Validation of the xylazine/ketamine anesthesia test as a predictor of the emetic potential of pharmacological compounds in rats

Nelissen, Ellis; Goethem, Nick P. van; Bonassoli, Vivian Taciany; Heckman, Pim R. A.; Hagen, B.; Suay, Dila; Wouters, Carine; Prickaerts, Jos

doi:10.1016/j.neulet.2019.01.026

Cited by 19 publications

(26 citation statements)

References 42 publications

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“…Whether gastroparesis or the duration of xylazine/ketamine‐induced anesthesia in mice accurately predicts the role of PDE4 subtypes in inducing emesis in humans remains to be established. As suggested by Prickaerts and colleagues, 60 while the xylazine/ketamine‐anesthesia test is a reliable measure for α 2 ‐adrenoreceptor antagonism, it may have limitations as a predictor of emetic potential 60 . For example, there are critical species differences in that α 2 ‐adrenoceptor antagonism induces emesis in ferrets, whereas the opposite, namely agonism at α 2 ‐adrenoceptors, induces emesis in cats and dogs 105‐109 .…”

Section: Discussionmentioning

confidence: 99%

“…For example, there are critical species differences in that α 2 ‐adrenoceptor antagonism induces emesis in ferrets, whereas the opposite, namely agonism at α 2 ‐adrenoceptors, induces emesis in cats and dogs 105‐109 . In addition, some drugs known to cause emesis in humans (eg, Imipramine) lengthen, rather than shorten, the duration of xylazine/ketamine‐anesthesia in rodents 60 . While the xylazine/ketamine‐induced anesthesia test may have limitations, it also remains to be shown whether PDE4 inhibition induces gastroparesis, and thereby induces emesis and nausea, in humans.…”

Section: Discussionmentioning

confidence: 99%

“…As suggested by Prickaerts and colleagues, 60 while the xylazine/ketamine-anesthesia test is a reliable measure for α 2 -adrenoreceptor antagonism, it may have limitations as a predictor of emetic potential. 60 For example, there are critical species differences in that α 2 -adrenoceptor antagonism induces emesis in ferrets, whereas the opposite, namely agonism at α 2 -adrenoceptors, induces emesis in cats and dogs. [105][106][107][108][109] In addition, some drugs known to cause emesis in humans (eg, Imipramine) lengthen, rather than shorten, the duration of xylazine/ ketamine-anesthesia in rodents.…”

Section: Role Of Pde4d In Mediating the Side Effects Of Pan-pde4 Inmentioning

confidence: 99%

“…[105][106][107][108][109] In addition, some drugs known to cause emesis in humans (eg, Imipramine) lengthen, rather than shorten, the duration of xylazine/ ketamine-anesthesia in rodents. 60 While the xylazine/ketamine-induced anesthesia test may have limitations, it also remains to be shown whether PDE4 inhibition induces gastroparesis, and thereby induces emesis and nausea, in humans. It is not surprising, however, that the two models produce a different pattern of PDE4 subtype involvement in mice given that PDE4 inhibitors induce antagonism at α 2 -adrenoreceptor to shorten xylazine/ketamine-induced anesthesia, whereas agonism, but not antagonism at α 2 -adrenoreceptor induces gastroparesis ( Figure 7A).…”

Section: Role Of Pde4d In Mediating the Side Effects Of Pan-pde4 Inmentioning

confidence: 99%

“…This has led to significant efforts to develop PDE4 inhibitors selective for PDE4B over PDE4D in expectation of an improved safety profile 45,56‐59 ; at the same time largely forgoing any therapeutic benefits potentially derived from the inhibition of PDE4D. However, while the xylazine/ketamine‐anesthesia test is a reliable measure for α 2 ‐adrenoreceptor antagonism, it does have limitations as a predictor of emetic potential, as shown recently 60 . 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 46 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Role Of Pde4d In Mediating the Side Effects Of Pan-pde4 Inmentioning

confidence: 99%

Section: Role Of Pde4d In Mediating the Side Effects Of Pan-pde4 Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways

Jino,

Miyamoto,

Kanbara

et al. 2023

Psychopharmacology

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Phosphodiesterase-4 Inhibition in Parkinson’s Disease: Molecular Insights and Therapeutic Potential

et al. 2023

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Validation of the xylazine/ketamine anesthesia test as a predictor of the emetic potential of pharmacological compounds in rats

Cited by 19 publications

References 42 publications

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

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

Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways

Phosphodiesterase-4 Inhibition in Parkinson’s Disease: Molecular Insights and Therapeutic Potential

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