CYCLIC AMP-SPECIFIC PDEs: A PROMISING THERAPEUTIC TARGET FOR CNS REPAIR

Research to date has indicated that cAMPspecific PDEs, particularly the members of PDE4 family, play a crucial role in the pathogenesis of CNS injury and neurodegeneration by downregulating intracellular levels of cAMP in various cell types. Reduced cAMP signaling results in immune cell activation, inflammation, secondary tissue damage, scar formation and axon growth failure, ultimately leading to an exacerbation of injury, the prevention of endogenous repair and limited functional recovery. Although inhibition of cAMPspecific-PDE activity through the use of drugs like Rolipram has been shown to reverse these deficiencies and mediate neurorepair, an inability to develop selective agents and/or reduce dose-limiting side-effects associated with PDE4 inhibition has hampered their clinical translation. Recent work with more selective pharmacological inhibitors of cAMP-specific PDEs and molecular targeting approaches, along with improved understanding of the basic biology and role of PDEs in pathological processes may enable this promising therapeutic approach to advance clinically and have a similar impact on CNS injury and disease as PDE5 inhibitors have had on the treatment of sexual dysfunction.