Therapeutic Opportunities for Caffeine and A_2A Receptor Antagonists in Retinal Diseases

Abstract

Caffeine, the major component of coffee, is the most consumed psychostimulant in the world. Caffeine is an adenosine analog and acts as a nonselective adenosine receptor antagonist. The majority of the effects of caffeine are mainly mediated by the blockade of adenosine receptors, and the proved neuroprotective effects of caffeine in brain disorders have been mimicked by the blockade of adenosine A_2A receptor (A_2AR). A growing body of evidence demonstrates that microglia-mediated neuroinflammation plays a key role in the pathophysiology of brain and retinal diseases. Moreover, the control of microglia reactivity by blocking A_2AR has been proposed to be the mechanism underlying the observed protective effects of caffeine. Hence, it is conceivable that caffeine and A_2AR antagonists offer therapeutic value for the treatment of retinal diseases, mainly those involving microglia-mediated neuroinflammation.

Blockade of microglial adenosine A2A receptor suppresses elevated pressure‐induced inflammation, oxidative stress, and cell death in retinal cells

“…The blockade of A 2A R confers neuroprotection in several models of neurodegeneration, including in the retina (Boia et al, ; Boia et al, ; Cunha, ; Gomes, Kaster, Tome, Agostinho, & Cunha, ; Gyoneva et al, ; Liu et al, ; Madeira, Boia, et al, ; Madeira, Elvas, et al, ). One of the mechanisms that may explain the protective properties of A 2A R antagonists is the control of microglia‐mediated neuroinflammation (Cunha, ; Gomes et al, ).…”

“…Adenosine is a neuromodulator in the central nervous system acting through the activation of four receptors, A 1 , A 2A , A 2B , and A 3 . We demonstrated that the blockade of adenosine A 2A receptor (A 2A R) confers neuroprotection to the retina in glaucoma models through the control of microglia responsiveness (Boia et al, ; Boia, Ambrósio, & Santiago, ; Madeira et al, ; Madeira, Elvas, et al, ; Santiago et al, ). However, the specific role of microglial cells was not addressed, as well as the impact of A 2A R blockade in microglial cells in the context of glaucoma.…”

Caffeine administration prevents retinal neuroinflammation and loss of retinal ganglion cells in an animal model of glaucoma

“…The effects of caffeine to ocular tissues have also been reported, like the prevention of diabetic cataract in galactose-fed animals and reduction of corneal thickness43. The effects of consumption of caffeine in IOP are not yet clarified.…”

Neuroprotective Strategies for Retinal Ganglion Cell Degeneration: Current Status and Challenges Ahead

“…Its expression increases in microglia in models of glaucoma [78,79], and A 2A R antagonists were shown to confer protection to retinal neurons, including RGCs, through the control of microglia reactivity [78,79,228]. Caffeine, a non-selective adenosine antagonist, also protects RGCs by hampering microglial cell response and controlling the neuroinflammatory environment in models of transient retinal ischemia and ocular hypertension [230,234,235]. KW6002, another A 2A R antagonist with good oral bioavailability, confers protection to the retina, including RGCs, through the control of microglia-mediated neuroinflammation [234].…”