Prevention of CA2+-Overload and Structural Brain Damage after Transient Cerebral Ischemia

Evidence exists that focal hypoxia occurs in the course of a migraine attack (11, that Ca2+-shifts coincide with the onset and progression of hypoxia-induced structural damage ( 2 ) and that Ca2+-entry blockers protect against cerebral hypoxia ( 3 ) . Morphologic evaluation of cerebral damage was performed in two incomplete ischemia models in which 20 min and 8 min ischemic periods were induced respectively by transient occlusion of both vertebral and carotid arteries and by combination of severe hypotension with bilateral carotid artery occlusion ( 4 ) . Early structural changes became visible within the first Eew minutes after the insult. Microvacuoles, identified in the electron microscope as swollen mitochondria and cell processes, quickly disappeared within the first 15 min after reoxygenation. More than 24 h post-ischemia, irreversible structural changes became apparent. They could be classified into two main groups : coagulative cell change and edematous cell change. Although these alterations are in some way related to the severity and duration of the primary insult, secondary phenomena during the reoxygenation period. are held responsible for delayed neuronal cell death ( 4 ) . Using a cytochemical technique for subcellular demonstration of Ca2+, it could been shown that this cation rapidly shifts towards the intraneuronal space after the onset of an ischemic episode. Initially, swollen mitochondria and dilated astrocytic proEiles contain huge amounts of Ca2+. However this situation does not seem to be toxic to the cells since they quickly regain their normal morphology and Ca2+ distribution pattern once oxygen supply is restored (2, 4 ) . Nevertheless, in certain vulnerable areas and after a delayed maturation period, irreversible neuronal necrosis occurs, concomitant with severe Ca2+-overload of the cytosol (2. 4 ) . This means that the definite signal for irreversible deterioration in these areas, most probably is given during the recirculation phase by an unknown mechanism. In both incomplete ischemia models. CAI hippocampal neurons become selectively damaged. In this area post-ischemic Ca2t-shiEts could easily be followed in a time-related way ( 4 ) . At 1 h post ischemia. after the initial defensive Ca2+-sequestration had been reversed, but still before signs of irreversible cell destruction could be detected, other changes in Ca*+-distribution became apparent. pronounced at 24 h and consisted of increased Ca2t-accumulation in presynaptic axon terminals and in the postsynaptic dendritic tree. CaZ+-entry in presynaptic terminals. which were morphologically identified as Schaffer collateral endings, apparently has no pathological effect since CA pyramidal cells rarely exhibited necrosis. Postsynaptic Caj+-overload, on the other hand, was correlated with flocculent structural degeneration preceeding coagulative cell change. Not only dendritic processes but also cell bodies of CAI pyramidal cells showed Ca2+-overload and flocculent degeneration. cytoplasm many dilated profiles of endoplasmic reticulum became visible. all or them containing elevated amounts of Ca2+-precipitate. time period also nuclei became pyknotic. disintegrated and Ca2+ disappeared from the cell body. If the pathophysiological processes, leading to irreversible neuronal necrosis originate with some delay after an ischemic attack, it may remain possible to preserve the brain when pharmacological intervention These consisted of microvacuolation and astrocytic swelling.