Ischemic stroke is a consequence of transient or permanent reduction of blood flow to a focal region of the brain, usually caused by the occlusion of an artery by an embolus or thrombus. Cerebral ischemia may also occur globally in the setting of cardiac arrest and resuscitation. While historically brain damage has been considered to be an inexorable consequence of focal or global ischemic insults, in recent years a growing understanding of the underlying mechanisms responsible for brain cell death has led to the identification of new therapeutic approaches. Two main approaches have emerged. The first aims to restore lost blood flow by dissolving the thrombus responsible for cerebral artery obstruction (in ischemic stroke). Thrombolysis has become an established treatment for ischemic stroke after the efficacy of intravenous tissue plasminogen activator (tPA) was demonstrated in a landmark study (The NINDS rt-PA Stroke Study Group, 1995). Promising results have also been reported for the thrombolytic agent pro-urokinase, delivered by intra-arterial catheter directly to the site of intravascular thrombus (Furlan et al., 1999). The second approach, neuroprotection, aims to reduce the intrinsic vulnerability of brain tissue to ischemia; it will be the topic of this chapter.

Mechanisms of ischemic neuronal death

The brain is more vulnerable to ischemia than many other tissues, so it seems plausible that the cellular mechanisms of this heightened vulnerability could be delineated and blocked. Over the last 15 years evidence has accumulated indicating that normal brain signaling and immune defense mechanisms may become harmful after ischemic insults (Rothman & Olney, 1986; Choi, 1988; del Zoppo et al., 2000). In particular, substantial evidence now implicates excitotoxicity, programmed cell death, and inflammation in the pathogenesis of ischemic neuronal death.

Excitotoxicity

The excitatory transmitter glutamate normally mediates most fast synaptic transmission throughout the CNS, but it also has a surprising ability to trigger central neuronal death upon prolonged exposure, a phenomenon called ‘excitotoxicity’ by Olney (1969). Excitotoxicity now appears to be involved in the pathogenesis of several CNS diseases including ischemic brain injury (Rothman & Olney, 1986; Choi, 1988). Under ischemic conditions, neurons deprived of oxygen and glucose r apidly lose ATP and become depolarized, leading to abnormally high levels of glutamate release (initially mediated by vesicular release from nerve terminals, and later by reverse transport from astrocytes).