PAN‐selective inhibition of cAMP‐phosphodiesterase 4 (PDE4) induces gastroparesis in mice

Abstract

Inhibitors of cAMP‐phosphodiesterase 4 (PDE4) exert a number of promising therapeutic benefits, but adverse effects, in particular emesis and nausea, have curbed their clinical utility. Here, we show that PAN‐selective inhibition of PDE4, but not inhibition of PDE3, causes a time‐ and dose‐dependent accumulation of chow in the stomachs of mice fed ad libitum without changing the animals' food intake or the weight of their intestines, suggesting that PDE4 inhibition impairs gastric emptying. Indeed, PDE4 inhibition induced gastric retention in an acute model of gastric motility that traces the passage of a food bolus through the stomach over a 30 minutes time period. In humans, abnormal gastric retention of food is known as gastroparesis, a syndrome predominated by nausea (>90% of cases) and vomiting (>80% of cases). We thus explored the abnormal gastric retention induced by PDE4 inhibition in mice under the premise that it may represent a useful correlate of emesis and nausea. Delayed gastric emptying was produced by structurally distinct PAN‐PDE4 inhibitors including Rolipram, Piclamilast, Roflumilast, and RS25344, suggesting that it is a class effect. PDE4 inhibitors induced gastric retention at similar or below doses commonly used to induce therapeutic benefits (e.g., 0.04 mg/kg Rolipram), thus mirroring the narrow therapeutic window of PDE4 inhibitors in humans. YM976, a PAN‐PDE4 inhibitor that does not efficiently cross the blood‐brain barrier, induced gastroparesis only at significantly higher doses (≥1 mg/kg). This suggests that PDE4 inhibition may act in part through effects on the autonomic nervous system regulation of gastric emptying and that PDE4 inhibitors that are not brain‐penetrant may have an improved safety profile. The PDE4 family comprises four subtypes, PDE4A, B, C, and D. Selective ablation of any of these subtypes in mice did not induce gastroparesis per se, nor did it protect from PAN‐PDE4 inhibitor‐induced gastroparesis, indicating that gastric retention may result from the concurrent inhibition of multiple PDE4s. Thus, potentially, any of the four PDE4 subtypes may be targeted individually for therapeutic benefits without inducing nausea or emesis. Acute gastric retention induced by PDE4 inhibition is alleviated by treatment with the widely used prokinetic Metoclopramide, suggesting a potential of this drug to alleviate the side effects of PDE4 inhibitors. Finally, given that the cause of gastroparesis remains largely idiopathic, our findings open the possibility that a physiologic or pathophysiologic downregulation of PDE4 activity/expression may be causative in a subset of patients.

The cAMP-phosphodiesterase 4 (PDE4) controls β-adrenoceptor- and CFTR-dependent saliva secretion in mice

“…Indeed, a prior study has shown that inhibition of PDE4 promoted the release of amylase from parotid acinar cells in culture 33 , which is consistent with the notion that βadrenoceptor-and cAMP-dependent saliva secretions are rich in protein 1,2 . Conversely, we propose that in awake mice, PDE4 inhibition may induce salivation via additional, central/neuronal regulations, in line with the high expression of PDE4 in brain 34 and the fact that PDE4 inhibition has been shown to affect other autonomic nervous system regulations including control of body temperature or gastrointestinal motility 17,20 . In an intriguing parallel, although the most widely used drug to induce salivation, Pilocarpine, can induce salivation by acting directly on the salivary glands (see Fig.…”

“…PDE inhibitors were generally administered at a dose of 1 mg/kg (i.p. ), which has been shown to produce ≥50% of maximal efficacy on a variety of acute phenotypes of PDE4 inhibition in mice 17,19,20 , and thus likely reflects ≥50% target engagement.…”

“…PDE4C knockout mice (Pde4c tm1.1(KOMP)Wtsi/J ) were generated by the National Institutes of Health (NIH) Knockout Mouse Program (KOMP; www.komp.org) and kindly distributed via the KOMP repository at the University of California at Davis. Please find a description of the PDE4C knockout mouse here 17 ; additional details are available on the website of the Mutant Mouse Regional Resource Centers (MMRRC; http://www.mmrrc.org; Stock number 049025-UCD). Mice carrying the ΔF508-CFTR (Cftr tm1Kth ) mutation, that is common among cystic fibrosis patients, were generated by Dr. Kirk R. Thomas (University of Utah) and kindly distributed via The Jackson Laboratory (stock 002515 | ΔF; Bar Harbor, ME, USA).…”

“…Moreover, at least one study has shown that inhibitors with some selectivity for PDE4D exhibited reduced vomiting compared to PAN-PDE4 inhibitors in several species 32 . Finally, using gastric retention as an alternative correlate of nausea and emesis in mice, we recently suggested that it may be the concurrent inhibition of multiple PDE4 subtypes that is responsible for the adverse effects of PAN-PDE4 inhibitors 17 . Thus, in our opinion, the association of individual PDE4 subtypes with emesis and/or nausea remains inconclusive.…”

Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice

“…This raises the question of whether PDE4 inhibitor-induced hypothermia may also represent an accurate and thus valuable correlate of the emetic potential of this particular class of drugs. Intriguingly, the potency of PAN-PDE4 inhibitors to induce nausea and/or emesis in humans [ 59 , 76 ], the potency of the same drugs to induce vomiting in animals [ 65 , 80 , 81 ], as well as the potency of these drugs to induce correlates of emesis in animals, such as shortening the duration of α 2 -adrenoceptor-dependent anesthesia [ 52 , 63 , 64 ] and gastric retention [ 54 , 82 ], as well as hypothermia [ 42 ], all align to indicate that first-generation PDE4 inhibitors, such as Rolipram or RS25344, are significantly more emetic than second-generation PDE4 inhibitors. This pattern is confirmed in the present study.…”