Targets of cytoprotection in acute ischemic stroke: present and future

Cerebrovasc Dis. 2006:21 Suppl 2:1-8. doi: 10.1159/000091698. Epub 2006 May 2.

Abstract

Although the management of stroke has improved remarkably over the last decade due mainly to the advent of thrombolysis, most neuroprotective agents, although successful in animal studies, have failed in humans. Our increasing knowledge concerning the ischemic cascade is leading to a considerable development of pharmacological tools suggesting that each step of this cascade might be a target for cytoprotection. Glutamate has long been recognized to play key roles in the pathophysiology of ischemia. However, although some trials are still ongoing, the results from several completed trials with drugs interfering with the glutamatergic pathway have been disappointing. Regarding the inhibition of glutamate release as a possible target for cytoprotection, it might be afforded either by decreasing glutamate efflux or by increasing glutamate uptake. In this context, it has been shown that glutamate transport is the primary and only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels. This transport is executed by the five high-affinity, sodium-dependent plasma membrane glutamate transporters. Among them, the transporter EAAT2 is responsible for up to 90% of all glutamate transport. We will discuss the effect of different neuroprotective tools (membrane stabilizers or endogenous neuroprotection) affecting glutamate efflux and/or expression of EAAT2. We will also describe the finding of a novel polymorphism in the EAAT2 promoter region which could be responsible for differences in both gene function and regulation under pathological conditions such as cerebral ischemia, and which might well account for the failure of glutamate antagonists in the clinical practice. These results may possess important therapeutic implications in the management of patients at risk of ischemic events, since it has been demonstrated that those patients with progressing stroke have higher plasma concentrations of glutamate which remain elevated up to 24 h when compared to the levels in patients without neurological deterioration.

MeSH terms

  • Animals
  • Brain / blood supply
  • Brain / drug effects*
  • Brain / metabolism
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism
  • Cytidine Diphosphate Choline / pharmacology
  • Cytidine Diphosphate Choline / therapeutic use
  • Cytoprotection*
  • Drug Evaluation, Preclinical
  • Excitatory Amino Acid Transporter 2 / drug effects
  • Excitatory Amino Acid Transporter 2 / genetics
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Glutamic Acid / metabolism
  • Humans
  • Ischemic Preconditioning*
  • Meta-Analysis as Topic
  • Neuropharmacology / trends
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Polymorphism, Genetic
  • Promoter Regions, Genetic / genetics
  • Randomized Controlled Trials as Topic
  • Stroke / drug therapy*
  • Stroke / genetics
  • Stroke / metabolism

Substances

  • Excitatory Amino Acid Transporter 2
  • Neuroprotective Agents
  • Glutamic Acid
  • Cytidine Diphosphate Choline