POTENTIATION OF EXCITATORY AMINO ACID-EVOKED ADENOSINE RELEASE FROM RAT CORTEX BY INHIBITORS OF ADENOSINE KINASE AND ADENOSINE-DEAMINASE AND BY ACADESINE

Endogenous extracellular adenosine provides some protection against ex citotoxicity in the central nervous system, but it appears to be incom plete. Potentiating the formation of extracellular adenosine that occu rs when excitatory amino acid receptors are activated might provide ad ditional protection. We studied the effects of AICAR (AICA riboside, a cadesine) and of inhibitors of adenosine metabolism on the release of adenosine from rat cortical slices. AICAR had no effects on basal N-me thyl-D-aspartate (NMDA)- or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isox asole propionic acid (AMPA)-evoked adenosine release, but it increased kainate-evoked adenosine release 1.4-fold. This selective action of A ICAR may make it useful for treating kainate receptor-mediated excitot oxicity. Inhibition of adenosine kinase with either 20 mu M 5'-amino-5 '-deoxyadenosine or 5'-iodotubercidin had a much greater effect on exc itatory amino acid-evoked adenosine release than on basal adenosine re lease. Inhibition of adenosine kinase increased excitatory amino acid- evoked adenosine release 3-7-fold whereas inhibition of adenosine deam inase only increased evoked adenosine release 2-2.5-fold. Finally, 0.2 mu M 5'-iodotubercidin and 200 mu M 2'-deoxycoformycin caused similar increases in the basal rates of extracellular adenosine formation, bu t 5'-iodotubercidin produced over twice as much potentiation of the ra te of NMDA-evoked adenosine formation than did 2'-deoxycoformycin. The se findings suggest that adenosine kinase inhibitors may produce an ev ent-specific potentiation of evoked adenosine formation, i.e. more eff ect on evoked formation than on basal formation. If so, adenosine kina se inhibitors may prove useful for preventing/treating diseases associ ated with excessive excitation in the brain, such as seizures, excitot oxicity and neurodegeneration.