MRS3997, a dual adenosine A2A/A2B receptor agonist, reduces brain ischemic damage and alleviates neuroinflammation in rats

The endogenous neuromodulator adenosine is massively released during hypoxic/ischemic insults and differentially modulates post-ischemic damage depending on the expression and recruitment of its four metabotropic receptor subtypes, namely A₁, A_2A, A_2B and A₃ receptors (A₁Rs, A_2ARs, A_2BRs and A₃Rs). We previously demonstrated, by using a model of transient middle cerebral artery occlusion (tMCAo) in rats, that selective activation of A_2ARs, as well as A_2BRs, ameliorates post-ischemic brain damage in contrast to neuroinflammation. In the present study, we investigated whether the multitarget nucleoside MRS3997, a full agonist at both A_2ARs and A_2BRs, would afford higher neuroprotection in post-ischemic damage. Chronic systemic treatment with MRS3997 reduced neurological deficit, body weight loss and infarct volume in the cortex and striatum measured 7 days after ischemia. The dual agonist counteracted neuronal loss, reduced myelin damage, and prevented morphological changes indicative of microglia and astrocyte activation. Finally, MRS3997 shifted plasma cytokine levels to an anti-inflammatory profile. These effects were preceded, at 2 days after the insult, by a reduced granulocyte infiltration in the ischemic cortex and, differently from what was observed with selective A_2AR or A_2BR agonism, also in striatum. In summary, we demonstrate here that MRS3997, systemically administered for 7 days after tMCAO, protects ischemic areas from neuronal and glial damage and inhibits neuroinflammation, therefore representing an attractive strategy to ameliorate post-stroke damage and neurological symptoms.