Abstract
Adenosine is well known to be released during cerebral metabolic stress and is believed to be neuroprotective. ATP release under similar circumstances has been much less studied. We have now used biosensors to measure and compare in real time the release of ATP and adenosine during in vitro ischaemia in hippocampal slices. ATP release only occurred following the anoxic depolarisation, whereas adenosine release was apparent almost immediately after the onset of ischaemia. ATP release required extracellular Ca2+. By contrast adenosine release was enhanced by removal of extracellular Ca2+, whilst TTX had no effect on either ATP release or adenosine release. Blockade of ionotropic glutamate receptors substantially enhanced ATP release, but had only a modest effect on adenosine release. Carbenoxolone, an inhibitor of gap junction hemichannels, also greatly enhanced ischaemic ATP release, but had little effect on adenosine release. The ecto-ATPase inhibitor ARL 67156, whilst modestly enhancing the ATP signal detected during ischaemia, had no effect on adenosine release. Adenosine release during ischaemia was reduced by pre-treament with homosysteine thiolactone suggesting an intracellular origin. Adenosine transport inhibitors did not inhibit adenosine release, but instead they caused a twofold increase of release. Our data suggest that ATP and adenosine release during ischaemia are for the most part independent processes with distinct underlying mechanisms. These two purines will consequently confer temporally distinct influences on neuronal and glial function in the ischaemic brain.
Highlights
The purines ATP and adenosine exert powerful modulatory influences in the mammalian central nervous system
The inability to consistently detect the adenosine tone, readily observable on excitatory synaptic transmission through the use of adenosine A1 antagonists is possibly because of the limitations of the two-stage measuring method, as pharmacological manipulations to reduce the breakdown of ATP consistently revealed a loss of adenosine tone
In slices that had been subjected to ischaemia, when measured some 30 min following the end of the ischaemic episode, an adenosine tone was detectable
Summary
The purines ATP and adenosine exert powerful modulatory influences in the mammalian central nervous system. 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 A1 receptors causes rapid depression of excitatory synaptic transmission during hypoxia/ischaemia in vitro and in vivo (Gervitz et al 2001; Ilie et al 2006) This conclusion is strengthened by the close temporal association of adenosine release with the depression of excitatory synaptic transmission (Frenguelli et al 2003; Pearson et al 2006). Unlike adenosine release, the timing, dynamics and quantity of ATP release during ischaemia has not been documented
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
