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While two\u2010day caffeine exposure has previously been shown to confer neuroprotection in this context, it remained unclear whether acute administration during an ischemic event could yield similar benefits. In this study, we used an\n                    <jats:italic>ex vivo<\/jats:italic>\n                    model of oxygen and glucose deprivation (OGD) in chick embryo retinas to investigate whether a single, acute dose of caffeine applied during the insult reduces cell death and engages intracellular survival pathways. Results showed a significant reduction in OGD\u2010induced cytotoxicity by caffeine exposure. However, unlike in the context of chronic exposure, acute caffeine exposure did not increase BDNF expression. Furthermore, antioxidant agents failed to mimic caffeine's protective effects, and acute caffeine exposure did not induce the expression of antioxidant response genes, nor oxidative stress or VEGF expression, suggesting that oxidative stress mitigation is not the primary mechanism for this effect. However, pharmacological antagonism of adenosine A\n                    <jats:sub>2A<\/jats:sub>\n                    receptors with ZM241385 reproduced the neuroprotective effects of caffeine and reduced extracellular glutamate levels during OGD. These findings indicate that acute caffeine administration protects the developing retina primarily through A\n                    <jats:sub>2A<\/jats:sub>\n                    receptor antagonism and inhibition of glutamate excitotoxicity, rather than by activating canonical survival signaling pathways. 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