1 The e ects of treatment with rolipram, a speci®c 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. 2 Sustained cerebral ischaemia was induced by the injection of 900 microspheres (48 mm in diameter) into the right hemisphere of the rat brain. The animals were treated once daily with 3 mg kg 71 rolipram i.p. from 6 h after the onset of the operation for consecutive 10 days. 3 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. 4 ME decreased the cyclic AMP content, cytosolic PKA Cb level, and nuclear PKA Ca and Cb 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. 5 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 e ect may be partly attributed to activation of the cyclic AMP/PKA/CREB signal transduction system.

These results indicate that high glucose decreased the levels and functions of Gi proteins in A10 VSMC and aorta. It may thus be suggested that decreased levels and activity of Gi proteins and adenylyl cyclase signaling induced by hyperglycemia may be one of the important mechanisms contributing to the cardiovascular complications associated with diabetes.

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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 e ects of ne®racetam, 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 mm in diameter) into the right hemisphere of rats. Daily oral administration of ne®racetam (10 mg kg 71 day 71 ) was started from 15 h after the operation. 4 The delayed treatment with ne®racetam 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 Cb level, nuclear PKA Ca and Cb 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 ne®racetam. 6 These results suggest that ne®racetam preserved cognitive function, or prevented cognitive dysfunction, after sustained cerebral ischaemia and that the e ect is, in part, attributable to the prevention of the ischaemia-induced impairment of the AC/cAMP/PKA/CREB signal transduction pathway.

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