The Journal of Neuroscience, April 1, 2001, 21(7):2298-2307
A Depletable Pool of Adenosine in Area CA1 of the Rat
Hippocampus
Tim
Pearson2,
Feruza
Nuritova2,
Darren
Caldwell2,
Nicholas
Dale1, and
Bruno G.
Frenguelli2
1 Department of Biological Sciences, University of
Warwick, Coventry CV4 7AL, United Kingdom, and 2 Department
of Pharmacology and Neuroscience, University of Dundee, Ninewells
Hospital and Medical School, Dundee DD1 9SY, United Kingdom
Adenosine plays a major modulatory and neuroprotective role in the
mammalian CNS. During cerebral metabolic stress, such as hypoxia or
ischemia, the increase in extracellular adenosine inhibits excitatory
synaptic transmission onto vulnerable neurons via presynaptic adenosine
A1 receptors, thereby reducing the activation of
postsynaptic glutamate receptors. Using a combination of extracellular
and whole-cell recordings in the CA1 region of hippocampal slices from
12- to 24-d-old rats, we have found that this protective depression of
synaptic transmission weakens with repeated exposure to hypoxia,
thereby allowing potentially damaging excitation to both persist for
longer during oxygen deprivation and recover more rapidly on
reoxygenation. This phenomenon is unlikely to involve A1
receptor desensitization or impaired nucleoside transport. Instead, by
using the selective A1 antagonist
8-cyclopentyl-1,3-dipropylxanthine and a novel adenosine sensor,
we demonstrate that adenosine production is reduced with repeated
episodes of hypoxia. Furthermore, this adenosine depletion can be
reversed at least partially either by the application of exogenous
adenosine, but not by a stable A1 agonist,
N6-cyclopentyladenosine, or by endogenous
means by prolonged (2 hr) recovery between hypoxic episodes. Given
the vital neuroprotective role of adenosine, these findings suggest
that depletion of adenosine may underlie the increased neuronal
vulnerability to repetitive or secondary hypoxia/ischemia in
cerebrovascular disease and head injury.
Key words:
adenosine; hypoxia; ischemia; sensor; depletion; replenishment; glutamate; hippocampus; head injury; TBI; stroke; TIA; neuroprotection; adenosine deaminase; nucleoside phosphorylase; xanthine oxidase
Copyright © 2001 Society for Neuroscience 0270-6474/01/2172298-10$05.00/0