title: Interstitial adenosine, inosine, and hypoxanthine are increased after experimental traumatic brain injury in the rat.
abstract: Adenosine is a putative neuroprotectant in ischemia, but its role after traumatic brain injury (TBI) is not clear. Metabolites of adenosine, particularly inosine and hypoxanthine, are markers of ischemia and energy failure. Adenosine triphosphate (ATP) breakdown early after injury and metabolism of cyclic adenosine monophosphate (cAMP) are potential sources of adenosine. Further delineation of the magnitude, location, time course, and source of production of adenosine after TBI is needed. We measured adenosine, inosine, and hypoxanthine in brain interstitial fluid after controlled cortical impact (CCI) in the rat. Rats (n = 15) were prepared for TBI induced by CCI. A microdialysis probe was placed in the cortex, and samples were collected every 10 min. After 3 h of equilibration, the catheter was removed, CCI was performed (4 m/sec, depth 2.5 mm), and the catheter was replaced. In the shams, the catheter was removed and replaced without CCI. The injury group included rats (n = 10) subjected to CCI. Within the injury group, the microdialysis probe was placed in the center of the eventual contusion (center, n = 5) or in the penumbral region (penumbra, n = 5). Purine metabolites were measured using ultraviolet-based high-pressure liquid chromatography. Adenosine, inosine, and hypoxanthine were dramatically increased after injury (61-fold, 37-fold, and 16-fold, respectively sham, all p < 0.05, two-way analysis of variance for repeated measures). No changes in cAMP were observed (p = 0.62 vs. sham). Adenosine peaked in the first 20 min and returned to near baseline 40 min, whereas inosine and hypoxanthine peaked at 30 min and remained increased for 40 min after CCI. Interstitial brain adenosine, inosine, and hypoxanthine were increased early after CCI in rats in the contusion and penumbra. ATP breakdown is a potential source of adenosine in this early period while metabolism of cAMP does not appear to play a role. Confirmation of these data in humans may suggest new strategies targeting this important metabolic pathway.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh, Safar Center for Resuscitation Research, Pennsylvania 15260, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bell
authors.forename: P M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: J A
authors.initials: JA
authors.lastname: Carcillo
authors.forename: Z
authors.initials: Z
authors.lastname: Mi
authors.forename: J K
authors.initials: JK
authors.lastname: Schiding
authors.forename: S R
authors.initials: SR
authors.lastname: Wisniewski
authors.forename: R S
authors.initials: RS
authors.lastname: Clark
authors.forename: C E
authors.initials: CE
authors.lastname: Dixon
authors.forename: D W
authors.initials: DW
authors.lastname: Marion
authors.forename: E
authors.initials: E
authors.lastname: Jackson
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D019271:Hypoxanthine / Q000378:metabolism*; D007288:Inosine / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet
chemical_list: D019271:Hypoxanthine; D007288:Inosine; D000242:Cyclic AMP; D000241:Adenosine