Apoptosis: future targets for neuroprotective strategies.
Focal permanent or transient cerebral artery occlusion produces massive cell death in the central core of the infarction, whereas in the peripheral zone (penumbra) nerve cells are subjected to various determining survival and death signals. Cell death in the core of the infarction and in the adult brain is usually considered a passive phenomenon, although events largely depend on the partial or complete disruption of crucial metabolic pathways. Cell death in the penumbra is currently considered an active process largely dependent on the activation of cell death programs leading to apoptosis. Yet cell death in the penumbra includes apoptosis, necrosis, intermediate and other forms of cell death. A rather simplistic view implies poor prospects regarding cell survival in the core of the infarction and therapeutic expectations in the control of cell death and cell survival in the penumbra. However, the capacity for neuroprotection depends on multiple factors, primarily the use of the appropriate agent, at the appropriate time and during the appropriate interval. Understanding the mechanisms commanding cell death and survival area is as important as delimiting the therapeutic time window and the facility of a drug to effectively impact on specific targets. Moreover, the detrimental effects of homeostasis and the activation of multiple pathways with opposing signals following ischemic stroke indicate that better outcome probably does not depend on a single compound but on several drugs acting in combination at the optimal time in a particular patient.
Ferrer
Isidro
I
Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Spain. 8082ifa@comb.es
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D013997:Time Factors; D015291:Transforming Growth Factors / Q000494:pharmacology / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000627:therapeutic use
D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D018698:Glutamic Acid; D015291:Transforming Growth Factors; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium