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.