Ischemia and lesion induced imbalances in cortical function.

Cortical structures are often critically affected by ischemic and traumatic lesions which may cause transient or permanent functional disturbances. These disorders consist of changes in the membrane properties of single cells and alterations in synaptic network interactions within and between cortical areas including large-scale reorganizations in the representation of the peripheral input. Prominent functional modifications consisting of massive membrane depolarizations, suppression of intracortical inhibitory synaptic mechanisms and enhancement of excitatory synaptic transmission can be observed within a few minutes following the onset of cortical hypoxia or ischemia and probably represent the trigger signals for the induction of neuronal hyperexcitability, irreversible cellular dysfunction and cell death. Pharmacological manipulation of these early events may therefore be the most effective approach to control ischemia and lesion induced disturbances and to attenuate long-term neurological deficits. The complexity of secondary structural and functional alterations in cortical and subcortical structures demands an early and powerful intervention before neuronal damage expands to intact regions. The unsatisfactory clinical experience with calcium and N-methyl-D-aspartate antagonists suggests that this result might be achieved with compounds that show a broad spectrum of actions at different ligand-activated receptors, voltage-dependent channels and that also act at the vascular system. Whether the same therapy strategies developed for the treatment of ischemic injury in the adult brain may be applied for the immature cortex is questionable, since young cortical networks with a high degree of synaptic plasticity reveal a different response pattern to hypoxic and ischemic insults. Age-dependent molecular biological, morphological and physiological parameters contribute to an enhanced susceptibility of the immature brain to these noxae during early ontogenesis and have to be investigated in more detail for the development of adequate clinical therapy.