Caffeine exposure ameliorates acute ischemic cell death in avian developing retina

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Abstract
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 A2A 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 GABAA 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 A2A 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.
Funding Information
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (2008/57904-0)
  • Coordination of Superior Level Staff Improvement (fellowship, Fellowship)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/110.475/2014, E26/112.040/2012, Fellowship)
  • The program of Nucleus of Excellence / Ministry of science and technology
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Fellowship)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (420351/2016-7)

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