Phosphodiesterases: CNS Functions and Diseases

Anjana Munshi, Satrupa Das, Munshi, Anjana, Das, Satrupa

Phosphodiesterase (PDE) gene family is a large family having at least 21 genes and multiple versions (isoforms) of the phosphodiesterase enzymes. These enzymes catalyze the inactivation of intracellular mediators of signal transduction such as cAMP and cGMP and therefore, play a pivotal role in various cellular functions. PDE inhibitors (PDEI) are drugs that block one or more of the five subtypes of the PDE family and thereby prevent inactivation of the intracellular cAMP and cGMP by the respective PDE-subtypes. The first clinical use of PDEI was reported almost three decades ago. Studies later found the ability of these compounds to increase the levels of ubiquitous secondary messenger molecules that can cause changes in vascular tone, cardiac function and other cellular events and thus these findings paved the way for their use in various medical emergencies. PDEs are found to be distributed in many tissues including brain. Therefore, new therapeutic agents in the form of PDEI are being explored in neurodegenerative diseases including stroke. Although studies have revealed their use in cerebral infarction prevention, their full-fledged application in times of neurological emergency or stroke in specific has been very limited so far. Nevertheless, recent investigations suggest PDE4 and PDE5 inhibitors to play a vital role in mitigating stroke symptoms by modulating signaling mechanisms in PDE pathway. Further, extensive research in terms of their pharmacological properties like dosing, drug specific activities, use of simultaneous medications, ancillary properties of these compounds and studies on adverse drug reactions needs to be carried out to set them as standard drugs of use in stroke.