title: The brain in vivo expresses the 2',3'-cAMP-adenosine pathway.
abstract: Although multiple biochemical pathways produce adenosine, studies suggest that the 2',3'-cAMP-adenosine pathway (2',3'-cAMP→2'-AMP/3'-AMP→adenosine) contributes to adenosine production in some cells/tissues/organs. To determine whether the 2',3'-cAMP-adenosine pathway exists in vivo in the brain, we delivered to the brain (gray matter and white matter separately) via the inflow perfusate of a microdialysis probe either 2',3'-cAMP, 3',5'-cAMP, 2'-AMP, 3'-AMP, or 5'-AMP and measured the recovered metabolites in the microdialysis outflow perfusate with mass spectrometry. In both gray and white matter, 2',3'-cAMP increased 2'-AMP, 3'-AMP and adenosine, and 3',5'-cAMP increased 5'-AMP and adenosine. In both brain regions, 2'-AMP, 3-AMP and 5'-AMP were converted to adenosine. Microdialysis experiments in 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) wild-type mice demonstrated that traumatic brain injury (controlled cortical impact model) activated the brain 2',3'-cAMP-adenosine pathway; similar experiments in CNPase knockout mice indicated that CNPase was involved in the metabolism of endogenous 2',3'-cAMP to 2'-AMP and to adenosine. In CSF from traumatic brain injury patients, 2',3'-cAMP was significantly increased in the initial 12 h after injury and strongly correlated with CSF levels of 2'-AMP, 3'-AMP, adenosine and inosine. We conclude that in vivo, 2',3'-cAMP is converted to 2'-AMP/3'-AMP, and these AMPs are metabolized to adenosine. This pathway exists endogenously in both mice and humans.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Verrier
authors.forename: Travis C
authors.initials: TC
authors.lastname: Jackson
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bansal
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: Ava M
authors.initials: AM
authors.lastname: Puccio
authors.forename: David O
authors.initials: DO
authors.lastname: Okonkwo
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000172:deficiency; D000227:Adenine Nucleotides / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000328:Adult; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001930:Brain Injuries / Q000134:cerebrospinal fluid / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D015600:Glasgow Coma Scale; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D055815:Young Adult
chemical_list: D000227:Adenine Nucleotides; D000249:Adenosine Monophosphate; C010565:2',3'-cyclic AMP; D000242:Cyclic AMP; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000241:Adenosine