COADMINISTRATION OF ADENOSINE KINASE AND DEAMINASE INHIBITORS PRODUCES SUPRAADDITIVE POTENTIATION OF N-METHYL-D-ASPARTATE-EVOKED ADENOSINE FORMATION IN CORTEX

Activation of glutamate receptors triggers the release of adenosine, w hich exerts important inhibitory actions in the brain. Evoked adenosin e release is potentiated when either adenosine kinase or adenosine dea minase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on N-methyl-D-aspartate (N MDA)-evoked formation of extracellular adenosine in slices of rat pari etal cortex, to determine if combinations of inhibitors of adenosine k inase and adenosine deaminase can produce supra-additive potentiation of this adenosine formation. Combinations of low-concentrations of the adenosine kinase inhibitors. 5'-amino-5'-deoxyadenosine (0.2 mu M) or 5'-iodotubercidin (0.01 mu 1) with a low concentration of the adenosi ne deaminase inhibitor 2'-deoxycoformycin (0.2 mu M) produced additive potentiations of NMDA-evoked adenosine release from slices of rat par ietal cortex. However. combinations of low concentrations of 5'-amino- 5'-droxyadenosine (0.2 mu M) or 5'-iodotubercidin (0.01 mu M) with a m aximal concentration of 2'-deoxycoformycin (200 mu M) produced supra-a dditive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with ade nosine deaminase inhibitors may provide useful strategies for developi ng therapies to treat disorders associated with excessive NMDA recepto r activation, such as seizures, ischemic damage and neurodegenerative diseases. (C) 1998 Elsevier Science B.V.