AimsChronic hypobaric hypoxia frequently results in memory deficits, with severe cases showing marked alterations in dopamine levels and its metabolites. This research explores caffeine's modulation of the adenosine A2A receptor (A2AR) and its regulatory effects on tyrosine hydroxylase (TH), aiming to restore dopamine homeostasis and mitigate memory impairments associated with hypoxia. The goal is to identify novel preventive strategies against cognitive decline induced by hypoxia.MethodsNetwork pharmacological analysis was employed to predict the interactions between caffeine, cognitive function, and hypobaric hypoxia‐related disorders. The novel object recognition and Y‐maze tests were utilized to assess caffeine's impact on memory deficits under hypobaric hypoxia conditions in male mice. LC–MS/MS analysis was subsequently conducted to examine the variations in dopamine and its metabolites within the midbrain. Molecular docking further confirmed the binding affinities between A2AR and caffeine, as well as TH and caffeine. Additionally, immunofluorescence and protein‐protein docking were employed to elucidate the interaction between A2AR and TH.ResultsThe findings highlight the pivotal role of adenosine receptors and dopamine‐related pathways in the interplay between caffeine, cognition, and hypobaric hypoxia‐related disorders. Behavioral tests demonstrated that caffeine effectively alleviated memory impairments caused by chronic hypobaric hypoxia. LC–MS/MS results revealed significant differences in dopamine, metanephrine, and 3‐hydroxyanthranilic acid levels following caffeine treatment for hypoxia‐induced cognitive deficits. Molecular docking confirmed the high affinity between A2AR and caffeine, as well as TH and caffeine, while immunofluorescence and protein–protein docking provided insights into the A2AR‐TH interaction and its modulation during hypobaric hypoxia.ConclusionsCaffeine exhibits potent neuroprotective effects against chronic high‐altitude‐induced cognitive impairments, potentially through its action on A2AR, leading to enhanced TH expression and subsequent release of dopamine and its related neurotransmitters.
