Longitudinal imaging evaluation of the inflammatory role of purinergic A2A receptors during subacute and chronic ischemic stroke.

Abstract

Adenosine A₂ receptors (A₂ARs) have shown promising therapeutic properties despite their controversial role in modulating stroke outcome. However, the temporal evolution of cerebral A₂ARs density after cerebral ischemia and its subsequent neuroinflammatory response have been scarcely explored. In this study, the expression of A₂ARs after transient middle cerebral artery occlusion (MCAO) was evaluated in rats by positron emission tomography (PET) with [¹¹C]SCH442416 and immunohistochemistry (IHC). In addition, the role of A₂ARs in stroke inflammation with pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [¹⁸F]DPA-714 (TSPO), IHC, western-blot, and autoradiography. After cerebral ischemia, [¹¹C]SCH442416 and IHC revealed neural expression of A₂ARs 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 A₂ARs 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 A₂ARs density dynamics after cerebral ischemia that might guide the therapeutic management of stroke by modulating adenosine receptors.