[The molecular mechanisms of cerebral ischemia: the possible therapeutic interventions].
Therapeutic interventions for acute ischemic stroke have not yet been established in clinical practice. The recognition of an area of reduced blood flow in which neuronal death may be prevented has focused attention on treatments aiming at minimizing ischemic brain damage, if they are initiated within short time after occlusion. The combination of restoring blood flow and providing neuroprotection may be the most productive approach in human acute ischemic stroke, but this combined therapy requires testing through clinical trials. To gain insight into the molecular mechanisms of cerebral ischemia, this review examines the excito-toxic cascade, synthesis and role of nitric oxide and oxidants, gene regulation and possible neuroprotective therapeutic targets. As neuroprotectants, glutamate-antagonists, calcium-antagonists and free radical scavengers have been investigated. The role of nitric oxide is very complex, as it can be cytotoxic or cytoprotective in relation to sources, time of synthesis, and medium redox state. Animal gene studies suggest that nitric oxide produced by endothelial nitric oxide synthase may be advantageous, while nitric oxide produced by neuronal and inducible nitric oxide synthase disadvantageous. A treatment strategy could involve the use of selective inhibitors of different types of nitric oxide synthase. Cell death after cerebral ischemia occurs through the dual pathway of ischemic necrosis and apoptosis. Novel therapies may be directed at genes mediating either recovery or apoptosis. There are, as yet, no conclusive data concerning the safety and efficacy of neuroprotectants in humans. Differences between animal models and clinical conditions may justify the discrepancy between experimental data and clinical practice.
Basile
A M
AM
Clinica Neurologica III, Università degli Studi di Firenze.
Nencini
P
P
Inzitari
D
D
D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D018846:Excitatory Amino Acids / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology
D018846:Excitatory Amino Acids; D005609:Free Radicals; D009569:Nitric Oxide
Meccanismi molecolari dell'ischemia cerebrale: possibili interventi terapeutici.