Prolongation by bifemelane of potentiation of AP1 DNA binding in hippocampal CA1 subfield of gerbils with transient forebrain ischemia.
In eukaryotes, protein de novo synthesis is mainly under the control of transcription factors at the level of gene transcription in cell nuclei. Gel retardation electrophoresis was employed for determination of DNA-binding activity of the transcription factor activator protein-1 (AP1), which is a dimer between c-Fos and c-Jun protein families. Binding of a radiolabeled double-stranded oligonucleotide probe for AP1 was rapidly potentiated in the CA1 and CA3 subfields and the dentate gyrus of the hippocampus of gerbils with forebrain ischemia for 5 min. Similarly marked potentiation was seen in the thalamus and the striatum, but not in the frontal cortex, following the recirculation of blood supply. The potentiation was transient in the vulnerable CA1 subfield, but was rather persistent in the thalamus and the striatum in addition to the resistant CA3 subfield and dentate gyrus. However, administration of the neuroprotective drug bifemelane (10 to 20 mg/kg, i.p.) resulted in prolongation of the potentiation of AP1 binding in the CA1 subfield up to 6 hr after ischemia, without significantly affecting that in other central structures. Limited proteolysis revealed that bifemelane induced expression of the AP1 consisting of constructive proteins different from those expressed in control animals in the CA1 subfield. These results suggest that bifemelane may protect neuronal cells against ischemic injuries through molecular mechanisms associated with prolongation of the potentiation of AP1 binding in the vulnerable CA1 subfield after ischemia.
Yoneda
Y
Y
Department of Pharmacology, Setsunan University, Hirakata, Osaka, Japan.
Kuramoto
N
N
Azuma
Y
Y
Inoue
K
K
Ogita
K
K
Mitani
A
A
Yanase
H
H
Masuda
S
S
Zhang
L
L
Kataoka
K
K
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D004586:Electrophoresis / Q000379:methods; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005849:Gerbillinae; D006624:Hippocampus / Q000098:blood supply / Q000737:chemistry / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D018696:Neuroprotective Agents / Q000032:analysis / Q000378:metabolism; D015345:Oligonucleotide Probes; D016548:Prosencephalon / Q000098:blood supply / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D001559:Benzhydryl Compounds; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D015345:Oligonucleotide Probes; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; C031906:bifemelane