Coppi, Elisabetta;
Gibb, Alasdair J;
(2022)
Selective block of adenosine A2A receptors prevents ischaemic-like effects induced by oxygen and glucose deprivation in rat medium spiny neurons.
British Journal of Pharmacology
10.1111/bph.15922.
(In press).
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Abstract
BACKGROUND AND PURPOSE: Ischemia is known to cause massive neuronal depolarization, termed anoxic depolarization (AD), due to energy failure and loss of membrane ion gradients. The neuromodulator adenosine accumulates extracellularly during ischemia and activates four metabotropic receptors: A1 , A2A , A2B and A3 . Striatal medium spiny neurons (MSNs) express high levels of A2A receptors (A2A Rs) and are particularly vulnerable to ischemic insults. It is known that A2A R blockade reduces acute striatal post-ischemic damage but the cellular mechanisms involved are still unknown. EXPERIMENTAL APPROACH: We performed patch-clamp recordings from MSNs in rat striatal slices subjected to oxygen and glucose deprivation (OGD) in order to investigate the effects of A2A R ligands or ion channel blockers on AD and OGD-induced ionic imbalance, measured as a positive shift in Erev of ramp currents. KEY RESULTS: Our data indicate that the A2A R antagonist SCH58261 (10μM) significantly attenuated ionic imbalance and AD appearance in MSNs exposed to OGD. The K+ channel blocker Ba2+ (2mM) or the Na+ channel blocker tetrodotoxin (1μM) exacerbated and attenuated, respectively, OGD-induced changes. Spontaneous excitatory post-synaptic current (sEPSC) analysis in MSNs revealed that the A2A R agonist CGS21680 (1μM) prevented OGD-induced decrease of sEPSCs within the first 5 min of the insult, an effect shared by the K+ channel blocker Ba2+ , thus indicating facilitated glutamate release. CONCLUSION AND IMPLICATIONS: We conclude that adenosine, released during striatal OGD, activates A2A Rs that may exacerbate OGD-induced damage through K+ channel inhibition. Our results could help to develop A2A R-selective therapeutic tools for the treatment of brain ischemia.
| Type: | Article |
|---|---|
| Title: | Selective block of adenosine A2A receptors prevents ischaemic-like effects induced by oxygen and glucose deprivation in rat medium spiny neurons |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bph.15922 |
| Publisher version: | https://doi.org/10.1111/bph.15922 |
| Language: | English |
| Additional information: | © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | adenosine A2A receptor, anoxic depolarization, brain ischaemia, K+ currents, mediium spiny neurons, spontaneous and miniature excitatory, postsynaptic currents |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10152809 |
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