Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Joya A

PROVIDER: S-EPMC7681082 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Joya Ana A Ardaya María M Montilla Alejandro A Garbizu Maider M Plaza-García Sandra S Gómez-Vallejo Vanessa V Padro Daniel D Gutiérrez Juan José JJ Rios Xabier X Ramos-Cabrer Pedro P Cossío Unai U Pulagam Krishna R KR Higuchi Makoto M Domercq María M Cavaliere Fabio F Matute Carlos C Llop Jordi J Martín Abraham A

Theranostics 20210101 1

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 ...[more]

PMID: 33391483

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Project description:There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of [(11)C]DPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased [(11)C]DPA-713 binding to TSPO, may be linked to history of NFL play. [(11)C]DPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to deficits in verbal learning and memory after NFL play.

Project description:BackgroundMultiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on the choroid plexus (CP), a key site for the first wave of immune cell infiltration in experimental autoimmune encephalomyelitis (EAE), for the control of immune cells trafficking. Adenosine A2A receptor (A2AR) is emerging as a potential pharmacological target to control EAE pathogenesis. However, the cellular basis for the A2AR-mediated protection remains undetermined.MethodsIn the EAE model, we assessed A2AR expression and leukocyte trafficking determinants in the CP by immunohistochemistry and qPCR analyses. We determined the effect of the A2AR antagonist KW6002 treatment at days 8-12 or 8-14 post-immunization on T cell infiltration across the CP and EAE pathology. We determined the critical role of the CP-A2AR on T cell infiltration and EAE pathology by focal knock-down of CP-A2AR via intracerebroventricular injection of CRE-TAT recombinase into the A2ARflox/flox mice. In the cultured CP epithelium, we also evaluated the effect of overexpression of A2ARs or the A2AR agonist CGS21680 treatment on the CP permeability and lymphocytes migration.ResultsWe found the specific upregulation of A2AR in the CP associated with enhanced CP gateway activity peaked at day 12 post-immunization in EAE mice. Furthermore, the KW6002 treatment at days 8-12 or 8-14 post-immunization reduced T cell trafficking across the CP and attenuated EAE pathology. Importantly, focal CP-A2AR knock-down attenuated the pathogenic infiltration of Th17+ cells across the CP via inhibiting the CCR6-CCL20 axis through NFκB/STAT3 pathway and protected against EAE pathology. Lastly, activation of A2AR in the cultured epithelium by A2AR overexpression or CGS21680 treatment increased the permeability of the CP epithelium and facilitated lymphocytes migration.ConclusionThese findings define the CP niche as one of the primary sites of A2AR action, whereby A2AR antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A2AR represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP.

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

Publications

<i>In vivo</i> multimodal imaging of adenosine A<sub>1</sub> receptors in neuroinflammation after experimental stroke.

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