In vivo multimodal imaging of adenosine A2A receptors after experimental stroke

[EN] Ischemic stroke is an acute cerebrovascular disease characterised by a cascade of pathological events including excitotoxicity, inflammation and cellular death. Ischemia also leads to an increase of the concentrations of purines including adenosine and, as a result, adenosine receptors (AR) have become of interest in the recent years. Previous studies have shown that in vivo imaging modalities are useful techniques to analyse the distribution of AR such as A1ARs after stroke. However, the in vivo distribution of A2ARs has been scarcely explored so far. Therefore, the aim of the present study was to evaluate the in vivo distribution of A2ARs before and after transient middle cerebral artery occlusion (MCAO) with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [11C]SCH442416. Furthermore, the Simplified Reference Tissue Model (SRTM) was used to obtain a more concise quantification of [11C]SCH442416 brain kinetics. These results demonstrated that A2ARs were mainly expressed in the rat striatum in healthy conditions. Additionally, non-displaceable binding potential (BPnd) showed an increase at day 3 in relation to day 1 after cerebral ischemia in the ipsilateral striatum. Overall, these data provide evidence that PET imaging is a useful technique for quantifying the in vivo distribution of A2AR in healthy and brain ischemic conditions.[ES] El ictus isquémico es una enfermedad cerebrovascular aguda caracterizada por una cascada de acontecimientos patológicos que incluyen excitotoxicidad, inflamación y muerte celular. La isquemia también provoca un aumento de las concentraciones de purinas, incluida la adenosina, por lo que los receptores de adenosina (RA) han cobrado interés en los últimos años. Estudios anteriores han demostrado que las modalidades de imagen in vivo son técnicas útiles para analizar la distribución de los RA, como los A1AR, después del accidente cerebrovascular. Sin embargo, la distribución in vivo de los A2ARs ha sido escasamente explorada hasta ahora. Por lo tanto, el objetivo del presente estudio fue evaluar la distribución in vivo de A2ARs antes y después de la oclusión transitoria de la arteria cerebral media (MCAO) con imágenes de resonancia magnética (MRI) y tomografía por emisión de positrones (PET) utilizando [11C]SCH442416. Además, se utilizó el modelo tisular de referencia simplificado (SRTM) para obtener una cuantificación más concisa de la cinética cerebral de [11C]SCH442416. Estos resultados demostraron que los A2AR se expresaban principalmente en el estriado de la rata en condiciones de salud. Además, el potencial de unión no desplazable (BPnd) mostró un aumento en el día 3 en relación con el día 1 después de la isquemia cerebral en el estriado ipsilateral. En general, estos datos proporcionan evidencia de que la imagen PET es una técnica útil para cuantificar la distribución in vivo de A2AR en condiciones sanas y de isquemia cerebral

In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats

In vivopositron emission tomography of neuroinflammation has mainly focused on the evaluation of glial cell activation using radiolabeled ligands. However, the non-invasive imaging of neuroinflammatory cell proliferation has been scarcely evaluated so far.In vivoandex vivoassessment of gliogenesis after transient middle cerebral artery occlusion (MCAO) in rats was carried out using PET imaging with the marker of cell proliferation 3 '-Deoxy-3 '-[18F] fluorothymidine ([F-18]FLT), magnetic resonance imaging (MRI) and fluorescence immunohistochemistry. MRI-T2W studies showed the presence of the brain infarction at 24 h after MCAO affecting cerebral cortex and striatum.In vivoPET imaging showed a significant increase in [F-18]FLT uptake in the ischemic territory at day 7 followed by a progressive decline from day 14 to day 28 after ischemia onset. In addition, immunohistochemistry studies using Ki67, CD11b, and GFAP to evaluate proliferation of microglia and astrocytes confirmed the PET findings showing the increase of glial proliferation at day 7 after ischemia followed by decrease later on. Hence, these results show that [F-18]FLT provides accurate quantitative information on the time course of glial proliferation in experimental stroke. Finally, this novel brain imaging method might guide on the imaging evaluation of the role of gliogenesis after stroke.The authors would like to thank A. Leukona, X. Rios-Anglada, and V. Salinas for technical support in the radiosynthesis. This study was funded by grants from the Spanish Ministry of Education and Science/FEDER RYC-2017-22412, SAF2016-75292-R, PID2019-107989RB-I00, the Basque Government (IT1203/19, BIO18/IC/006) and CIBERNED. Maria Ardaya holds a fellowship from the University of Pais Vasco. Ana Joya acknowledges funding from Fundacio La Marato de TV3 (17/C/2017). Part of the work has been performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (Grant No. MDM-2017-0720)

