INCREASES IN LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTOR MESSENGER-RNA AND ITS PROMOTERS AFTER TRANSIENT FOREBRAIN ISCHEMIA IN THE RAT-BRAIN

Expression of brain-derived neurotrophic factor (BDNF) may play a role in the mechanism of neuronal cell death after cerebral ischemia. We i nvestigated the changes in levels of mRNAs encoding BDNF and its promo ters in the rat brain after transient forebrain ischemia. Transient fo rebrain ischemia was induced by occlusion of bilateral common carotid arteries and systemic hypotension for 8 min. The alterations in BDNF g ene expression in the hippocampus and in the cerebral cortex were exam ined by in situ hybridization using a mouse BDNF cDNA probe and cDNA p robes including exon-specific promoters. BDNF transcripts were rapidly enhanced after the ischemic insult, both in the hippocampus and the c erebral cortex. NBQX suppressed the enhanced gene expression of BDNF m arkedly in the dentate gyrus (DG). In contrast, MK-801 had little effe ct on BDNF expression. In the piriform cortex, MK-801 or NBQX reduced the expression only moderately. After the ischemic insult, promoter sp ecific BDNF 5'-exon I and exon III were increased remarkably in the DG . The increase in exon I in DG was suppressed partially by MK-801 and NBQX, while the increase in exon III in CA3 was suppressed by MK-801 b ut that in DG was not suppressed by either antagonist. In the piriform cortex, exon III was increased remarkably and this increase was not i nfluenced by either agonist. These results suggest that the gene expre ssion of BDNF was enhanced by transient ischemia both in the hippocamp us and the cerebral cortex and that the cerebral ischemia stimulated a t least two different promoter-and neuron type-specific pathways regul ating expression of the BDNF gene mediated by glutamate receptors of n on-NMDA type and NMDA type. (C) 1998 Elsevier Science Ltd. All rights reserved.