The role of the ATP-adenosine axis in ischemic stroke

Abstract

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 A1 receptors and inhibition of glutamatergic excitotoxicity, while the anti-inflammatory capacities of adenosine have been primarily attributed to A2A 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.

Role of microglia in stroke

“…Microglial CD73 produces adenosine, which negatively regulates excitatory neuronal activity via the A1 receptor (Badimon et al, 2020). Microglia is also enriched in adenosine A2A and A3 receptors, which again mediate complex effects in brain ischemia, as extensively discussed in previous reviews (Pedata et al, 2016;Schädlich et al, 2023).…”

“…Interestingly, deleting the P2X4 receptor specifically in myeloid cells provides acute protection against stroke but leads to chronic susceptibility to depression‐like behavior following the stroke (Verma et al, 2017). Nonetheless, there are ongoing drug developments for P2X4 inhibition to attenuate acute inflammation after stroke (Schädlich et al, 2023; Srivastava et al, 2020). P2X7 is predominantly expressed in microglia (Kaczmarek‐Hajek et al, 2018).…”

“…In contrast, other studies reported enhanced brain edema after stroke in constitutive P2X7 −/− mice (Kaiser et al, 2016). The role of microglial P2X receptors in stroke has been reviewed in more detail elsewhere (Pedata et al, 2016; Schädlich et al, 2023).…”

Development of endothelial-targeted CD39 as a therapy for ischaemic stroke

“…These findings support the notion that eATP catabolism would reduce P2X7 receptor signaling(49, 50), microglial activation(47) and NLRP3 formation, thereby reducing neuroinflammation(51, 52). However, in animal studies, P2X7 inhibition or gene deletion alone does not consistently promote neuroprotection after MCAo(53). Although P2X7 inhibition has not yet been trialled for cardiovascular conditions, blocking P2X7-IL1β and IL-18 is not effective in suppressing inflammation in a rheumatoid arthritis clinical trial, where pathological P2X7 activation is implicated(54).…”

Retinoic acid alleviates the reduction of Akt and Bad phosphorylation and regulates Bcl-2 family protein interactions in animal models of ischemic stroke

“…Ischemic stroke blocks blood flow to the brain, resulting in a lack of oxygen and glucose supply [ 2 ]. It causes harmful changes in biochemical processes such as oxidative stress generation, ATP production reduction, neuroinflammatory response, and excitatory toxicity, which eventually cause irreversible brain damage [ 3 , 4 ].…”