Longitudinal imaging evaluation of the inflammatory role of purinergic A ₂ A receptors during subacute and chronic ischemic stroke

Adenosine A 2 receptors (A 2 ARs) have shown promising therapeutic properties despite their controversial role in modulating stroke outcome. However, the temporal evolution of cerebral A 2 ARs density after cerebral ischemia and its subsequent neuroinflammatory response have been scarcely explored. In this study, the expression of A 2 ARs after transient middle cerebral artery occlusion (MCAO) was evaluated in rats by positron emission tomography (PET) with [ 11 C]SCH442416 and immunohistochemistry (IHC). In addition, the role of A 2 ARs in stroke inflammation with pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [ 18 F]DPA-714 (TSPO), IHC, western-blot, and autoradiography. After cerebral ischemia, [ 11 C]SCH442416 and IHC revealed neural expression of A 2 ARs in the striatum in healthy brains, followed by a binding decrease at day 1 and a subsequent significant increase at day 3 after ischemia in microglia and infiltrated leukocytes. Furthermore, activation of A 2 ARs with the agonist CGS-21680 resulted in a reduction in stroke volume, along with an increase in TSPO expression in immune cells in the striatum. Our results provide novel evidence on A 2 ARs density dynamics after cerebral ischemia that might guide the therapeutic management of stroke by modulating adenosine receptors.