The role of the ATP-adenosine axis in ischemic stroke

In ischemic stroke, the primary neuronal injury caused by the disruption of energy supply is further exacerbated by secondary sterile inflammation. The inflammatory cascade is largely initiated by the purine adenosine triphosphate (ATP) which is extensively released to the interstitial space during brain ischemia and functions as an extracellular danger signaling molecule. By engaging P2 receptors, extracellular ATP activates microglia leading to cytokine and chemokine production and subsequent immune cell recruitment from the periphery which further amplifies post-stroke inflammation. The ectonucleotidases CD39 and CD73 shape and balance the inflammatory environment by stepwise degrading extracellular ATP to adenosine which itself has neuroprotective and anti-inflammatory signaling properties. The neuroprotective effects of adenosine are mainly mediated through A(1) receptors and inhibition of glutamatergic excitotoxicity, while the anti-inflammatory capacities of adenosine have been primarily attributed to A(2A) receptor activation on infiltrating immune cells in the subacute phase after stroke. In this review, we summarize the current state of knowledge on the ATP-adenosine axis in ischemic stroke, discuss contradictory results, and point out potential pitfalls towards translating therapeutic approaches from rodent stroke models to human patients.

Automated summary

In ischemic stroke, disruption of energy supply leads to primary neuronal injury and secondary sterile inflammation. ATP released during brain ischemia triggers an inflammatory cascade by activating microglia and recruiting immune cells, while the CD39 and CD73 enzymes degrade ATP into adenosine to balance the inflammatory environment. Adenosine has neuroprotective effects through A(1) receptor-mediated inhibition of excitotoxicity and anti-inflammatory capacities via A(2A) receptor activation.