Inhibition of type 4 cAMP-phosphodiesterases (PDE4s) in mice induces hypothermia via effects on behavioral and central autonomous thermoregulation

McDonough, Will; Rich, Justin; Aragon, Ileana; Saleh, Lina Abou; Boyd, Abigail; Richter, Aris; Koloteva, Anna; Richter, Wito

doi:10.1016/j.bcp.2020.114158

Cited by 13 publications

(25 citation statements)

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“…Immediately after SAS injection some of the mice did not show their normal behavior but were lying on their abdomen and seemed to be panting. As this behavior has been described to be related to thermoregulation ( McDonough et al, 2020 ), we evaluated the effect of SAS injection on the body temperature of the mice. As presented in Figure 4A , saline-treated xCT +/+ mice showed a normal stress-induced hyperthermic reaction after an i. p. injection ( Olivier et al, 2003 ), with an initial 2°C increase of their body temperature, which normalizes after 120 min (Wilcoxon MSRT compared to baseline, 10 min: p = 0.0020, 60 min: p = 0.0059, 120 min: p = 0.2598).…”

Section: Resultsmentioning

confidence: 99%

Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

et al. 2021

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Despite ample evidence for the therapeutic potential of inhibition of the cystine/glutamate antiporter system xc− in neurological disorders and in cancer, none of the proposed inhibitors is selective. In this context, a lot of research has been performed using the EMA- and FDA-approved drug sulfasalazine (SAS). Even though this molecule is already on the market for decades as an anti-inflammatory drug, serious side effects due to its use have been reported. Whereas for the treatment of the main indications, SAS needs to be cleaved in the intestine into the anti-inflammatory compound mesalazine, it needs to reach the systemic circulation in its intact form to allow inhibition of system xc−. The higher plasma levels of intact SAS (or its metabolites) might induce adverse effects, independent of its action on system xc−. Some of these effects have however been attributed to system xc− inhibition, calling into question the safety of targeting system xc−. In this study we chronically treated system xc− - deficient mice and their wildtype littermates with two different doses of SAS (160 mg/kg twice daily or 320 mg/kg once daily, i.p.) and studied some of the adverse effects that were previously reported. SAS had a negative impact on the survival rate, the body weight, the thermoregulation and/or stress reaction of mice of both genotypes, and thus independent of its inhibitory action on system xc−. While SAS decreased the total distance travelled in the open-field test the first time the mice encountered the test, it did not influence this parameter on the long-term and it did not induce other behavioral changes such as anxiety- or depressive-like behavior. Finally, no major histological abnormalities were observed in the spinal cord. To conclude, we were unable to identify any undesirable system xc−-dependent effect of chronic administration of SAS.

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Section: Resultsmentioning

confidence: 99%

Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

et al. 2021

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“…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.…”

Section: Distinguishing Central and Direct Effects Of Pde4 Inhibition On Salivationmentioning

confidence: 87%

“…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.…”

Section: Measurement Of Saliva Secretion Ratementioning

confidence: 99%

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

Boyd

Aragon

Saleh

et al. 2021

Biochemical Journal

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Saliva, while often taken for granted, is indispensable for oral health and overall well-being, as inferred from the significant impairments suffered by patients with salivary gland dysfunction. Here, we show that treatment with several structurally-distinct PAN-PDE4 inhibitors, but not a PDE3 inhibitor, induces saliva secretion in mice, indicating it is a class-effect of PDE4 inhibitors. In anesthetized mice, while neuronal regulations are suppressed, PDE4 inhibition potentiates a β-adrenoceptor-induced salivation, that is ablated by the β-blocker Propranolol and is absent in homozygous ΔF508-CFTR mice lacking functional CFTR. These data suggest that PDE4 acts within salivary glands to gate saliva secretion that is contingent upon the cAMP/PKA-dependent activation of CFTR. Indeed, PDE4 contributes the majority of total cAMP-hydrolytic capacity in submandibular-, sublingual-, and parotid glands, the three major salivary glands of the mouse. In awake mice, PDE4 inhibitor-induced salivation is reduced by CFTR deficiency or β-blockers, but also by the muscarinic blocker Atropine, suggesting an additional, central/neuronal mechanism of PDE4 inhibitor action. The PDE4 family comprises four subtypes, PDE4A-D. Ablation of PDE4D, but not PDE4A-C, produced a minor effect on saliva secretion, implying that while PDE4D may play a predominant role, PDE4 inhibitor-induced salivation results from the concurrent inactivation of multiple (at least two) PDE4 subtypes. Taken together, our data reveal a critical role for PDE4/PDE4D in controlling CFTR function in an in vivo model and in inducing salivation, hinting at a therapeutic potential of PDE4 inhibition for cystic fibrosis and conditions associated with xerostomia.

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“…Core body temperature was measured as described [ 42 ] using a thermocouple thermometer (MicroTherma 2T) with mouse rectal probe (RET-3), both from Braintree Scientific (Braintree, MA, USA), following the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…We have shown recently that PDE4s play a critical role in the autonomic regulation of body temperature in mice and that treatment with PAN-PDE4 inhibitors induces a fast-onset (within 10 min), substantial (up to −5 °C) and long-lasting (up to 5 h) hypothermia in the animals [ 42 ]. Intriguingly, an increasing body of research closely correlates nausea with a significant disturbance in thermoregulation in mammals [ 43 , 44 , 45 , 46 , 47 ].…”

Section: Introductionmentioning

confidence: 99%

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

Boyd

Aragon

Rich

et al. 2021

Biology

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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.

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Inhibition of type 4 cAMP-phosphodiesterases (PDE4s) in mice induces hypothermia via effects on behavioral and central autonomous thermoregulation

Cited by 13 publications

References 103 publications

Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

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

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

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