Phosphodiesterase Inhibitors for Cognitive Enhancement

Memory Pharmaceuticals Corp., 100 Philips Parkway, Montvale, NJ 07645, USA.
Current Pharmaceutical Design (Impact Factor: 3.45). 02/2005; 11(26):3329-34. DOI: 10.2174/138161205774370799
Source: PubMed


An effective treatment for age-related cognitive deficits remains an unmet medical need. Currently available drugs for the symptomatic treatment of Alzheimer's disease or other dementias have limited efficacy. This may be due to their action at only one of the many neurotransmitter systems involved in the complex mechanisms that underlie cognition. An alternative approach would be to target second messenger systems that are utilized by multiple neurotransmitters. Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a key role in biochemical processes that regulate the cognitive process of memory consolidation. Prolongation of cAMP signals can be accomplished by inhibiting phosphodiesterases (PDEs). Eleven PDE families, comprised of more than 50 distinct members, are currently known. This review summarizes the evidence demonstrating that rolipram, a selective inhibitor of cAMP-selective PDE4 enzymes, has positive effects on learning and memory in animal models. These data provide support for the general approach of second messenger modulation as a potential therapy for cognitive dysfunction, and specifically suggest that PDE4 inhibitors may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases.

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    • "This result plausibly corresponds to an effect of a PDE inhibitor, because inhibition of cAMP phosphodiesterase would prolong stimulus-induced cAMP elevation. Indeed, with cbp +/-mice, both LTP and learning have been improved by rolipram (Alarcon et al., 2004; Bourtchouladze et al., 2003), an inhibitor of cAMP phosphodiesterase 4 (PDE4) (Rose et al., 2005). By increasing cAMP levels, rolipram promotes PKA activation and CREB phosphorylation. "
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    ABSTRACT: Congenital cognitive dysfunctions are frequently due to deficits in molecular pathways that underlie the induction or maintenance of synaptic plasticity. For example, Rubinstein-Taybi syndrome (RTS) is due to a mutation in cbp, encoding the histone acetyltransferase CREB-binding protein (CBP). CBP is a transcriptional co-activator for CREB, and induction of CREB-dependent transcription plays a key role in long-term memory (LTM). In animal models of RTS, mutations of cbp impair LTM and late-phase long-term potentiation (LTP). As a step toward exploring plausible intervention strategies to rescue the deficits in LTP, we extended our previous model of LTP induction to describe histone acetylation and simulated LTP impairment due to cbp mutation. Plausible drug effects were simulated by model parameter changes, and many increased LTP. However no parameter variation consistent with a biochemical effect of a known drug class fully restored LTP. Thus we examined paired parameter variations consistent with effects of known drugs. A pair that simulated the effects of a phosphodiesterase inhibitor (slowing cAMP degradation) concurrent with a deacetylase inhibitor (prolonging histone acetylation) restored normal LTP. Importantly these paired parameter changes did not alter basal synaptic weight. A pair that simulated the effects of a phosphodiesterase inhibitor and an acetylase activator was similarly effective. For both pairs strong additive synergism was present. The effect of the combination was greater than the summed effect of the separate parameter changes. These results suggest that promoting histone acetylation while simultaneously slowing the degradation of cAMP may constitute a promising strategy for restoring deficits in LTP that may be associated with learning deficits in RTS. More generally these results illustrate how the strategy of combining modeling and empirical studies may provide insights into the design of effective therapies for improving long-term synaptic plasticity and learning associated with cognitive disorders.
    Journal of Theoretical Biology 07/2014; 360. DOI:10.1016/j.jtbi.2014.07.006 · 2.12 Impact Factor
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    • "These studies led to the identification of a number of PDE subfamilies as promising targets for memory improvement, in specific the PDE1, PDE2, PDE4, PDE5 and PDE9 subtype. In this study we focused on cAMP-selective PDE4 (Barad et al, 1998; Rose et al, 2005; Rutten et al, 2007a; Zhang et al, 2005), cGMP-selective PDE5 (Prickaerts et al, 2004; Rutten et al, 2005), and PDE2, which hydrolyzes both cAMP and cGMP (Boess et al, 2004; Rutten et al, 2007b). It has been suggested that the cognition-enhancing effects of PDE inhibitors are related to activation of cAMP/protein kinase A (PKA)/cAMP responsive element binding protein (CREB) and cGMP/protein kinase G (PKG)/CREB signaling pathways (Blokland et al, 2006; Reneerkens et al, 2009; Rutten et al, 2007b), which are both associated with late phase LTP (L-LTP). "
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    ABSTRACT: Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/PKG signaling mediates early memory consolidation as well as early-phase-LTP, while cAMP/PKA signaling mediates late consolidation and late-phase-like LTP. Additionally, we show for the first time that early-phase cGMP/PKG-signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation.Neuropsychopharmacology accepted article preview online, 12 May 2014; doi:10.1038/npp.2014.106.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2014; 39(11). DOI:10.1038/npp.2014.106 · 7.05 Impact Factor
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    • "The PDE family is comprised by 11 different subfamilies, being PDE1, PDE4, PDE7 and PDE10 highly expressed in brain. Since it has been suggested that cAMP pathways could be involved in neurodegenerative diseases, interfering with both the inflammatory and neurotransmitter cascades, selective inhibitors of these PDEs could represent a novel approach to treat several CNS diseases [9] [10]. PDE7 is a cAMP-specific enzyme not modulated by rolipram (PDE4 inhibitor), expressed across a variety of brain structures apart from its expression on T-cells [11]. "
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    ABSTRACT: A simple and efficient synthetic method for the preparation of quinazoline type phosphodiesterase 7 (PDE7) inhibitors, based on microwave irradiation, has been developed. The use of this methodology improved yields and reaction times, providing a scalable procedure. These compounds are pharmacologically interesting because of their in vivo efficacy both in spinal cord injury and Parkinson's disease models, as shown in previous studies from our group. Herein we describe for the first time that administration of one of the PDE7 inhibitors here optimized, 3-phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline (compound 5), ameliorated brain damage and improved behavioral outcome in a permanent middle cerebral artery occlusion (pMCAO) stroke model. Furthermore, we demonstrate that these PDE7 inhibitors are potent anti-inflammatory as well as neuroprotective agents in primary cultures of neural cells. These results led us to propose PDE7 inhibitors as a new class of therapeutic agents for neuroprotection.
    European Journal of Medicinal Chemistry 11/2011; 47(1):175-85. DOI:10.1016/j.ejmech.2011.10.040 · 3.45 Impact Factor
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