Altered gene expression in brain ischemia.

Abstract

Ischemia is one of the strongest stimuli for gene induction in the brain. More than 80 different mRNAs have been found to be induced by brain ischemia so far. Many of these genes encode protein products that are involved directly or indirectly in neuronal survival. These include genes that promote recovery by enhanced gene expression (for example, heat shock proteins or growth factors) or attempt to protect them from delayed neuronal death (for example anti-apoptosis genes). Neuronal degeneration can be promoted by induction of apoptosis genes or genes that cause a stress to the cells, such as free radical production by nNOS or iNOS. Even though so many ischemia-inducible genes have been identified, the general reduction of gene transcription and inhibition of protein translation affect neuronal survival the most. The lack of protein synthesis is especially significant when the cells are challenged by ischemia followed by the attack of free radicals during the subsequent recirculation. Even though the ischemia-induced gene expression has a dichotomy to beneficial and harmful genes, several genes such as those encoding transcription factors may participate in both cellular responses. Therefore, pinpointing the receptors and signal transduction mechanisms responsible for the induction of different genes is of interest. So far, only NMDA (Fig. 1) and possibly KA/ AMPA receptor and to some extent alpha 2-adrenoreceptor have proved to be involved in the regulation of perifocal gene induction. Nevertheless, interfering with gene expression offers a potential opportunity for the development of a novel stroke therapy.