Inhibition of Retinal AdoRA2a Activity Attenuates Myopia Progression

Although 7-methylxanthine, a nonselective adenosine receptor (AdoRs) antagonist, suppresses myopia, the specific receptor subtype and target tissue involved remain unclear. This study aimed to investigate whether the AdoRA2a subtype plays a critical role in the regulation of myopia progression.

Monocular form deprivation myopia (FDM) was induced in mice to measure retinal concentrations of adenosine and its synthetic enzymes (CD39/CD73). Retina-specific AdoRA2a knockout (AdoRA2a-CKO) mice and their wild-type littermates were subjected to unilateral FDM or normal, unobstructed vision. Male C57BL/6 mice were randomly divided into FDM and unobstructed vision groups, with each group further subdivided into four subgroups receiving intraperitoneal vehicle or the selective AdoRA2a antagonist KW6002 (0.33, 3.30, or 10.00 mg/kg). The effects of these treatments were also assessed in retina-specific dopamine D2 receptor gene knockout (Drd2-CKO) mice and their wild-type counterparts.

FDM significantly upregulated retinal adenosine levels and CD39/CD73 expression. Inhibition of AdoRA2a activity, by either AdoRA2a-CKO or KW6002 administration, significantly attenuated FDM progression in mice without affecting normal refractive development. AdoRA2a and Drd2 were colocalized in the retina, and the possibility of interactions between them was supported by the lack of an inhibitory effect of KW6002 on myopia progression in Drd2-CKO mice.

Our results demonstrate that retinal AdoRA2a plays a pivotal role in myopia progression. Our findings identify the retina as the critical site for AdoRA2a's action and suggest an underlying AdoRA2a-Drd2 interaction mechanism, revealing the possible therapeutic potential of KW6002 in myopia progression.