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.