Neuroprotective Therapy

Abstract

It is an old observation that hypothermia and barbiturate intoxication may protect the brain during cardiac arrest and that these conditions should be considered when a person is found with asystole [1]. The obvious neuroprotective properties of barbiturates, mediated by specific binding sites at the γ-aminobutryic acid A (GABA _A ) receptor-ion channel complex, and hypothermia, stimulated efforts to evaluate their potential for treatment of cerebral ischemia. These efforts are still unsuccessful, but the potential of an effective treatment that protects the brain during ischemia was encouraged by extended knowledge about the pathophysiology of ischemic stroke [2, 3•]. In stroke, ischemia is focal, following sudden deprivation of blood flow from an artery occluded by an embolus or a thrombus. Survival of neurons and other cells in the occluded territory depends on collateral arterial blood supply mainly over the surface of the brain. Ischemia is incomplete and the degree of compensatory blood flow determines whether cells die rapidly and form an infarct, or they survive by simply increasing the oxygen extraction from the blood. Although selective injury to vulnerable neurons may occur even with milder ischemia, most cells survive at least for a time even if the cerebral blood flow is less than 40% of normal values [4•]. At this level, release of neurotransmitters ceases and the neurons become electrically silent. The clinical correlate is loss of neurologic function, which may recover if ischemia is reversed. This is the therapeutic challenge: the sudden appearance of neurologic symptoms, a threat of a patient becoming dependent or worse, and the prospect that this may be reduced by rapid pharmacologic or nonpharmacologic intervention.