ROLE OF HYPERGLYCEMIA-RELATED ACIDOSIS IN ISCHEMIC BRAIN-DAMAGE

Although previous results have shown unequivocally that pre-ischaemic hyperglycaemia aggravates brain damage due to transient ischaemia, sev eral questions have remained unanswered. First, is the effect of hyper glycaemia due to a further fall in intra-and extracellular pH? Second, is aggravation of damage a step function or a continuous function of plasma glucose concentration or of pH? Third, which are the mechanisms responsible for aggravation of damage, notably for the transformation of selective neuronal damage to infarction, for oedema development, a nd for post-ischaemic seizures? Recent results have provided new infor mation on all of these issues. Thus, normoglycaemic animals with super imposed hypercapnia showed a similar, albeit not identical, aggravatio n of ischaemic damage, suggesting that acidosis is one major mediator. Furthermore, experiments with graded increase in plasma glucose conce ntration revealed a threshold effect at values of 10-12 mM, while micr oelectrode measurements showed a narrow extracellular pH range (6.4-6. 5) for post-ischaemic seizure development. These results suggest that aggravation of damage due to excessive acidosis is due to mechanisms w ith a steep pH dependence. Finally, results are now at hand suggesting that the effect of acidosis is not mediated by a further perturbation of cell calcium metabolism. The more likely mediators are free radica ls. Thus, acidosis is known to enhance iron-catalysed production of re active oxygen species, probably by releasing iron from its bindings to transferrin, ferritin and other proteins.