Cerebral hypoxia: some new approaches and unanswered questions

The apoplexy of Hippocrates’ time remains with us today, unchanged and untreated. We call this syndrome of acute brain damage “stroke”; we know that it most commonly reflects localized tissue hypoxia attributable to reduced blood flow (ischemia). Focal hypoxia-ischemia also occurs in such contexts as traumatic insults, or cerebral hemorrhages, while global hypoxia-ischemia occurs in cardiac arrest, near-drowning, and carbon monoxide poisoning. The centuries since Thomas Willis, Johann Wepfer, and Giovanni Morgagni have brought precise definition of cerebral vascular anatomy and the neurological consequences of focal brain lesions, permitting full comprehension of functional deficits; we can prognosticate with sad accuracy. But the medical management of stroke patients in 1990 is still the management of symptoms and associated conditions. Despite its status as a major worldwide cause of death and disability, we are no more able than Hippocrates to treat cerebral hypoxia itself. Nevertheless, hope for the development of effective therapy has endured, and in the last few years has been encouraged by the emergence of some promising strategies for reducing the brain’s intrinsic susceptibility to hypoxic insults. These tissuelevel approaches, sometimes referred to as “parenchymal” approaches to distinguish them from other strategies aimed at influencing blood how, are based on recent information suggesting that central neurotransmitter mechanisms, especially those related to the excitatory neurotransmitter glutamate, may play an important role in the pathogenesis of hypoxic neuronal death (Meldrum, 1985; Rothman and Olney, 1986; Choi, 1988b). In this essay I will comment on the possibility of new therapies for cerebral hypoxia directed at glutamate-mediated injury mechanisms, and will briefly mention some other potential approaches. Glutamate and hypoxic neuronal injury The brain is critically dependent on its blood flow for a continuous supply of oxygen and glucose. The oscillations of the electroencephalogram cease within seconds of cardiac arrest, and only a few minutes of severe ischemia can induce the selective degeneration of certain neuronal populations, including pyramidal neurons in the CA1 region of the hippocampal formation, striatal medium-sized neurons, neocortical neurons in layers 3,