Nonselective Inhibition of PDE4 Induces Gastroparesis in Mice

Purpose Non/PAN‐selective inhibitors of Type 4 phosphodiesterases (PDE4s), a group of isoenzymes that hydrolyze the second messenger cAMP, exert promising therapeutic benefits, such as anti‐inflammatory as well as cognition‐ and memory‐enhancing effects. However, these drugs also induce several side effects, in particular emesis and nausea, curbing their clinical use. The PDE4 family consists of four subtypes/genes (PDE4A to D). As each plays unique and non‐overlapping roles in the body, targeting individual PDE4 subtypes is a promising approach to separate the therapeutic benefits from the side effects of current PDE4 inhibitors. To this end, this study aimed to identify the specific PDE4s involved in emesis and nausea. While mice are anatomically unable to vomit, PDE4 inhibition in mice induces gastroparesis, an abnormal retention of food in the stomach, which is a well‐known cause of nausea and vomiting in humans and was thus used as a correlate. Methods Gastroparesis in knock‐out mice deficient in individual PDE4 subtypes and in mice treated with PAN‐PDE4 inhibitors was compared to their respective controls. We used a long term model, in which food accumulated in the stomach of mice fed ad libitum for 3 days, as well as an acute model, in which fasted mice were given a FITC‐labeled food bolus by oral gavage, euthanized 30 min later, and FITC/food‐retention in the stomach was then measured. Results Treatment of wildtype mice with PAN‐PDE4 inhibitors increased stomach sizes to twice that of controls without changing their food intake or the weight of their intestines, suggesting a specific effect of PDE4 inhibition in restricting gastric emptying. Structurally distinct PDE4 inhibitors all induced gastroparesis, indicating it is a class effect. Conversely, YM976, an inhibitor which does not cross the blood‐brain‐barrier, did not induce gastroparesis suggesting that PDE4 inhibitor‐induced gastroparesis results from altered neuronal regulation, rather than from PDE4 inhibition in the stomach/periphery. Ablation of PDE4A, B, C or D in the respective KO mice did not induce, nor did it protect the animals from PAN‐PDE4 inhibitor‐induced gastroparesis, implying that it results from the concurrent inhibition of multiple PDE4s. Conclusions Selective ablation of individual PDE4 subtypes does not induce gastroparesis in mice. Thus, potentially, any of the four PDE4 subtypes may be targeted individually for therapeutic benefits without inducing nausea or emesis. In addition, PDE4 inhibitors that do not cross the blood‐brain barrier may also be free of these side effects. Support or Funding Information Supported by grants from the NIH (HL76125, HL141473, HL066299).