A possible mechanism for improvement by a cognition-enhancer nefiracetam of spatial memory function and cAMP-mediated signal transduction system in sustained cerebral ischaemia in rats.
1. Accumulated evidence indicates that the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signal transduction system may be linked to learning and memory function. 2. The effects of nefiracetam, which has been developed as a cognition enhancer, on spatial memory function and the AC/cAMP/PKA/CREB signal transduction system in rats with sustained cerebral ischaemia were examined. 3. Microsphere embolism (ME)-induced sustained cerebral ischaemia was produced by injection of 700 microspheres (48 micro m in diameter) into the right hemisphere of rats. Daily oral administration of nefiracetam (10 mg kg(-1) day(-1)) was started from 15 h after the operation. 4. The delayed treatment with nefiracetam attenuated the ME-induced prolongation of the escape latency in the water maze task that was examined on day 7 to 9 after ME, but it did not reduce the infarct size. 5. ME decreased Ca(2+)/calmodulin (CaM)-stimulated AC (AC-I) activity, cAMP content, cytosolic PKA Cbeta level, nuclear PKA Calpha and Cbeta levels, and reduced the phosphorylation and DNA-binding activity of CREB in the nucleus in the right parietal cortex and hippocampus on day 3 after ME. The ME-induced changes in these variables did not occur by the delayed treatment with nefiracetam. 6. These results suggest that nefiracetam preserved cognitive function, or prevented cognitive dysfunction, after sustained cerebral ischaemia and that the effect is, in part, attributable to the prevention of the ischaemia-induced impairment of the AC/cAMP/PKA/CREB signal transduction pathway.
Takeo
Satoshi
S
Department of Pharmacology, Tokyo University of Pharmacy & Life Science, Hachioji, Tokyo 192-0392, Japan. takeos@ps.toyaku.ac.jp
Niimura
Makiko
M
Miyake-Takagi
Keiko
K
Nagakura
Akira
A
Fukatsu
Tomoko
T
Ando
Tsuyoshi
T
Takagi
Norio
N
Tanonaka
Kouichi
K
Hara
Junko
J
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
D018697:Nootropic Agents; D011760:Pyrrolidinones; C058876:nefiracetam; D000242:Cyclic AMP