often create a cerebral insult caused by the initial cessation of blood flow, followed by the incomplete ischemia of cardiopulmonary resuscitation (low flow), and, following the return of spontaneous circulation, by the post-resuscitation syndrome. A cascade of physiologic, vascular, and biochemical events is set in motion, including changes in neuropeptides, electrolytes such as calcium and magnesium, excitatory neurotransmitters such as glutamate and acetylcholine, lymphokines such as interleukin-1, and arachidonic acid metabolites such as prostaglandins and leukotrienes; and formation of oxygen free radicals and lactic acid. Oxygen free radical-induced lipid peroxidation appears to increase tissue injury during and after brain ischemia. The 21-aminosteroid U74006F (tirilazad mesylate) is a novel inhibitor of lipid membrane peroxidation induced by oxygen free radicals, which has been shown, in animal models of subarachnoid hemorrhage, central nervous system trauma, and cerebral ischemia, to limit the extent of secondary tissue damage, thus improving functional recovery. Since tirilazad appears to have little or no behavioral or physiologic side effects, it appears to be an ideal agent for widespread brain ischemia prophylaxis. Tirilazad mesylate studies in out-of-hospital cardiac arrest are currently being planned.
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PMID:Possibilities of brain protection with tirilazad after cardiac arrest. 871 85

Following CNS trauma or ischemia, peroxynitrite may be a toxic intermediate which forms in vivo when nitric oxide condenses with superoxide. Alone, peroxynitrite appears to directly react with aromatic and sulfhydryl nucleophiles. However, at physiological pH, peroxynitrite is protonated and, in that form, will rapidly (within seconds) decompose to species with hydroxyl radical and nitrogen dioxide characteristics. These reactive species are shown to initiate lipid peroxidation, hydroxylate aromatic residues, and nitrate aromatic residues. This reactivity may contribute to differential toxicity in vivo and in vitro. Tirilazad mesylate (TZ) is a lipid-soluble antioxidant shown to inhibit iron-dependent lipid peroxidation. It is an effective therapy in a variety of CNS injury and ischemia models and is currently undergoing human clinical evaluation in stroke, head injury, and spinal injury. This study was designed to investigate the cytoprotective properties of TZ in a cerebellar granule cell model of peroxynitrite toxicity. Cytoprotective efficacy of TZ was based on viability measurements, blockade of lipid hydroperoxide generation, and blockade of nitrotyrosine formation. Cell viability was determined by [3H]-aminoisobutyric acid (3H-AIB) uptake, and lipid hydroperoxide and nitrotyrosine content were determined by HPLC assays. Tirilazad mesylate was found to have similar cytoprotective effects (approximately 50% protection at 100 microM) when applied before or after exposure of cells to peroxynitrite. In contrast, post-treatment with superoxide dismutase (50 units/ml) or allopurinol (100 microM) failed to produce any cytoprotection. Furthermore, we discovered that TZ inhibited the peroxynitrite-induced increase of phosphatidylethanolamine hydroperoxide (PEOOH), but did not affect the peroxynitrite-induced formation of nitrotyrosine formation. This suggests that the ability of TZ to afford cytoprotection in this peroxynitrite toxicity model is due to the inhibition of membrane-localized lipid peroxidation, and not to the inhibition of nitration of tyrosine residues.
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PMID:Protective effects of tirilazad mesylate in a cellular model of peroxynitrite toxicity. 882 75

We have investigated endothelial function in a two-hit model of multiple organ failure. Male Fischer rats were subjected to 20 min of partial hepatic ischemia followed by reperfusion and administration of .5 mg/kg Salmonella enteritidis endotoxin at 30 min of reperfusion. After either 4 or 24 h of reperfusion, rings of aorta were prepared and suspended in bioassay baths, contracted with phenylephrine, and examined for endothelium-dependent relaxation in response to acetylcholine and endothelium-independent relaxation using nitroglycerin. Endothelium-dependent relaxation to acetylcholine was impaired in rings from animals exposed to endotoxin-enhanced reperfusion injury at both 4 h and 24 h. At 24 h of reperfusion the EC50 for acetylcholine relaxation was significantly increased from 45 +/- 8 nM to 258 +/- 105 nM. Endothelium-independent relaxation to nitroglycerin was not affected. The 21-aminosteroid Tirilazad mesylate (U-74006F) prevented endothelial dysfunction; at 24 h of reperfusion the EC50 for acetylcholine relaxation in U-74006F-treated animals was 55 +/- 8 nM. Thus, endothelial function is impaired in this model of multiple organ failure and this impairment is prevented by Tirilazad mesylate.
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PMID:Effect of endotoxin-enhanced hepatic reperfusion injury on endothelium-dependent relaxation in rat aorta. 885 44

The 21-aminosteroids (lazaroids) are inhibitors of lipid membrane peroxidation and appear to function as reactive free radical scavengers (RFRS). Freedox--a multimechanistic cytoprotective inhibitor of lipid peroxidation has been developed specifically to minimize secondary tissue damage. It is the first lazaroid compound used in clinical practice for critical care indications. Structurally described as a 21-aminosteroid, it has no glucocorticoid, mineralocorticoid, or other hormonal effects. Cytoprotective pathways of Freedox after its insertion into the lipid bi-layer of cell membrane include: scavenging reactive oxygen intermediates (ROI), stabilizing cell membrane by decreasing fluidity, preserving vitamin E content in membrane, increasing surface viscosity, preserving of post injury Ca+2 homeostasis. There was shown its efficacy in improving neurologic outcome following CNS trauma, subarachnoid hemorrhage, and ischemia. The therapeutic potential of the lazaroid Freedox has been extensively studied in several CNS disorders. There is an increasing experimental and clinical evidence about the oxygen free radical formation and cell membrane lipid peroxidation which play an important role in the pathogenesis of subarachnoid hemorrhage, spinal cord trauma, head injury and inflammatory processes of the NS. Freedox has also been tested in a variety of stroke models. (Fig. 1, Ref. 19.)
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PMID:[Tirilazad mesylate (Freedox)--an effective inhibitor of lipid membrane peroxidation]. 933 26