Effects of a phosphodiesterase IV inhibitor rolipram on microsphere embolism‐induced defects in memory function and cerebral cyclic AMP signal transduction system in rats

Abstract

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.

Modulation of the cAMP signaling pathway after traumatic brain injury

“…Together, these results suggest that the mechanism of rolipram's action may be through CREB. This is supported in other injury models as well where rolipram significantly increased CREB phosphorylation (Nagakura et al, 2002, Hosoi et al, 2003, Lee et al, 2004, Demarch et al, 2007.…”

Subchronic Rolipram Delivery Activates Hippocampal CREB and Arc, Enhances Retention and Slows Down Extinction of Conditioned Fear

“…Sizeable effects temporally related to the actual drug treatment were only observed in normal mice by using much higher doses (1.25 mg/kg/day for 15 days; Nakagawa et al, 2002a, b;Fujioka et al, 2004). Concerning rats, biochemical effects on the hippocampal cAMP system and restoration of behavioral impairment in normogenic, intact animals has been only reported for substantially higher doses of Rolipram (Giorgi et al, 2004;Nagakura et al, 2002;Egawa et al, 1997). Conditioned fear, while apparently a simple form of learning, is actually a rather complex phenomenon from a neurobiological point of view.…”

“…The consequent increase of cAMP-dependent cellular pathways has antidepressant action and reverses memory deficits caused by antagonists of NMDA receptor and other drugs (Fujimaki et al, 2000;Itho et al, 2004;Imanishi et al, 1997;Zhang et al, , 2004Sato et al, 2004;Vitolo et al, 2002). It also improves memory after ischemia and febrile seizures in a mouse model of Rubinstein-Taybi syndrome (Nagakura et al, 2002;Bourtchouladze et al, 2003;Chang et al, 2003). The dependence of LTP and hippocampus-dependent memories on the cAMP signaling cascade suggested that drugs enhancing this pathway could improve learning and reinforce memory.…”

Synaptic plasticity in early aging

“…One approach to achieving this would be to slow the hydrolysis of cAMP (which drives the kinase that activates CREB) by inhibiting the phosphodiesterase isozyme PDE-IV. This is reported, under some conditions at least, to increase CREB phosphorylation and CREB binding to DNA as well as retention scores in rats (Nagakura et al, 2002). Whether similar treatments would offset age-related failures of LTP is not known but, in any event, side effects associated with currently available PDE IV inhibitors are probably unacceptable (Zhu et al, 2001).…”