MECHANISMS OF SECONDARY BRAIN-DAMAGE IN GLOBAL AND FOCAL ISCHEMIA - ASPECULATIVE SYNTHESIS

The objective of this article is to amalgamate previous results into a speculative synthesis that sheds light on the causes of secondary bra in damage following either global/forebrain or focal ischemia. The hyp othesis is based on the well-founded assumption that the pathophysiolo gy of the brain damage incurred by global or forebrain ischemia is dif ferent from that of focal ischemia. In the former, the ischemia is usu ally dense and of brief duration and, provided that reperfusion is ade quate, cell damage is conspicuously delayed, mostly affecting selectiv ely vulnerable neurons. In contrast, focal ischemia is either long-las ting or permanent, and it is usually less severe, particularly in the perifocal penumbral regions. The lesion is typically pan-necrotic (''i nfarction''), initially affecting the focus supplied by the occluded a rtery, later invading the penumbra zone. Available results allow a res tatement of the calcium hypothesis of cell death. In global or forebra in ischemia, calcium influx through channels gated by voltage or gluta mate receptors is envisaged to trigger reactions that limit the surviv al of neurons during reperfusion, leading to secondary neuronal death after hours or days of survival, It can be hypothesized that the initi al insult leads to a sustained alteration of membrane calcium handling , resulting in slow, gradual calcium overload of mitochondria. Alterna tively, a sustained perturbation of the intracellular signal transduct ion pathway leads to changes in transcription or translation, bereavin g the cells of heat shock and stress proteins, of trophic factors, or of enzymes required for survival. However, with the possible exception of the gerbil, neither microvascular failure nor primary mitochondria l dysfunction is believed to be involved. In focal ischemia, similar r eactions are probably triggered by calcium influx, whether this is sus tained (the focus) or intermittent (the penumbra). However, these play a minor role in cell death since they are overridden by reactions pro ducing mediators of rapidly developing secondary damage, affecting eit her microvessels or mitochondria. Very probably, some of these mediato rs are free radicals, or nitric oxide, or other reactive metabolites, emanating from lipid hydrolysis and arachidonic acid metabolism. Durin g continuous ischemia, or during recirculation following 1-3 h of isch emia, these mediators activate adhesion molecules in endothelial cells or polymorphonuclear leucocytes, or oxidize key proteins. The result is either failure of microcirculation (''capillary plugging''), or sus tained mitochondrial failure. Since calcium influx is an initial event , agents reducing presynaptic depolarization and calcium entry through glutamate receptor-gated and other calcium channels have predictably a narrow therapeutic window; however, since spin trapping agents of th e nitrone dass act many hours after the induction of focal ischemia, t heir therapeutic window is potentially very wide. This may be because expression of mRNAs for adhesion molecules and their synthesis are rel atively slow processes, and because the nitrones act on events that in volve adhesion of leukocytes to the endothelial cells, with plugging o f capillaries and postcapillary venules, and on the ensuing inflammato ry response.