title: Potentiation of excitatory amino acid-evoked adenosine release from rat cortex by inhibitors of adenosine kinase and adenosine deaminase and by acadesine.
abstract: Endogenous extracellular adenosine provides some protection against excitotoxicity in the central nervous system, but it appears to be incomplete. Potentiating the formation of extracellular adenosine that occurs when excitatory amino acid receptors are activated might provide additional protection. We studied the effects of AICAR (AICA riboside, acadesine) and of inhibitors of adenosine metabolism on the release of adenosine from rat cortical slices. AICAR had no effects on basal N-methyl-D-aspartate (NMDA)- or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA)-evoked adenosine release, but it increased kainate-evoked adenosine release 1.4-fold. This selective action of AICAR may make it useful for treating kainate receptor-mediated excitotoxicity. Inhibition of adenosine kinase with either 20 microM 5'-amino-5'-deoxyadenosine or 5'-iodotubercidin had a much greater effect on excitatory amino acid-evoked adenosine release than on basal adenosine release. Inhibition of adenosine kinase increased excitatory amino acid-evoked adenosine release 3-7-fold whereas inhibition of adenosine deaminase only increased evoked adenosine release 2-2.5-fold. Finally, 0.2 microM 5'-iodotubercidin and 200 microM 2'-deoxycoformycin caused similar increases in the basal rates of extracellular adenosine formation, but 5'-iodotubercidin produced over twice as much potentiation of the rate of NMDA-evoked adenosine formation than did 2'-deoxycoformycin. These findings suggest that adenosine kinase inhibitors may produce an event-specific potentiation of evoked adenosine formation, i.e. more effect on evoked formation than on basal formation. If so, adenosine kinase inhibitors may prove useful for preventing/treating diseases associated with excessive excitation in the brain, such as seizures, excitotoxicity and neurodegeneration.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada. tom.white@dal.ca
authors.forename: T D
authors.initials: TD
authors.lastname: White
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012263:Ribonucleosides / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D058892:Adenosine Deaminase Inhibitors; D018690:Excitatory Amino Acid Agonists; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000248:Adenosine Kinase; D000241:Adenosine; D007608:Kainic Acid