Alterations of cAMP response element-binding activity in the aged rat brain in response to administration of rolipram, a cAMP-specific phosphodiesterase inhibitor.
Transcription factor, cAMP response element-binding protein (CREB), which is phosphorylated by cAMP-dependent kinase via an increase in cAMP, and regulates gene transcription by binding to the cAMP response element (CRE) on target genes. We examined age-dependent alterations in the DNA-binding activity of CREB in rat brain regions, and the effects of rolipram, a cAMP-specific phosphodiesterase (PDE) inhibitor on the CRE-binding activity by electrophoretic mobility-shift assay (EMSA). A marked age-dependent decrease in the CRE-binding activity was shown in all brain regions examined, especially in the basal forebrain, the striatum and the hippocampus. Furthermore, CRE-binding activities in the basal forebrain of both young-adult and aged rats significantly increased 2 h after rolipram administration (1 mg/kg, i.p.), and the rolipram treatment recovered the decreased CRE-binding activity in the aged rats. The saturation experiment in EMSA also revealed that rolipram reversed the decrease in the maximum CRE-bindings in the basal forebrain with aging. Since the 5' upstream region of the rat choline acetyltransferase (ChAT) gene contains CRE, and ChAT-positive neurons in the basal forebrain project to the frontal cortex and the hippocampus, rolipram may exert its previously reported ameliorating effect on the age-related reductions of ChAT activities in the frontal cortex and the hippocampus by phosphorylating CREB in the basal forebrain with activation of cAMP-dependent protein kinase via inhibition of PDE.
Asanuma
M
M
Department of Neuroscience, Okayama University Medical School, Japan.
Nishibayashi
S
S
Iwata
E
E
Kondo
Y
Y
Nakanishi
T
T
Vargas
M G
MG
Ogawa
N
N
D000344:Afferent Pathways; D000375:Aging / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003704:Dementia / Q000188:drug therapy / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D020889:Rolipram
D017362:Cyclic AMP Response Element-Binding Protein; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D000242:Cyclic AMP; D002795:Choline O-Acetyltransferase; D020889:Rolipram