INTERSTITIAL ADENOSINE, INOSINE, AND HYPOXANTHINE ARE INCREASED AFTEREXPERIMENTAL TRAUMATIC BRAIN INJURY IN THE RAT

Adenosine is a putative neuroprotectant in ischemia, but its role afte r traumatic brain injury (TBI) is not clear. Metabolites of adenosine, particularly inosine and hypoxanthine, are markers of ischemia and en ergy failure. Adenosine triphosphate (ATP) breakdown early after injur y and metabolism of cyclic adenosine monophosphate (cAMP) are potentia l sources of adenosine. Further delineation of the magnitude, location , time course, and source of production of adenosine after TBI is need ed. We measured adenosine, inosine, and hypoxanthine in brain intersti tial 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 c atheter was removed and replaced without CCI. The injury group include d rats (n = 10) subjected to CCI. Within the injury group, the microdi alysis probe was placed in the center of the eventual contusion (cente r, n = 5) or in the penumbral region (penumbra, n = 5). Purine metabol ites were measured using ultraviolet-based high-pressure liquid chroma tography. Adenosine, inosine, and hypoxanthine were dramatically incre ased after injury (61-fold, 37-fold, and 16-fold, respectively sham, a ll p < 0.05, two-way analysis of variance for repeated measures). No c hanges 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 a fter 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 whil e metabolism of cAMP does not appear to play a role. Confirmation of t hese data in humans may suggest new strategies targeting this importan t metabolic pathway.