The objective of this article is to amalgamate previous results into a speculative synthesis that sheds light on the causes of secondary brain damage following either global/forebrain or focal
ischemia. The hypothesis is based on the well-founded assumption that the pathophysiology of the brain damage incurred by global or forebrain
ischemia is different from that of focal
ischemia. In the former, the
ischemia is usually dense and of brief duration and, provided that reperfusion is adequate, cell damage is conspicuously delayed, mostly affecting selectively vulnerable neurons. In contrast, focal
ischemia is either long-lasting or permanent, and it is usually less severe, particularly in the perifocal penumbral regions. The lesion is typically pan-necrotic ("
infarction"), initially affecting the focus supplied by the occluded artery, later invading the penumbra zone. Available results allow a restatement of the
calcium hypothesis of cell death. In global or forebrain
ischemia,
calcium influx through channels gated by voltage or
glutamate receptors is envisaged to trigger reactions that limit the survival of neurons during reperfusion, leading to secondary neuronal death after hours or days of survival. It can be hypothesized that the initial insult leads to a sustained alteration of membrane
calcium handling, resulting in slow, gradual
calcium overload of mitochondria. Alternatively, a sustained perturbation of the intracellular signal transduction pathway leads to changes in transcription or translation, bereaving 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
mitochondrial dysfunction is believed to be involved. In focal
ischemia, similar reactions are probably triggered by
calcium influx, whether this is sustained (the focus) or intermittent (the penumbra). However, these play a minor role in cell death since they are overridden by reactions producing mediators of rapidly developing secondary damage, affecting either microvessels or mitochondria. Very probably, some of these mediators are
free radicals, or
nitric oxide, or other reactive metabolites, emanating from
lipid hydrolysis and
arachidonic acid metabolism. During continuous
ischemia, or during recirculation following 1-3 h of
ischemia, 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 sustained 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 the nitrone class act many hours after the induction of focal
ischemia, their therapeutic window is potentially very wide. This may be because expression of mRNAs for adhesion molecules and their synthesis are relatively slow processes, and because the
nitrones act on events that involve adhesion of leukocytes to the endothelial cells, with plugging of capillaries and postcapillary venules, and on the ensuing inflammatory response.