In vivo studies of the release of adenine 5′‐nucleotides, adenosine, and its metabolites from the rat brain

Abstract

AbstractAdenosine 5′ ‐triphosphate (ATP) and adenosine function as an excitatory neurotransmitter and a neuromodulator, respectively, in the central nervous system. Neuroexcitatory effects of ATP are mediated by P2X receptors: neuromodulator effects of adenosine by A1, A2, or A3 receptors. There is also evidence that ATP, acting a P2Y receptor, is involved in osmoregulatory responses to cell swelling. Studies on the release of ATP and/or adenosine into the interstitial fluid of the brain have served to clarify their roles in cerebral function. ATP release occurs during electrical or K+‐induced depolarization of cerebral tissues. Released ATP is rapidly hydrolyzed by ectonucleotidases, which may be released concurrently, to form adenosine 5′‐diphosphate (ADP) and adenine 5′‐monophosphate (AMP). In addition to synaptic release from neurons, there is evidence of glial release via gap‐junction hemichannels. Hydrolysis of AMP to adenosine initiates a further metabolic cascade with the formation of inosine, hypoxanthine, xanthine, and uric acid by adenosine deaminase, purine nucleoside phosphorylase, and xanthine oxidase. Hypoxanthine can be converted to inosine monophosphate by hypoxanthine phosphoribosyl transferase and thus used to replenish ATP. Cerebral ischemia causes ATP utilization, and adenosine formation. Adenosine can then be transported across the plasma membrane and released into the interstitial space. Hypoxemia‐evoked adenosine release from the cerebral cortex is inhibited by blockers of adenosine transport. Inhibition of purine metabolism by blockers of adenosine deaminase, purine nucleoside phosphorylase, and xanthine oxidase elevates upstream levels of adenosine and its metabolites. Exposure of the in vivo rat cerebral cortex to cerebrospinal fluid containing swelling‐inducing monocarboxylic acids elevated interstitial fluid levels of ADP and AMP, but not of adenosine. Taken together, these studies have led to a greater understanding of the metabolism and release of adenosine and the adenine nucleotides in the normoxic and ischemic brain. Drug Dev. Res. 58:412–419, 2003. © 2003 Wiley‐Liss, Inc.