Inhibition of the Phosphodiesterase 4 (PDE4) Enzyme Reverses Memory Deficits Produced by Infusion of the MEK Inhibitor U0126 into the CA1 Subregion of the Rat Hippocampus

Abstract

Cyclic AMP-specific phosphodiesterase 4 (PDE4), which is an integral component of NMDA receptor-mediated cAMP signaling, is involved in the mediation of memory processes. Given that NMDA receptors also mediate MEK/mitogen-activated protein kinase (MAPK, ERK) signaling, which is involved in synaptic plasticity, and that some PDE4 subtypes are phosphorylated and regulated by ERK, it was of interest to determine if PDE4 is involved in MEK/ERK signaling-mediated memory. It was found that rolipram, a PDE4-selective inhibitor, reversed the amnesic effect in the radial-arm maze test of the MEK inhibitor U0126 administered into the CA1 subregion of the rat hippocampus. Consistent with this, rolipram, either by peripheral administration or direct intra-CA1 infusion, enhanced the retrieval of long-term memory impaired by intra-CA1 infusion of U0126 using the step-through inhibitory avoidance test. The same dose of rolipram did not affect U0126-induced reduction of phospho-ERK1/2 levels in the CA1 subregion. However, in primary cultures of rat cerebral cortical neurons, pretreatment with U0126 increased PDE4 activity; this was correlated with the U0126-induced reduction of phospho-ERK1/2 levels. These results suggest that MEK/ERK signaling plays an inhibitory role in regulating PDE4 activity in the brain; this may be a novel mechanism by which MEK/ERK signaling mediates memory. PDE4 is likely to be an important link between the cAMP/PKA and MEK/ERK signaling pathways in the mediation of memory.

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

“…While overall inhibition of PDE4 enhances memory performance in animals (Barad et al, 1998;Zhang et al, 2004Zhang et al, , 2005, PDE4BÀ/À mice did not show significant changes in either short-or long-term memory in step-down passive avoidance and Morris water-maze tasks (Table 1 and Figure 5), two tests measuring hippocampus-based memory (Bevilaqua et al, 1997). This is consistent with the limited expression of PDE4B in the hippocampus (Cherry and Davis, 1999).…”

“…It is well established that PDE4 inhibitors such as rolipram produce antidepressant-like and memory-enhancing effects (Barad et al, 1998;O'Donnell and Zhang, 2004;Zhang et al, 2004Zhang et al, , 2006Zhang and O'Donnell, 2007). They also may induce anxiogenic-like effects and sedation (Heaslip and Evans, 1995;Imaizumi et al, 1994;Silvestre et al, 1999b), although an anxiolytic-like effect also has been reported (Silvestre et al, 1999a).…”

“…Administration of PDE4 inhibitors such as rolipram produces antidepressant-like effects (Zhang et al, 2002(Zhang et al, , 2006, reverses memory deficits induced pharmacologically, physically, or genetically (Bourtchouladze et al, 2003;Imanishi et al, 1997;Zhang et al, 2000Zhang et al, , 2004, alters anxiogenic-like behavior (Imaizumi et al, 1994;Silvestre et al, 1999a), and induces analgesia in rodents (Kumar et al, 2000). Inhibition of PDE4 also increases adult neurogenesis (Nakagawa et al, 2002), which is believed to be involved in antidepressant activity (Dranovsky and Hen, 2006;Malberg and Duman, 2003;Santarelli et al, 2003).…”

The cyclic AMP phenotype of fragile X and autism

“…PDE4 is a cAMP-specific PDE that is prevalent in the brain and is the target of antidepressant and cognitive enhancing pharmacotherapeutics. With activity being regulated by both cAMP and extracellular signal-regulated kinase (ERK) signaling, PDE4 is a key component in NMDAmediated memory processes (Zhang, Zhao et al 2004). The PDE4 subfamilies PDE4A, PDE4B, PDE4C, and PDE4D are highly expressed in human brain regions, whereas rat brain primarily expresses PDE4A, B, and D (Cherry and Davis 1999;Takahashi, Terwilliger et al 1999;Fujita, Zoghbi et al 2005;Parker, Matthews et al 2005).…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…PDE-4 inhibition could, thus, be associated with a complementary upstream mechanism that recruits adenylyl cyclase: for example, ␤-AR, 5-HT 4 , or 5-HT 6 receptor agonism. 113,117,118,231,232 Such a dual-acting drug should mainly inhibit PDE-4 (and hence favor cAMP generation) in structures where ␤-AR, 5-HT 4 or 5-HT 6 receptors are stimulated. This would increase the therapeutic window and enhance both the efficacy and duration of agonist-mediated actions.…”