Neuron protection as a therapeutic target in acute ischemic stroke.

Abstract

Involvement of various neurotransmitters and neuromodulators have been shown to contribute to the ischemic injury and neuronal death associated with stroke Role of excitatory amino acid receptor activation, calcium overload, nitric oxide, and oxidative stress in the pathogenesis of ischemic brain damage is well established. Several new strategies are currently emerging, based on recent advances in our understanding of molecular pathways that could be considered as potential therapeutic targets. For example reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI and brain ischemia. Furthermore, more recently, some authors concluded that nonanticoagulant 3K3A-APC exhibits greater neuroprotective efficacy with no risk for bleeding compared with drotrecogin-alfa activated, a hyperanticoagulant form of APC. Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. Included in the sequence of events leading to neuronal death in ischemic tissue following stroke is an excessive and toxic rise in the intracellular Ca(2+)-concentration, predominantly due to an influx of Ca2+ through nonselective cation-channels as well as Ca(2+)-channels.. Some authros conducted a study to investigate whether the enhancement of GABA receptor activity could inhibit NMDA receptor-mediated nitric oxide (NO) production by neuronal NO synthase (nNOS) in brain ischemic injury. The results showed that both the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen had neuroprotective effect, and the combination of two agonists could significantly protect neurons against death induced by ischemia/reperfusion. On this basis we conclude that neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection.

• Authors: Antonino Tuttolomondo, Riccardo Di Sciacca, Domenico Di Raimondo, Valentina Arnao, Chiara Renda, Antonio Pinto, Giuseppe Licata
• Journal: Current topics in medicinal chemistry (Curr Top Med Chem) Vol. 9 Issue 14 Pg. 1317-34 ( 2009) ISSN: 1873-4294 [Electronic] United Arab Emirates
• PMID: 19849659 (Publication Type: Journal Article, Review)

Chemical References

• Neuroprotective Agents
• Reactive Oxygen Species

Topics

• Brain Ischemia (drug therapy, metabolism, pathology)
• Humans
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Stroke (drug therapy, metabolism, pathology)