AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus.
5-Aminoimidazole-4-carboxamide riboside (AICA riboside; Acadesine) activates AMP-activated protein kinase (AMPK) in intact cells, and is reported to exert protective effects in the mammalian CNS. In rat cerebrocortical brain slices, AMPK was activated by metabolic stress (ischaemia > hypoxia > aglycaemia) and AICA riboside (0.1-10 mm). Activation of AMPK by AICA riboside was greatly attenuated by inhibitors of equilibrative nucleoside transport. AICA riboside also depressed excitatory synaptic transmission in area CA1 of the rat hippocampus, which was prevented by an adenosine A1 receptor antagonist and reversed by application of adenosine deaminase. However, AICA riboside was neither a substrate for adenosine deaminase nor an agonist at adenosine receptors. We conclude that metabolic stress and AICA riboside both stimulate AMPK activity in mammalian brain, but that AICA riboside has an additional effect, i.e. competition with adenosine for uptake by the nucleoside transporter. This results in an increase in extracellular adenosine and subsequent activation of adenosine receptors. Neuroprotection by AICA riboside could be mediated by this mechanism as well as, or instead of, by AMPK activation. Caution should therefore be exercised in ascribing an effect of AICA riboside to AMPK activation, especially in systems where inhibition of adenosine re-uptake has physiological consequences.
Gadalla
Anne E
AE
Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, UK.
Pearson
Tim
T
Currie
Ailsa J
AJ
Dale
Nicholas
N
Hawley
Simon A
SA
Sheehan
Mike
M
Hirst
Warren
W
Michel
Anton D
AD
Randall
Andrew
A
Hardie
D Grahame
DG
Frenguelli
Bruno G
BG
D055372:AMP-Activated Protein Kinases; D000241:Adenosine / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D033703:Nucleoside Transport Proteins / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D012263:Ribonucleosides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013312:Stress, Physiological / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D009097:Multienzyme Complexes; D033703:Nucleoside Transport Proteins; D009711:Nucleotides; D018047:Receptors, Purinergic P1; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; D018698:Glutamic Acid; C011651:acadesine; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000241:Adenosine