In vivo multimodal imaging of adenosine A 1 receptors in neuroinflammation after experimental stroke

• Published in: Theranostics Vol. 11; no. 1; pp. 410 - 425
• Main Authors: Joya, Ana, Ardaya, María, Montilla, Alejandro, Garbizu, Maider, Plaza-García, Sandra, Gómez-Vallejo, Vanessa, Padro, Daniel, Gutiérrez, Juan José, Rios, Xabier, Ramos-Cabrer, Pedro, Cossío, Unai, Pulagam, Krishna R, Higuchi, Makoto, Domercq, María, Cavaliere, Fabio, Matute, Carlos, Llop, Jordi, Martín, Abraham
• Format: Journal Article
• Language: English
• Published: Australia 2021
• Subjects: [18F]FLT; MRI; neuroinflammation; cerebral ischemia; A1ARs; [18F]CPFPX; [18F]DPA-714; PET
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.51046

Adenosine A
receptors (A
ARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of A
ARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far.
In this study, the expression of A
ARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [
F]CPFPX and immunohistochemistry (IHC). In addition, the role of A
ARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [
F]DPA-714 (TSPO) and [
F]FLT (cellular proliferation), as well as IHC and neurofunctional studies.
In the ischemic territory, [
F]CPFPX signal and IHC showed the overexpression of A
ARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the A
AR agonist ENBA showed a significant decrease in both [
F]DPA-714 and [
F]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of A
ARs promoted the reduction of the brain lesion, as measured with T
W-MRI, and the improvement of neurological outcome including motor, sensory and reflex responses. These results show for the first time the
PET imaging of A
ARs expression after cerebral ischemia in rats and the application of [
F]FLT to evaluate glial proliferation in response to treatment.
Notably, these data provide evidence for A
ARs playing a key role in the control of both the activation of resident glia and the
proliferation of microglia and macrophages after experimental stroke in rats.