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The impact of inosine on hippocampal synaptic transmission and plasticity involves the release of adenosine through equilibrative nucleoside transporters rather than the direct activation of adenosine receptors

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Abstract

Inosine has robust neuroprotective effects, but it is unclear if inosine acts as direct ligand of adenosine receptors or if it triggers metabolic effects indirectly modifying the activity of adenosine receptors. We now combined radioligand binding studies with electrophysiological recordings in hippocampal slices to test how inosine controls synaptic transmission and plasticity. Inosine was without effect at 30 μM and decreased field excitatory post-synaptic potentials by 14% and 33% at 100 and 300 μM, respectively. These effects were prevented by the adenosine A1 receptor antagonist DPCPX. Inosine at 300 (but not 100) μM also decreased the magnitude of long-term potentiation (LTP), an effect prevented by DPCPX and by the adenosine A2A receptor antagonist SCH58261. Inosine showed low affinity towards human and rat adenosine receptor subtypes with Ki values of > 300 µM; only at the human and rat A1 receptor slightly higher affinities with Ki values of around 100 µM were observed. Affinity of inosine at the rat A3 receptor was higher (Ki of 1.37 µM), while it showed no interaction with the human orthologue. Notably, the effects of inosine on synaptic transmission and plasticity were abrogated by adenosine deaminase and by inhibiting equilibrative nucleoside transporters (ENT) with dipyridamole and NBTI. This shows that the impact of inosine on hippocampal synaptic transmission and plasticity is not due to a direct activation of adenosine receptors but is instead due to an indirect modification of the tonic activation of these adenosine receptors through an ENT-mediated modification of the extracellular levels of adenosine.

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Funding

This study was supported by La Caixa Foundation (HP17/00523), Centro 2020 (CENTRO-01–0145-FEDER-000008: BrainHealth2020 and CENTRO-01–0246-FEDER-000010), FCT (POCI-01–0145-FEDER-03127, UIDB/04539/2020, and IF/01492/2015), and Deutsche Forschungsgemeinschaft (FOR2685, SFB1328).

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  1. CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal

    Pedro Valada, Cátia R. Lopes, Rodrigo A. Cunha & João Pedro Lopes

  2. Pharmaceutical & Medicinal Chemistry, University of Bonn, 53121, Bonn, Germany

    Sonja Hinz, Christin Vielmuth & Christa E. Müller

  3. Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Rodrigo A. Cunha

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Contributions

P. V., J. P. L., and C. R. L. carried out the electrophysiological experiments and analyzed the data; S. H. and C. V. carried out the receptor binding studies and analyzed the data; and J. P. L., R. A. C., and C. E. M. supervised the project and wrote the manuscript.

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Correspondence to Rodrigo A. Cunha.

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This study was approved by the ORBEA_128_2015/04122015 and certified by Direção Geral de Alimentação e Veterinária (DGAV; 0421/000/000/2016 Ref. 014420).

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RAC is a scientific consultant for the Institute for Scientific Information on Coffee (ISIC). All other authors declare no conflict of interests.

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Valada, P., Hinz, S., Vielmuth, C. et al. The impact of inosine on hippocampal synaptic transmission and plasticity involves the release of adenosine through equilibrative nucleoside transporters rather than the direct activation of adenosine receptors. Purinergic Signalling 19, 451–461 (2023). https://doi.org/10.1007/s11302-022-09899-7

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  • DOI: https://doi.org/10.1007/s11302-022-09899-7

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