STIMULUS-TRANSCRIPTION COUPLING IN FOCAL CEREBRAL-ISCHEMIA

Glutamate-mediated spreading depression is currently thought to be a k ey event in the pathogenesis of potential neuronal degeneration in the ischemic 'penumbra'. Glutamate receptor stimulation causes induction of transcription factors that belong to the class of immediate early g enes (IEGs), thought to be involved in coupling neuronal excitation to target gene expression. Focal cerebral ischemia elicits a homogeneous expression of several IEGs, prominently in cortex. In the ischemic co re, discrepancies are observed between mRNA and protein levels, due to a severe, persistent protein synthesis deficit, preventing the transl ation of IEG encoded mRNAs. Outside the ischemic core, widespread IEG expression occurs in the entire ipsilateral cortex at mRNA as well as at protein level. This homogeneous expression of transcription factors can be pinpointed to at least two different pathogenetic mechanisms b y means of appropriate pharmacological antagonists. Prolonged IEG indu ction in the 'penumbra', an area in which neurons are metabolically co mpromised but not yet energy-depleted, cannot be suppressed by the adm inistration of Iv-methyl-D-aspartate (NMDA) receptor antagonists. In c ontrast, short-lasting IEG induction in undamaged neurons remote from the ischemic territory, though also caused by ischemia-elicited spread ing depression, can be blocked by NMDA receptor antagonists. In both a reas, IEG expression identifies neurons destined to survive but is lik ely to be mediated by different signal transduction pathways, at the r eceptor, second messenger and/or the DNA level.