Neuroprotection and anti-ischemic drug development

A decade ago, there was little compelling evidence that pharmacological intervention could radically alter outcome after cerebral ischemia, even in experimental animals. By 1996, the pace of advance was such that a large number of drugs targeted at neurotransmitter receptors, and related mechanisms involved in ischemic damage, had advanced to clinical trials in stroke and head injury. The transformation of the pharmacology of cerebral ischemia had been achieved for two major reasons: first, the elucidation of neurochemical cascades initiated by ischemia, which revealed potential targets for intervention; and, second, the systematic assessment of drug efficacy using robust end-points (quantitative histopathology) in the most pertinent animal models. Since the elucidation of the excitotoxic cascade, numerous other pathological mechanisms have been identified by which neuroprotection can be achieved in ischemia. However, excitotoxicity remains central to current concepts of neuronal cell death and provides the prototype for anti-ischemic drug development for new pharmacological targets, i.e., reduction of the volume of neuronal perikaryal damage in models of focal cerebral ischemia.

Animal models of focal cerebral ischemia are generally recognized as the most pertinent in relation to human stroke. The most widely used models of focal cerebral ischemia involve occlusion of the middle cerebral artery (MCA) either by surgical division or intraluminal suture placement.