Effects of a phosphodiesterase IV inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cyclic AMP signal transduction system in rats.
The effects of treatment with rolipram, a specific phosphodiesterase IV inhibitor, on learning and memory function and on the cyclic AMP/PKA/CREB signal transduction system were examined in rats with microsphere embolism (ME)-induced cerebral ischaemia. Sustained cerebral ischaemia was induced by the injection of 900 microspheres (48 microm in diameter) into the right hemisphere of the rat brain. The animals were treated once daily with 3 mg kg(-1) rolipram i.p. from 6 h after the onset of the operation for consecutive 10 days. Microsphere-embolized rats showed prolongation of the escape latency in the water maze task starting from day 7 after the operation and lasting for 3 consecutive days. Treatment with rolipram reduced the escape latency. ME decreased the cyclic AMP content, cytosolic PKA Cbeta level, and nuclear PKA Calpha and Cbeta levels, as well as reduced the pCREB level and the DNA-binding activity of CREB in the cerebral cortex and hippocampus on day 10 after the operation. These alterations were attenuated by treatment with rolipram. These results suggest that ME-induced failure in learning and memory function may be mediated by dysfunction of the cyclic AMP/PKA/CREB signal transduction system, that rolipram may ameliorate ME-induced impairment of learning and memory function, and that the drug effect may be partly attributed to activation of the cyclic AMP/PKA/CREB signal transduction system.
Nagakura
Akira
A
Department of Pharmacology, Tokyo University of Pharmacy & Life Science, 1432-1, Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Niimura
Makiko
M
Takeo
Satoshi
S
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004617:Embolism / Q000150:complications*; D008297:Male; D008568:Memory / Q000187:drug effects*; D008863:Microspheres; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D021122:Protein Subunits; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D010726:Phosphodiesterase Inhibitors; D021122:Protein Subunits; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram