Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N-methyl-D-aspartate-evoked adenosine formation in cortex.
Activation of glutamate receptors triggers the release of adenosine, which exerts important inhibitory actions in the brain. Evoked adenosine release is potentiated when either adenosine kinase or adenosine deaminase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on N-methyl-D-aspartate (NMDA)-evoked formation of extracellular adenosine in slices of rat parietal cortex, to determine if combinations of inhibitors of adenosine kinase 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 microM) or 5'-iodotubercidin (0.01 microM) with a low concentration of the adenosine deaminase inhibitor 2'-deoxycoformycin (0.2 microM) produced additive potentiations of NMDA-evoked adenosine release from slices of rat parietal cortex. However, combinations of low concentrations of 5'-amino-5'-deoxyadenosine (0.2 microM) or 5'-iodotubercidin (0.01 microM) with a maximal concentration of 2'-deoxycoformycin (200 microM) produced supra-additive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with adenosine deaminase inhibitors may provide useful strategies for developing therapies to treat disorders associated with excessive NMDA receptor activation, such as seizures, ischemic damage and neurodegenerative diseases.
Hebb
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MO
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
White
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TD
D000241:Adenosine / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003839:Deoxyadenosines / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D015649:Pentostatin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; C057928:5'-amino-5'-deoxyadenosine; C034214:5-iodotubercidin; D015649:Pentostatin; D016202:N-Methylaspartate; D000248:Adenosine Kinase; D000241:Adenosine; D014372:Tubercidin