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 μm 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 Cβ level, and nuclear PKA Cα and Cβ 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. British Journal of Pharmacology (2002) 135, 1783–1793; doi:10.1038/sj.bjp.0704629