Excitotoxicity and Stroke

Introduction

A long-standing goal of stroke research has been to elucidate the mechanisms responsible for the high vulnerability of brain tissue to hypoxic-ischemic insults. Understanding these mechanisms will aid the development of specific countermeasures that could be employed in the acute treatment of stroke victims.

One such mechanism, “excitotoxicity,” was implicated in the 1980s as a prominent contributor to neuronal death after transient or permanent focal brain ischemia, and became the focus of many laboratory and clinical studies during the 1990s. However, the failure of several novel antiexcitotoxic therapies to show efficacy in clinical trials diminished interest. This chapter will briefly summarize the excitotoxic concept, and outline how it might be more effectively countered to reduce brain damage during stroke.

What Is Excitotoxicity?

In keeping with its widespread role in central fast excitatory neurotransmission , glutamate is present at millimolar levels throughout CNS gray matter. Under normal conditions, most of this glutamate is highly concentrated within nerve terminals, and energy-dependent cellular uptake rapidly clears synaptically released glutamate from the extracellular space. Thus neurons are exposed only briefly and focally to glutamate in the course of excitatory neurotransmission. This normal synaptic glutamate exposure is not injurious.

However, under certain disease conditions, for example, when tissue energy stores are compromised by hypoxia-ischemia, increased glutamate efflux from depolarized neurons and astrocytes together with reduced cellular glutamate uptake can produce an abnormally large and sustained buildup of extracellular glutamate that is no longer restricted to synaptic zones . In addition, energy depletion reduces the ability of neurons to correct or manage the cellular changes induced by glutamate exposure, especially increases in intracellular calcium. Sustained exposure to high concentrations of extracellular glutamate, with or without energy depletion can quickly kill neurons, a phenomenon named “excitotoxicity” by John Olney , and primarily triggered by ion channels directly gated by glutamate (see later discussion).

Abnormal activation of other neurotransmitter pathways, or ionic/metabolic derangements mediated by other events, can also promote neuronal injury by mechanisms convergent with those underlying excitotoxicity. Although vulnerability to excitotoxicity was originally thought to be an exclusive property of neurons, mature oligodendrocytes can also be damaged by glutamate receptor overactivation, perhaps contributing to ischemic white matter damage. Even certain cells outside the brain, such as renal cells, can be injured by glutamate receptor overactivation .