Date of Award


Document Type


Degree Name



Basic Medical Sciences

Committee Chair

Wito Richter, Ph.D.


Type 4 cAMP phosphodiesterases (PDE4s) comprise a family of four isoenzymes, PDE4A to D, that hydrolyze and inactivate the second messenger cAMP. Non/PAN selective PDE4 inhibitors, which inhibit all four subtypes simultaneously, produce many promising therapeutic benefits, such as anti-inflammatory or cognition- and memory-enhancing effects. However, unwanted side effects, principally, nausea, diarrhea, and emesis, have long hampered their clinical and commercial success. Targeting individual PDE4 subtypes has been proposed for developing drugs with an improved safety profile, but which PDE4 subtype(s) is/are actually responsible for nausea and emesis remains ill defined. In mice treated with PAN-selective inhibitors, there is substantial impairment of autonomic nervous system functions, including gastroparesis (retention of food in the stomach), and hypothermia, both of which are associated with nausea and emesis in humans. Selective inactivation of any of the four PDE4 subtypes does not induce gastroparesis in the mice, nor does it change their body temperature, suggesting that these adverse effects are not mediated by a single subtype, but require concurrent inhibition of multiple (at least two) PDE4 subtypes. As mice are anatomically incapable of vomiting, we have identified these effects as novel correlates of nausea in these animals. Importantly, these studies suggest that subtype-selective inactivation of individual subtypes may be free of certain adverse effects and thus have an improved safety profile relative to PAN-selective inhibition.