Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

Abstract

A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic.

Keywords: CNS; PDE; cell death; clinical trials; cyclic AMP; cyclic GMP; cyclic nucleotides; phosphodiesterase; phosphodiesterase inhibitor; regeneration; repair.

Figure 1

The effects of cyclic nucleotide:PDE signaling on pathological and reparative processes after neurological disease and injury. Cyclic nucleotides and their downstream effectors are critical signaling molecules for a myriad of cellular functions from neurogenesis and myelination to vascular remodeling and neuroplasticity (black arrows). During neurological disease or injury, increased expression and/or activity of various PDE enzymes leads to the hydrolysis of cyclic AMP and GMP to 5′AMP or 5′GMP, respectively (black arrow loops), antagonizing these processes and altering the balance of cell responses towards inflammation, cell death and neurodegeneration (red arrows).