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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
Author(s) -
Takeo Satoshi,
Niimura Makiko,
MiyakeTakagi Keiko,
Nagakura Akira,
Fukatsu Tomoko,
Ando Tsuyoshi,
Takagi Norio,
Taaka Kouichi,
Hara Junko
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705096
Subject(s) - creb , cyclic adenosine monophosphate , adenylyl cyclase , signal transduction , chemistry , protein kinase a , endocrinology , medicine , neuroscience , phosphorylation , biochemistry , biology , receptor , transcription factor , gene
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. 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. Microsphere embolism (ME)‐induced sustained cerebral ischaemia was produced by injection of 700 microspheres (48 μm 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. 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. ME decreased Ca 2+ /calmodulin (CaM)‐stimulated AC (AC‐I) activity, cAMP content, cytosolic PKA Cβ level, nuclear PKA Cα and Cβ 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. 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.British Journal of Pharmacology (2003) 138 , 642–654. doi: 10.1038/sj.bjp.0705096