PAN-selective inhibition of cAMP-phosphodiesterase 4 (PDE4) induces gastroparesis in mice
© 2020 Federation of American Societies for Experimental Biology..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
|---|---|
| Enthalten in: |
FASEB journal : official publication of the Federation of American Societies for Experimental Biology - 34(2020), 9 vom: 11. Sept., Seite 12533-12548 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
McDonough, Will [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 11.03.2021 Date Revised 03.09.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1096/fj.202001016RR |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM313135576 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM313135576 | ||
| 003 | DE-627 | ||
| 005 | 20231225145921.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1096/fj.202001016RR |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1043.xml |
| 035 | |a (DE-627)NLM313135576 | ||
| 035 | |a (NLM)32738081 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a McDonough, Will |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PAN-selective inhibition of cAMP-phosphodiesterase 4 (PDE4) induces gastroparesis in mice |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.03.2021 | ||
| 500 | |a Date Revised 03.09.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Federation of American Societies for Experimental Biology. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a PDE4D | |
| 650 | 4 | |a emesis | |
| 650 | 4 | |a gastric retention | |
| 650 | 4 | |a nausea | |
| 650 | 4 | |a xylazine/ketamine anesthesia | |
| 650 | 7 | |a Aminopyridines |2 NLM | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 650 | 7 | |a Cyclopropanes |2 NLM | |
| 650 | 7 | |a Phosphodiesterase 4 Inhibitors |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a Pyrimidinones |2 NLM | |
| 650 | 7 | |a YM 976 |2 NLM | |
| 650 | 7 | |a Roflumilast |2 NLM | |
| 650 | 7 | |a 0P6C6ZOP5U |2 NLM | |
| 650 | 7 | |a Cyclic Nucleotide Phosphodiesterases, Type 4 |2 NLM | |
| 650 | 7 | |a EC 3.1.4.17 |2 NLM | |
| 650 | 7 | |a Rolipram |2 NLM | |
| 650 | 7 | |a K676NL63N7 |2 NLM | |
| 650 | 7 | |a piclamilast |2 NLM | |
| 650 | 7 | |a WM58D7C3ZT |2 NLM | |
| 700 | 1 | |a Aragon, Ileana V |e verfasserin |4 aut | |
| 700 | 1 | |a Rich, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Murphy, James M |e verfasserin |4 aut | |
| 700 | 1 | |a Abou Saleh, Lina |e verfasserin |4 aut | |
| 700 | 1 | |a Boyd, Abigail |e verfasserin |4 aut | |
| 700 | 1 | |a Koloteva, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Richter, Wito |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t FASEB journal : official publication of the Federation of American Societies for Experimental Biology |d 1989 |g 34(2020), 9 vom: 11. Sept., Seite 12533-12548 |w (DE-627)NLM01261730X |x 1530-6860 |7 nnns |
| 773 | 1 | 8 | |g volume:34 |g year:2020 |g number:9 |g day:11 |g month:09 |g pages:12533-12548 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1096/fj.202001016RR |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 34 |j 2020 |e 9 |b 11 |c 09 |h 12533-12548 | ||