Impairment of adenylyl cyclase and of spatial memory function after microsphere embolism in rats.
The purpose of the present study was to characterize alterations in the adenylyl cyclase (AC), cyclic adenosine 3',5'-monophosphate (cAMP), and spatial memory function after sustained cerebral ischemia. Sustained cerebral ischemia was induced by injection of 900 microspheres (48 microm in diameter) into the right (ipsilateral) hemisphere of rats. Alterations in the AC and cAMP in the cerebral cortex and hippocampus were examined up to 7 days after the embolism. A decrease in the cAMP content was seen in the ipsilateral hemisphere throughout the experiment. Microsphere embolism (ME) decreased the activity of Ca(2+)/calmodulin (CaM)-sensitive AC in the ipsilateral hemisphere throughout the experiment, whereas the basal and 5'-guanylyl imidodiphosphate (Gpp(NH)p)-sensitive AC activities were not altered. Immunoblotting analysis of AC subtypes with specific antibodies showed a decrease in the immunoreactivity of AC-I in the ipsilateral hemisphere during these periods. No significant differences in the immunoreactivity of AC-V/VI and AC-VIII were observed after ME. The levels of GTP-binding proteins Galpha(s), Galpha(i), and Gbetawere unchanged. Furthermore, microsphere-embolized rats showed prolongation of the escape latency in the water maze task determined on the seventh to ninth day after the operation. These results suggest that sustained cerebral ischemia may induce the impairment of the AC, particularly a selective reduction in the AC-I level and activity, coupled with the decrease in cAMP content. This reduction may play an appreciable role in the disturbance in cAMP-mediated signal transduction system, possibly leading to learning and memory dysfunction.
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan.
Akira
A
Nagakura
Keiko
K
Miyake-Takagi
Norio
N
Takagi
Masato
M
Fukui
Satoshi
S
Takeo
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002341:Carotid Artery Thrombosis / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006624:Hippocampus / Q000201:enzymology / Q000503:physiopathology; D002542:Intracranial Embolism and Thrombosis / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007527:Isoenzymes / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D008863:Microspheres; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013687:Telencephalon / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology
D007527:Isoenzymes; D006165:Guanylyl Imidodiphosphate; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D002118:Calcium