POSSIBLE INVOLVEMENT OF ACTIVATOR PROTEIN-1 DNA-BINDING IN MECHANISMSUNDERLYING ISCHEMIC TOLERANCE IN THE CA1 SUBFIELD OF GERBIL HIPPOCAMPUS

Transcription factors are nuclear proteins with an ability to recogniz e particular nucleotide sequences on double stranded genomic DNAs and thereby modulate the activity of RNA polymerase II which is responsibl e for the formation of messenger RNAs in cell nuclei. Gel retardation electrophoresis revealed that transient forebrain ischemia for 5 min l ed to drastic potentiation of binding of a radiolabelled double-strand ed oligonucleotide probe for the transcription factor activator protei n-1, in the thalamus as well as the CA1 and CA3 subfields and the dent ate gyrus of the hippocampus of the gerbils previously given ischemia for 2 min two days before, which is known to induce tolerance to subse quent severe ischemia in the CA1 subfield. By contrast, ischemia for 5 min resulted in prolonged potentiation of activator protein-1 binding in the vulnerable CAL subfield of the gerbils with prior ischemia for 5 min 14 days before, which is shown to induce delayed death of the p yramidal neurons exclusively in this subfield. Similar prolongation wa s seen with activator protein-1 binding in the vulnerable thalamus but not in the resistant CA3 subfield and dentate gyrus of the gerbils wi th such repeated ischemia for 5 min. Limited proteolysis by Staphyloco ccus aureus V8 protease as well as supershift assays using antibodies against c-Fos and c-Jun proteins demonstrated the possible difference in constructive partner proteins of activator protein-1 among nuclear extracts of the CA1 subfield obtained from gerbils with single, tolera ted and repeated ischemia. These results suggest that de novo protein synthesis may underlie molecular mechanisms associated with acquisitio n of the ischemic tolerance through modulation at the level of gene tr anscription by activator protein-1 composed of different constructive partner proteins in the CA1 subfield. Possible participation of glial cells in the modulation is also suggested in particular situations. (C ) 1998 IBRO. Published by Elsevier Science Ltd.