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Open AccessArticle

Adenosine A2A Receptor Antagonists Affects NMDA Glutamate Receptor Function. Potential to Address Neurodegeneration in Alzheimer’s Disease

1
Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, 08028 Barcelona, Spain
2
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Valderrebollo, 5, 28031 Madrid, Spain
3
Departament of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, Universitat de Barcelona, 08028 Barcelona, Spain
4
Institut de Neurociències, Department de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(5), 1075; https://doi.org/10.3390/cells9051075
Received: 27 March 2020 / Revised: 17 April 2020 / Accepted: 19 April 2020 / Published: 26 April 2020
(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)
(1) Background. N-methyl d-aspartate (NMDA) ionotropic glutamate receptor (NMDAR), which is one of the main targets to combat Alzheimer’s disease (AD), is expressed in both neurons and glial cells. The aim of this paper was to assess whether the adenosine A2A receptor (A2AR), which is a target in neurodegeneration, may affect NMDAR functionality. (2) Methods. Immuno-histo/cytochemical, biophysical, biochemical and signaling assays were performed in a heterologous cell expression system and in primary cultures of neurons and microglia (resting and activated) from control and the APPSw,Ind transgenic mice. (3) Results. On the one hand, NMDA and A2A receptors were able to physically interact forming complexes, mainly in microglia. Furthermore, the amount of complexes was markedly enhanced in activated microglia. On the other hand, the interaction resulted in a novel functional entity that displayed a cross-antagonism, that could be useful to prevent the exacerbation of NMDAR function by using A2AR antagonists. Interestingly, the amount of complexes was markedly higher in the hippocampal cells from the APPSw,Ind than from the control mice. In neurons, the number of complexes was lesser, probably due to NMDAR not interacting with the A2AR. However, the activation of the A2AR receptors resulted in higher NMDAR functionality in neurons, probably by indirect mechanisms. (4) Conclusions. A2AR antagonists such as istradefylline, which is already approved for Parkinson’s disease (Nouriast® in Japan and Nourianz® in the US), have potential to afford neuroprotection in AD in a synergistic-like fashion. i.e., via both neurons and microglia. View Full-Text
Keywords: G-protein-coupled receptors; functional selectivity; microglia; neuroprotection; cognition; signaling G-protein-coupled receptors; functional selectivity; microglia; neuroprotection; cognition; signaling
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MDPI and ACS Style

Franco, R.; Rivas-Santisteban, R.; Casanovas, M.; Lillo, A.; Saura, C.A.; Navarro, G. Adenosine A2A Receptor Antagonists Affects NMDA Glutamate Receptor Function. Potential to Address Neurodegeneration in Alzheimer’s Disease. Cells 2020, 9, 1075.

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