Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4)

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Abstract

Despite initial promise, the development of type 4 phosphodiesterase (PDE4) inhibitors as antidepressants has not advanced significantly. This is due to an incomplete understanding of the functional importance of PDE4 subtypes and high-affinity and low-affinity inhibitor-binding conformers. However, recent developments have rekindled interest in the therapeutic potential of PDE4 inhibitors. First, PDE4 has been shown to be involved in cAMP signaling pathways that are affected by antidepressants. Second, data obtained using mouse knockout lines indicate that PDE4D and PDE4B mediate antidepressant effects. Third, it appears that the interaction of inhibitors with the high-affinity binding conformer of PDE4 is particularly important for antidepressant efficacy. These developments highlight the difficulties of dissociating the actions of PDE4 inhibitors and provide a guide for future research.

Section snippets

The PDE superfamily and PDE4

PDE enzymes comprise an eleven-family group (PDE1–PDE11); there are multiple isoforms in each family, caused by multiple genes and alternative splicing 8, 9. The PDE families differ in their primary structure, ability to hydrolyze cAMP and cGMP, tissue and intracellular distribution, and sensitivity to modulators (e.g. Ca2+, calmodulin and cGMP) and pharmacological inhibitors.

The PDE4 enzyme family, which also is referred to as the low Km, cAMP-selective PDE and the rolipram-sensitive PDE,

Antidepressant effects of PDE4 inhibitors

Rolipram and other PDE4 inhibitors [e.g. Ro201724 (see Chemical names) and ICI63197] produce antidepressant-like effects in several preclinical models. They reduce the time of immobility in the forced-swim test, decrease response rate and increase reinforcement rate under a differential-reinforcement-of-low-rate schedule, reverse the effects of chronic, mild stress, normalize the behavioral deficits observed in Flinders sensitive-line and olfactory-bulbecomized rats, antagonize the effects of

PDE4 in antidepressant-sensitive signaling pathways

In general, clinically used antidepressants enhance noradrenaline-mediated and serotonin (5-HT)-mediated neurotransmission, either by inhibiting reuptake catabolism or by blocking inhibitory, presynaptic α-adrenoceptors (either autoreceptors or heteroreceptors) [25]. Thus, it was of interest to determine whether PDE4 is involved in signaling mechanisms that are associated with these two neurotransmitters (Figure 2). PDE4 was found to be either the predominant or exclusive PDE that mediates the

PDE4 subtypes in the mediation of antidepressant effects

As yet, no highly selective inhibitors of the PDE4 subtypes have been developed; available compounds are only about 10-fold selective, which limits their utility for studies in vivo. The most-studied inhibitors, such as rolipram and Ro201724, are equipotent at inhibiting the four PDE4 subtypes. Thus, it is necessary to examine the behavioral phenotype and pharmacological sensitivity of mouse lines that are deficient in a particular subtype to assess the relative roles of the PDE4 subtypes in

Inhibitor binding to conformers of PDE4

Another level of complexity in understanding the actions of PDE4 inhibitors concerns the high-affinity and low-affinity binding conformers (the HARBS and LARBS). The first indication that rolipram binding might be somewhat complex was the finding that whereas [3H]-rolipram binds with high affinity to brain membranes (Ki=1–10 nM), little high-affinity binding is detected in preparations of peripheral organs [46]. A systematic analysis of binding using a technique that assesses both high-affinity

Future directions

Much has been learned in the past several years about the mechanisms that mediate the antidepressant actions of PDE4 inhibitors. However, several areas need to be addressed more fully. First, the field would be advanced significantly by the development of highly subtype-selective PDE4 inhibitors. This has proved difficult because the catalytic site to which PDE4 inhibitors bind is highly conserved across subtypes [10]. However, as understanding of PDE4 structure and inhibitor binding increase,

Acknowledgements

Research in our laboratory was supported by research grants and an Independent Scientist Award from the National Institute of Mental Health.

References (59)

  • E Panconi

    MK-801 and enantiomers: potential antidepressants or false positives in classical screening models

    Pharmacol. Biochem. Behav.

    (1993)
  • H.T Zhang

    Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism

    Neuropsychopharmacology

    (2000)
  • M Conti

    Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling

    J. Biol. Chem.

    (2003)
  • H.T Zhang

    Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme

    Neuropsychopharmacology

    (2002)
  • S Lamontagne

    Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey

    Brain Res.

    (2001)
  • H.H Schneider

    Stereospecific binding of the antidepressant rolipram to brain protein structures

    Eur. J. Pharmacol.

    (1986)
  • J.E Souness et al.

    Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases

    Cell. Signal.

    (1997)
  • I McPhee

    Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B. Consequences for rolipram inhibition

    J. Biol. Chem.

    (1999)
  • S.J Yarwood

    the RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5

    J. Biol. Chem.

    (1999)
  • H Wachtel

    Characteristic behavioral alterations in rats induced by rolipram and other selective adenosine cyclic 3′,5′-monophosphate phosphodiesterase inhibitors

    Psychopharmacology (Berl.)

    (1982)
  • E Zeller

    Results of a phase II study of the antidepressant effect of rolipram

    Pharmacopsychiatry

    (1984)
  • M.A Giembycz

    Phosphodiesterase 4 inhibitors and the treatment of asthma: where are we now and where do we go from here?

    Drugs

    (2000)
  • J.B Marriott

    Immunotherapeutic and antitumor potential of thalidomide analogues

    Expert Opin. Biol. Ther.

    (2001)
  • S Jacobitz

    Mapping the functional domains of human recombinant phosphodiesterase 4A: structural requirements for catalytic activity and rolipram binding

    Mol. Pharmacol.

    (1996)
  • J.H Soderling et al.

    Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions

    Curr. Opin. Cell Biol.

    (2000)
  • S.H Francis

    Cyclic nucleotide phosphodiesterases: relating structure and function

    Prog. Nucleic Acid Res. Mol. Biol.

    (2001)
  • M.D Houslay

    PDE4 cAMP-specific phosphodiesterases

    Prog. Nucleic Acid Res. Mol. Biol.

    (2001)
  • S Iona

    Characterization of the rolipram-sensitive, cyclic AMP-specific phosphodiesterases: identification and differential expression of immunologically distinct forms in the rat brain

    Mol. Pharmacol.

    (1998)
  • J.A Cherry et al.

    Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect

    J. Comp. Neurol.

    (1999)
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