title: Adenosine A₁ receptors control the metabolic recovery after hypoxia in rat hippocampal slices.
abstract: Adenosine is a neuromodulator that protects neurons from hypoxia. This effect is attributed to the ability of adenosine A1 receptors (A1 R) to inhibit excitatory synaptic transmission. However, A1 R activation also protects non-brain tissues from hypoxic insults by controlling metabolism. Thus, we now tested the hypothesis that A1 R-mediated neuroprotection after a hypoxic insult in superfused hippocampal slices also involves the control of neuronal and astrocytic metabolism. A 90-min hypoxia insult increased lactate, alanine, and pyruvate levels and decreased energy charge (EC), phosphocreatine/creatine ratio, and glutamine content. These metabolic modifications were fully recovered after reoxygenation for 3 h. The presence of the A1 R-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine stimulated glycolysis, prevented the hypoxia-induced decrease of EC, and increased the levels of GABA. A1 R blockade further blunted the recovery of metabolism on reoxygenation after hypoxia, as typified by a sustained decreased EC and an increased mitochondrial metabolism, as confirmed by a greater [U-(13) C]glucose oxidation through the tricarboxylic acid cycle. These results demonstrate that A1 R blockade prevents the recovery of hypoxia-induced metabolic alterations during reoxygenation, which indicates that the ability of A1 R to control primary metabolism in the brain tissue may be a hitherto unrecognized mechanism of A1 R-mediated neuroprotection. This study demonstrates that tonic activation of adenosine A1 receptors (A1 R) plays an important role in the reoxygenation recovery of the metabolic alterations caused by transient hypoxia in rat hippocampal slices. This ability of A1 R to inhibit neuronal metabolism may be a key mechanism by which adenosine affords neuroprotection upon acute hypoxia, thus preventing the long-term impairment of neuronal circuits.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: João M N
authors.initials: JM
authors.lastname: Duarte
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.identifier: http://orcid.org/0000-0003-2550-6422
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Rui A
authors.initials: RA
authors.lastname: Carvalho
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism*; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D043682:Receptor, Adenosine A1; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine
keywords: 13C isotopomer analysis; NMR spectroscopy; adenosine; energy metabolism; hippocampus; hypoxia