In infants, the main cause of blindness is retinopathy of prematurity that stems in a hypoxic-ischemic condition. Caffeine is a psychoactive compound that at low to moderate concentrations, selectively inhibits adenosine A₁ and A_2A receptors. Caffeine exerts beneficial effects in central nervous system of adult animal models and humans, whereas it seems to have malefic effect on the developing tissue. We observed that 48-h exposure (during synaptogenesis) to a moderate dose of caffeine (30 mg/kg of egg) activated pro-survival signaling pathways, including ERK, CREB, and Akt phosphorylation, alongside BDNF production, and reduced retinal cell death promoted by oxygen glucose deprivation in the chick retina. Blockade of TrkB receptors and inhibition of CREB prevented caffeine protection effect. Similar signaling pathways were described in previously reported data concerning chemical preconditioning mechanism triggered by NMDA receptors activation, with low concentrations of agonist. In agreement to these data, caffeine increased NMDA receptor activity. Caffeine decreased the levels of the chloride co-transporter KCC2 and delayed the developmental shift on GABA_A receptor response from depolarizing to hyperpolarizing. These results suggest that the caffeine-induced delaying in depolarizing effect of GABA could be facilitating NMDA receptor activity. DPCPX, an A₁ adenosine receptor antagonist, but not A_2A receptor inhibitor, mimicked the effect of caffeine, suggesting that the effect of caffeine occurs through A₁ receptor blockade. In summary, an in vivo caffeine exposure could increase the resistance of the retina to ischemia-induced cell death, by triggering survival pathways involving CREB phosphorylation and BDNF production/TrkB activation.

中文翻译：

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咖啡因暴露可改善禽类视网膜发育过程中急性缺血细胞的死亡。

在婴儿中，失明的主要原因是早产儿视网膜病变，其发生在缺氧缺血性疾病中。咖啡因是一种精神活性化合物，在低至中等浓度时会选择性抑制腺苷A ₁和A _2A受体。咖啡因对成年动物模型和人类的中枢神经系统具有有益作用，而咖啡因似乎对发育中的组织具有杀雄作用。我们观察到，在中等剂量的咖啡因（30 mg / kg鸡蛋）中暴露48小时（在突触形成过程中）激活了生存前信号通路，包括ERK，CREB和Akt磷酸化，以及BDNF产生，并减少了视网膜细胞死亡由鸡视网膜中的氧葡萄糖剥夺促进。TrkB受体的阻断和CREB的抑制阻止了咖啡因的保护作用。在先前报道的数据中也描述了类似的信号通路，该数据涉及由低浓度的激动剂引起的NMDA受体激活触发的化学预处理机制。与这些数据一致，咖啡因增加了NMDA受体的活性。_甲从去极化到超极化受体响应。这些结果表明，咖啡因诱导的GABA去极化作用的延迟可能促进了NMDA受体的活性。DPCPX是一种A ₁腺苷受体拮抗剂，但不是A _2A受体抑制剂，它模拟了咖啡因的作用，表明咖啡因的作用是通过A ₁受体的阻断而发生的。总之，体内咖啡因的暴露可以通过触发涉及CREB磷酸化和BDNF产生/ TrkB激活的生存途径来增加视网膜对局部缺血诱导的细胞死亡的抵抗力。