br Therapeutic advantages and clinical implications of caffe

Therapeutic advantages and clinical implications of caffeine treatment in ROP The demonstration of the role of the adenosine receptor in development of ROP and protection by caffeine suggests two potential therapeutic strategies with high translational potential: a) modification of caffeine treatment paradigm for TAK-715 of prematurity to the specific prophylaxis and treatment for ROP; and b) development of A2AR antagonists -based treatment for ROP. A2AR antagonists such as KW6002 and preledenet are safe according to the safety profiles in clinical phase III trials and have been approved for clinical use in Japan. Importantly, our analyses demonstrate that genetic inactivation of A2ARs (Liu et al., 2010) or A1Rs (Zhang et al., 2015) or treatment with A2AR antagonists (caffeine and KW602) (Zhou et al., 2015) selectively controls pathological OIR without affecting normal retinal development. The mechanism underlying this selectivity may be related to local increase of adenosine-adenosine receptor signaling in response to stress, hypoxia and inflammation (Chen et al., 2013). Thus, the preferential effect of caffeine and KW6002 on OIR confers a critical advantage over anti-VEGF antibody strategy which is limited by delayed eye growth and abnormal vasculature and neural development of preterm retina since VEGF activity is necessary not only for pathological angiogenesis, but also for normal retinal vascularization during development. Since the publication of the Caffeine for Apnea of Prematurity randomized clinical trial in 2006, the use of caffeine for prophylactic purposes has been suggested (i.e, administration is commenced very soon after birth or before a diagnosis of apnea of prematurity is made). Thus, caffeine may also represent a novel prophylactiv strategy for ROP. Additionally, dissection of the adenosine receptor and VEGF signaling pathways leading to distinct physiological development and pathological angiogenesis are needed to fulfill the potential of caffeine and A2AR antagonists to achieve maximal therapeutic effects with minimal unwanted side effects. In particular, it should be noted that despite of lack of the general developmental effect on postnatal brain (specifically retinal vasculature) functions, there is lingering concerns on the possible specific effect of caffeine on embryonic development (Ma et al., 2014, Back et al., 2006) and possible postnatal development and maturation of cortical GABAergic neurons at the microstructural level by perinatal exposure to caffeine (Ardais et al., 2014, Silva et al., 2013).
Adenosine receptors and other proliferative retinopathies Lastly, it would be important to explore whether the protection of OIR by A2AR inactivation can be extended to other pathological proliferative retinopathy including diabetic retinopathy in adults and MD in aging population. In diabetic retina, A1R and A2AR levels were elevated (Vindeirinho et al., 2013). Interestingly, the variants of the human A2AR gene are associated with reduced risk of developing diabetic retinopathy in a prospective study (Charles et al., 2011), suggesting the involvement of the A2AR in diabetic retinopathy. In diabetic retinopathy model, genetic inactivation of the A2AR increased apoptotic cells, TNF-α release, and intercellular adhesion molecule-1 expression compared with wild-type mice (Liou et al., 2011, Ibrahim et al., 2011, Elsherbiny et al., 2013b). Thus, it is expected that caffeine and KW6002 may exacerbate retinal damage in diabetic retinopathy, in contrast with the caffeine-mediated protection against OIR-induced retina (Liu et al., 2010, Zhou et al., 2015). This suggesting the distinct molecular/cellular mechanisms (including neuronal, inflammatory and vascular mechanisms) may underlie distinct effects of A2AR-mediated modulation of retinal vascularization. Future studies to clarify the possible distinct role of A2AR in development of DR and MD may stimulate required clinical studies to translate this novel adenosine receptor-based pharmacologic therapies for the treatment of ROP and other proliferative retinopathies.