Sustained elevation of extracellular adenosine and activation of A1 receptors underlie the post-ischaemic inhibition of neuronal function in rat hippocampus in vitro.
Adenosine is released from the compromised brain and exerts a predominately neuroprotective influence. However, the time-course of adenosine release and its relationship to synaptic activity during metabolic stress is not fully understood. Here, we describe experiments using an enzyme-based adenosine sensor to show that adenosine potently (IC50 approximately 1 microm) inhibits excitatory synaptic transmission in area CA1 during oxygen/glucose deprivation ('ischaemia'), and that the prolonged post-ischaemic presence of extracellular adenosine sustains the depression of the field excitatory postsynaptic potential (fEPSP). N-methyl-D-aspartate (NMDA) receptor antagonism promotes post-ischaemic recovery of the fEPSP, in parallel with reduced release of adenosine. Paradoxically, however, after ischaemia the fEPSP recovers in the face of concentrations of adenosine capable of fully eliminating synaptic transmission during ischaemia. This hysteresis is not prevented by NMDA receptor antagonism, is observed during repeated ischaemia when adenosine release is reduced, and does not reflect desensitization of adenosine A1 receptors. We conclude that adenosine exerts powerful inhibitory actions on excitatory synaptic transmission both during, and for some considerable time after, ischaemia. Therapeutic strategies designed to exploit both the continued presence of adenosine and activity of A1 receptors could provide benefits in individuals who have suffered acute injury to the CNS.
Pearson
Tim
T
Neurosciences Institute, Division of Pathology & Neuroscience, University of Dundee, Ninewells Hospital, Dundee, UK.
Damian
Karen
K
Lynas
Rachel E
RE
Frenguelli
Bruno G
BG
D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D058907:Adenosine A1 Receptor Agonists; D018691:Excitatory Amino Acid Antagonists; D043682:Receptor, Adenosine A1; D016194:Receptors, N-Methyl-D-Aspartate; D000241:Adenosine