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

Abstract

Simple SummaryType 4 cAMP-phosphodiesterases (PDE4s) comprise a family of four isoenzymes, PDE4A to D, that hydrolyze and inactivate the second messenger cAMP. Non/PAN-selective PDE4 inhibitors, which inhibit all four PDE4 subtypes simultaneously, produce many promising therapeutic benefits, such as anti-inflammatory or cognition- and memory-enhancing effects. However, unwanted side effects, principally, nausea, diarrhea, and emesis, have long hampered their clinical and commercial success. Targeting individual PDE4 subtypes has been proposed for developing drugs with an improved safety profile, but which PDE4 subtype(s) is/are actually responsible for nausea and emesis remains ill-defined. Based on the observation that nausea is often accompanied by hypothermia in humans and other mammals, we used the measurement of core body temperatures of mice as a potential correlate of nausea induced by PDE4 inhibitors in humans. We find that selective inactivation of any of the four PDE4 subtypes did not change the body temperature of mice, suggesting that PAN-PDE4 inhibitor-induced hypothermia (and hence nausea in humans) requires the simultaneous inhibition of multiple PDE4 subtypes. This finding contrasts with prior reports that proposed PDE4D as the subtype mediating these side effects of PDE4 inhibitors and suggests that subtype-selective inhibitors that target any individual PDE4 subtype, including PDE4D, may not cause nausea.Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of α2-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic α2-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α2-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.