Review

Regulation of adenosine levels during cerebral ischemia

Authors: Stephanie Chu, Wei Xiong, Dali Zhang, Hanifi Soylu, Chao Sun, Benedict C Albensi, Fiona E Parkinson
DOI: 10.1038/aps.2012.127

Abstract

Stephanie CHU1, Wei XIONG1, Dali ZHANG1, Hanifi SOYLU1, Chao SUN1, Benedict C ALBENSI1, 2, Fiona E PARKINSON1, *

1Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada R3E 0W3; 2Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, Canada R2H 2A6

Adenosine is a neuromodulator with its level increasing up to 100-fold during ischemic events, and attenuates the excitotoxic neuronal injury. Adenosine is produced both intracellularly and extracellularly, and nucleoside transport proteins transfer adenosine across plasma membranes. Adenosine levels and receptor-mediated effects of adenosine are regulated by intracellular ATP consumption, cellular release of ATP, metabolism of extracellular ATP (and other adenine nucleotides), adenosine influx, adenosine efflux and adenosine metabolism. Recent studies have used genetically modified mice to investigate the relative contributions of intra- and extracellular pathways for adenosine formation. The importance of cortical or hippocampal neurons as a source or a sink of adenosine under basal and hypoxic/ischemic conditions was addressed through the use of transgenic mice expressing human equilibrative nucleoside transporter 1 (hENT1) under the control of a promoter for neuron-specific enolase. From these studies, we conclude that ATP consumption within neurons is the primary source of adenosine in neuronal cultures, but not in hippocampal slices or in vivo mice exposed to ischemic conditions.


Keywords: adenosine; cerebral ischemia; ATP; nucleoside transport; hENT1 transgenic mice; hippocampus

Research in the authors’ laboratories is supported by the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Manitoba, the Natural Sciences and Engineering Research Council of Canada and the St Boniface General Hospital Research Foundation. BCA is a Research Affiliate at the University of Manitoba’s Centre on Aging and the Everett Endowment Fund Chair.
* To whom correspondence should be addressed.
E-mail fiona.parkinson@med.umanitoba.ca
Received 2012-04-27 Accepted 2012-07-24
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