Date of Award
Type-4-cAMP-phosphodiesterases (PDE4s) are a group of isoenzymes that hydrolyze the second messenger cyclic adenosine monophosphate (cAMP). PDE4 inhibitors have many therapeutic uses including reducing inflammation, however, they also have side effects like nausea and emesis, which have diminished the clinical utility of PDE4 inhibitors. When administered to mice, PDE4 inhibitors have been shown to cause hypothermia. Given that nausea and emesis in humans are also associated hypothermia, this project served to determine whether PDE4 inhibitor-induced hypothermia may represent a correlate of nausea and/or emesis in mice. To this end, the current literature was screened for articles that explore nausea, emesis and hypothermia in any species, and experiments were performed to test the validity of the nausea to hypothermia correlate. The PDE4 family comprises 4 subtypes, PDE4A-D, each playing unique roles in the body. Body temperature was measured in mice deficient of individual PDE4 subtypes. The results show that baseline body temperature was not different in any of the PDE4KO (knockout) animals, and treatment with a PDE4 inhbitor induced substantial hypothermia in the WT and KO mice. Together, these data suggest that inactivation of any single PDE4 subtype does not induce hypothermia, and that PAN-PDE4 inhibitors thus induce hypothermia via the concurrent inhibition of multiple PDE4 subtypes. If hypothermia in mice indeed represents a useful correlate of nausea in humans, then PDE4 inhibitor-induced nausea and emesis must also result from the simultaneous inhibition of multiple PDE4 subtypes, and inhibitors selective for specific PDE4 subtypes should be free of these side effects.
Oditt, Marianna Susan, "Assessment of Hypothermia as a Correlate of PDE4 Inhibitor-Induced Nausea in Mice" (2021). Undergraduate Theses . 20.