Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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