Mitochondrial dysfunction and maturation of brain damage after transient ischemia

The damage incurred by neurons and glial cells after ischemia and reperfusion is caused by events occurring during three periods: the period of ischemia, the maturation period, and the sequence of events leading to the final demise of cells. The ischemic period sets the stage for the subsequent steps since it is associated with bioenergetic failure and loss of ion homeostasis, the latter leading to uncontrolled influx of calcium into cells. Presynaptic release of glutamate and influx of calcium trigger events that can give rise to immediate or delayed neuronal land glial cell) damage. These events encompass activation of kinases and phosphatases which change the expression of many transcription factors, and of genes that modulate the cell response to the initial ischemic insult. Some of these events may be instrumental in causing delayed tissue damage, such as the expression of inducible nitric oxide synthetase and cyclo-oxygenase-2, both of which would promote an inflammatory and immunological reaction. Several lines of evidence incriminate mitochondrial dysfunction in the pathogenesis of delayed ischemic brain damage. Mitochondria may be damaged by being exposed to a constant (post-ischemic) load of calcium and/or to oxidative stress. This may cause peroxidation of lipids, constituting the backbone of the mitochondrial membranes, oxidation of proteins in respiratory complexes, or the assembly of a mitochondrial permeability transition (MPT) pore. The anti-ischemic effects of the immunosuppressants cyclosporin A (CsA) and FK506 suggest that the rotamase activity of the immunophilins, or the effect of ischemia on calcineurin, play important pathogenetic roles. However, since CsA has effects over and above those of FK506, an MPT pore assembly may play a contributory and, under certain circumstances, dominant role.