Delayed and remote effects of focal cortical infarctions: secondary damage and reactive plasticity.

Following cortical ischemia, several processes have been identified that occur in remote brain areas: (i) At the lesion border, in partially ischemic areas, inflammatory reactions with invasion of polymorphonuclear leukocytes and T lymphocytes, an immediate activation of microglia, and a delayed invasion of macrophages occur, and neurons in close contact to inflammatory cells show apoptotic cell death. These factors may affect the extent of the ensuing lesion. Leukocytes adhering to the endothelium after expression of cell adhesion molecules have a detrimental effect on reperfusion. (ii) In nonischemic brain areas remote from the lesion, alterations can be caused by electrical or chemical signals emanating from the infarct. Thus activation of astrocytes by spreading depressions probably initiate a partial resistance for further ischemia. (iii) In nonischemic, structurally connected brain areas, diaschisis effects are observed. Both ipsilateral to the lesion as well as contralateral to it an increase of neuronal excitability and a decrease of GABAergic inhibition are observed. This is associated with a down-regulation of GABA receptor binding, and an altered composition of GABA receptors by different subunits. These alterations may favor functional adaptive processes, but may also cause postischemic seizures and neuronal dysfunction. (iv) Adaptive changes in remote brain areas can be influenced by ischemia-induced remote alterations of brain functions. Furthermore, experimentally observed differential activation of NMDA responses may contribute to a differential propensity for adaptive processes in different brain areas. The investigations indicate potential new targets for therapeutic interventions after the first few hours following onset of stroke.