In vivo multimodal imaging of adenosine A1 receptors in neuroinflammation after experimental stroke

Adenosine A(l) receptors (A(l)ARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of A(l)ARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far. Methods: In this study, the expression of A(1)ARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [F-18]CPFPX and immunohistochemistry (IHC). In addition, the role of AIARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [F-18]DPA-714 (TSPO) and [F-18]FLT (cellular proliferation), as well as IHC and neurofunctional studies. Results: In the ischemic territory, [F-18]CPFPX signal and IHC showed the overexpression of A(l)ARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the AAR agonist ENBA showed a significant decrease in both [F-18]DPA-714 and [F-18]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of A(l)AR promoted the reduction of the brain lesion, as measured with T2W-MRI, and the improvement of neurological outcome including motor, sensory and reflex responses. These results show for the first time the in vivo PET imaging of A(l)AR expression after cerebral ischemia in rats and the application of [F-18]FLT to evaluate glial proliferation in response to treatment. Conclusion: Notably, these data provide evidence for A(l)AR playing a key role in the control of both the activation of resident glia and the de novo proliferation of microglia and macrophages after experimental stroke in rats.The authors would like to thank A. Leukona and V. Salinas for technical support in the radiosynthesis. This study was funded by grants from the Spanish Ministry of Education and Science/FEDER RYC-201722412, SAF2016-75292-R, SAF2017-87670-R and PID2019-107989RB-I00, the Basque Government (IT1203/19, BIO18/IC/006) and CIBERNED. Maria Ardaya holds a fellowship from the University of Pais Vasco. Ana Joya acknowledges funding from Fundacio La Marato de TV3 (17/C/2017). Juan Jose Gutierrez acknowledges funding from Euskampus Fundazioa. Jordi Llop also acknowledges The Spanish Ministry of Economy and Competitiveness (Grant CTQ2017-87637-R). Part of the work has been performed under the Maria de Maeztu Units of Excellence Program from the Spanish State Research Agency (Grant No. MDM-2017-0720)

In vivo multimodal imaging of adenosine A1 receptors in neuroinflammation after experimental stroke

Adenosine A1 receptors (A1ARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of A1ARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far.Methods: In this study, the expression of A1ARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [18F]CPFPX and immunohistochemistry (IHC). In addition, the role of A1ARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [18F]DPA-714 (TSPO) and [18F]FLT (cellular proliferation), as well as IHC and neurofunctional studies.Results: In the ischemic territory, [18F]CPFPX signal and IHC showed the overexpression of A1ARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the A1AR agonist ENBA showed a significant decrease in both [18F]DPA-714 and [18F]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of A1ARs promoted the reduction of the brain lesion, as measured with T2W-MRI, and the improvement of neurological outcome including motor, sensory and reflex responses. These results show for the first time the in vivo PET imaging of A1ARs expression after cerebral ischemia in rats and the application of [18F]FLT to evaluate glial proliferation in response to treatment.Conclusion: Notably, these data provide evidence for A1ARs playing a key role in the control of both the activation of resident glia and the de novo proliferation of microglia and macrophages after experimental stroke in rats

sj-pdf-1-jcb-10.1177_0271678X231197946 - Supplemental material for Multimodal imaging of the role of hyperglycemia following experimental subarachnoid hemorrhage

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231197946 for Multimodal imaging of the role of hyperglycemia following experimental subarachnoid hemorrhage by Ana Joya, Sandra Plaza-García, Daniel Padro, Laura Aguado, Leyre Iglesias, Maider Garbizu, Vanessa Gómez-Vallejo, Carlos Laredo, Unai Cossío, Ramon Torné, Sergio Amaro, Anna M Planas, Jordi Llop, Pedro Ramos-Cabrer, Carles Justicia and Abraham Martín in Journal of Cerebral Blood Flow & Metabolism</p