A-33

There is a high rate of comorbidity between binge eating (BE) and binge drinking (BD) behaviors, suggesting a common neuropathology. Recently, phosphodiesterase 4B ( PDE4B ) was identified as a pleiotropic gene associated with comorbid alcohol use disorder (AUD) and anorexia nervosa with BE in a genome-wide association study, implicating PDE4B as a potential contributor to shared genetic risk between these disorders. Here, we developed a novel mouse model of comorbid BE and BD in C57BL/6NJ mice in which mice underwent 10 d of BE, followed by 10 d of BD. Females exhibited cross-sensitization from BE to BD, which was apparent on the first day of ethanol access, whereas cross-sensitization emerged in males over multiple trials of BD. Accordingly immunoblotting of the nucleus accumbens tissue indicated a female-selective increase in PDE4B protein expression that was apparent on both the first and last day of BD in mice with a prior BE history. Acute pretreatment with the selective PDE4B inhibitor A33 (1.0 mg/kg) reduced the expression of cross-sensitization to BD in females on Day 1, and this effect was maintained during a 5 d A33 treatment regimen. The 5 d A33 treatment regimen also reduced expression of cross-sensitization to BD that had emerged in males over repeated sessions. These results provide preclinical, functional validation of PDE4B as a driver of food–ethanol cross-sensitization in a novel model for BE and BD comorbidity and support PDE4B in the shared genetic risk for these behavioral pathologies and as a target for pharmacotherapeutic intervention in comorbid AUD and BE behaviors.

Chronic liver disease leads to ~2 million deaths annually. Cyclic AMP (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects. The PDE4 inhibitor 2-(4-([2-(5-Chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl]amino)phenyl)acetic acid) (known as A-33) has yet to be explored for the treatment of metabolic diseases.

Herein, we evaluated the efficacy of A-33 in the treatment of animal models of alcohol-associated liver disease and steatotic liver disease. We demonstrated that A-33 effectively ameliorated the signs and symptoms of chronic liver disease, resulting in significant decreases in serum alanine aminotransferase and aspartate aminotransferase levels, decreased overall fat and collagen deposition in the liver, decreased intrahepatic triglyceride concentrations, and normalized expression of genes related to β-oxidation of fatty acids, inflammation, and extracellular matrix deposition. We also designed and synthesized a novel analog of A-33, termed MDL3, which inhibited both phosphodiesterase 4B and PDE5A and was more effective in ameliorating pathophysiological signs and symptoms of liver injury and inflammation. In addition, MDL3 re-sensitized obese mice to glucose and significantly inhibited the pathological remodeling of adipose tissue, which was not observed with A-33 administration.

In conclusion, we synthesized and demonstrated that MDL3, a novel phosphodiesterase 4B and PDE5A inhibitor, presents a promising avenue of exploration for treating chronic liver disease.