Istradefylline, an adenosine A2a receptor antagonist, ameliorates neutrophilic airway inflammation and psoriasis in mice

Abstract

Objective: Extracellular adenosine is produced from secreted adenosine triphosphate by cluster of differentiation (CD)39 and CD73. Both are critical nucleotide metabolizing enzymes of the adenosine generating pathway and are secreted by neuronal or immune cells. Adenosine plays a role in energy processes, neurotransmission and endogenous regulation of inflammatory responses. Istradefylline is a selective adenosine A2a receptor antagonist used for the treatment of Parkinson's disease. We have reported that adenosine primes hypersecretion of interleukin (IL)-17A through the adenosine A2a receptor. Istradefylline, as well as an inhibitor of CD39 (ARL67156) and an inhibitor of CD73 (AMP-CP), suppressed IL-17A production, and the administration of istradefylline to mice with experimental autoimmune encephalomyelitis led to the marked amelioration of the disease. These previous results suggest that adenosine is an endogenous modulator of neutrophilic inflammation. We investigated the effect of istradefylline, ARL67156 and AMP-CP on other mouse models of neutrophilic inflammation. Methods:We tested the effect of istradefylline, ARL67156 and AMP-CP on ovalbumin-induced neutrophilic airway inflammation or imiquimod-induced psoriasis in mice. The two mice models received these drugs orally or percutaneously, respectively. The production of IL-17A in the lung and ear thickness were used as an index of the effects. Results:We show that istradefylline, ARL67156 and AMP-CP suppressed the ovalbumin-induced IL-17A production in the lung and imiquimod-induced psoriasis. Conclusion:These results show that adenosine-mediated IL-17A production plays a role in neutrophilic inflammation models, and furthermore, istradefylline, ARL67156 and AMP-CP are effective in animal models of neutrophilic inflammation. Some clinical relevancies in coronavirus disease 2019 are discussed.

Caffeine and Purine Derivatives: A Comprehensive Review on the Chemistry, Biosynthetic Pathways, Synthesis‐Related Reactions, Biomedical Prospectives and Clinical Applications

“…Another xanthine derivative namely, istradefylline ( 24 ) was identified as an adenosine A 2A receptor antagonist. It suppressed the ovalbumin‐induced IL‐17 A production in the lung of neutrophilic airway inflammation mouse models [100] …”

“…It suppressed the ovalbumin-induced IL-17 A production in the lung of neutrophilic airway inflammation mouse models. [100]…”