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

Abstract

Adenosine 5 0 -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 A 1 , A 2 , or A 3 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 0 -diphosphate (ADP) and adenine 5 0 -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.

Temporal and mechanistic dissociation of ATP and adenosine release during ischaemia in the mammalian hippocampus1

“…In vivo , basal ATP levels have been estimated to be as low as a few nmol/L (Phillis and O’Regan 2003; Melani et al. 2005), which is below the level of detection in the present study.…”

“…In vivo, basal ATP levels have been estimated to be as low as a few nmol/L (Phillis and O'Regan 2003;Melani et al 2005), which is below the level of detection in the present study. Accordingly, it is not clear whether this low basal level of ATP is sufficient to exert any influence via P2 receptors (Dulla et al 2005;da Silva et al 2005).…”

“…Adenosine is well known to be released during cerebral hypoxia/ischaemia both in vitro and in vivo (Latini and Pedata 2001; Frenguelli et al. 2003; Phillis and O’Regan 2003). Indirect studies using pharmacological antagonists (Fowler 1989; Pearson et al.…”

“…Adenosine is well known to be released during cerebral hypoxia/ischaemia both in vitro and in vivo (Latini and Pedata 2001;Frenguelli et al 2003;Phillis and O'Regan 2003). Indirect studies using pharmacological antagonists (Fowler 1989;Pearson et al 2006), receptor knockouts (Johansson et al 2001) or focal receptor deletion (Arrigoni et al 2005) demonstrate that activation of presynaptic adenosine A 1 receptors causes rapid depression of excitatory synaptic transmission during hypoxia/ischaemia in vitro and in vivo (Gervitz et al 2001;Ilie et al 2006).…”

Sustained elevation of extracellular adenosine and activation of A1 receptors underlie the post‐ischaemic inhibition of neuronal function in rat hippocampus in vitro

“…As valuable as these approaches are, they offer little insight into the dynamics of adenosine release and its relationship to on‐going synaptic activity, especially if, as in the case of brain tissue subjected to metabolic insults, electrophysiological activity is depressed. Direct measurement of extracellular adenosine in vitro (Latini and Pedata 2001) and in vivo (Phillis and O'Regan 2003) during physiological and pathological conditions has been extremely informative but is constrained by the spatial and temporal (≥ 2 min) resolution of the available HPLC techniques.…”