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The Many Roles of Adenosine in Traumatic Brain Injury

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Adenosine

Abstract

Many secondary mechanisms regulate the evolution of damage and repair after traumatic brain injury (TBI). Bench-to-bedside studies from our team have shown that adenosine plays a key role in several secondary injury pathways in the brain, namely, excitotoxicity, neuroinflammation, and cerebral blood flow (CBF) dysregulation. Studies of adenosine A1-receptor (A1R) knockout (KO) mice strongly support a key role for adenosine-dependent effects at this receptor in attenuating posttraumatic excitotoxicty. A1R KO mice develop lethal status epilepticus after experimental TBI. Evidence also supports a role of the A1R in human TBI since A1R gene variants are associated with posttraumatic seizures in patients with TBI. A1R also modulates the neuroinflammatory response to TBI. A1R KO mice exhibit enhanced microglial proliferation early after TBI. Adenosine acting at A2A and/or A2B receptors also modulates posttraumatic CBF. Local injection of either the nonselective AR agonist 2-chloroadenosine or the A2AR agonist CGS21680 markedly increases CBF in naïve or brain-injured rats. However, whether the effects of adenosine on CBF after TBI are beneficial or detrimental is controversial. Mitigation of ischemia by adenosine produced from breakdown of ATP after TBI has been suggested, and consistent with this hypothesis, we reported increases in brain interstitial adenosine levels in patients with severe TBI during episodes of ischemia. However, in studies of CBF in patients after severe TBI, we also noted an association between cerebrospinal fluid (CSF) adenosine levels and uncoupling of CBF and metabolism (cerebral metabolic rate for oxygen [CMRO2]). Uncoupling of CBF and CMRO2 is associated with intracranial hypertension. Thus, adenosine may represent a two-edged sword after TBI. Additional evidence supporting a protective role of adenosine in TBI comes from clinical studies showing a powerful association between CSF caffeine levels and favorable outcome after TBI—given the interplay between caffeine and adenosine in neuroprotection. Finally, our work also suggests that the newly discovered 2,3-cyclic AMP pathway represents an important component of the adenosine response to TBI.

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References

  • Akahane M, Ono H, Ohgushi H, Tamai S (2001) Viability of ischemia/reperfused muscles in rat: a new evaluation method by RNA degradation. J Orthop Res 19:559–564

    Article  CAS  PubMed  Google Scholar 

  • Avsar E, Empson RM (2004) Adenosine acting via A1 receptors, controls the transition to status epilepticus-like behaviour in an in vitro model of epilepsy. Neuropharmacology 47:427–437

    Article  CAS  PubMed  Google Scholar 

  • Bell MJ, Kochanek PM, Carcillo JA, Mi Z, Schiding JK, Wisniewski SR, Clark RS, Dixon CE, Marion DW, Jackson E (1998) Interstitial adenosine, inosine, and hypoxanthine are increased after experimental traumatic brain injury in the rat. J Neurotrauma 15:163–170

    Article  CAS  PubMed  Google Scholar 

  • Bell MJ, Robertson CS, Kochanek PM, Goodman JC, Gopinath SP, Carcillo JA, Clark RS, Marion DW, Mi Z, Jackson EK (2001) Interstitial brain adenosine and xanthine increase during jugular venous oxygen desaturations in humans after traumatic brain injury. Crit Care Med 29:399–404

    Article  CAS  PubMed  Google Scholar 

  • Bouma GJ, Muizelaar JP, Stringer WA, Choi SC, Fatouros P, Young HF (1992) Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 77:360–368

    Article  CAS  PubMed  Google Scholar 

  • Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, Manley GT, Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, Videtta W, Wilberger JE, Wright DW (2007) Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis. J Neurotrauma 24 (suppl 1): S83–S86

    Google Scholar 

  • Catts VS, Catts SV, Fernandez HR, Taylor JM, Coulson EJ, Lutze-Mann LH (2005) A microarray study of post-mortem mRNA degradation in mouse brain tissue. Brain Res 138:164–177

    Article  CAS  Google Scholar 

  • Centers for Disease Control and Prevention. http://www.cdc.gov/TraumaticBrainInjury/statistics.html. Accessed 26 June 2011

  • Chen JF, Pedata F (2008) Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Curr Pharm Des 14:1490–1499

    Article  CAS  PubMed  Google Scholar 

  • Chevyreva I, Faull RLM, Green CR, Nicholson LFB (2008) Assessing RNA quality in postmortem human brain tissue. Exp Mol Pathol 84:71–77

    Article  CAS  PubMed  Google Scholar 

  • Clark RS, Carcillo JA, Kochanek PM, Obrist WD, Jackson EK, Mi Z, Wisneiwski SR, Bell MJ, Marion DW (1997) Cerebrospinal fluid adenosine concentration and uncoupling of cerebral blood flow and oxidative metabolism after severe head injury in humans. Neurosurgery 41:1284–1292, discussion 1292–1293

    Article  CAS  PubMed  Google Scholar 

  • Clark RS, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM (1994) Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop and controlled cortical impact models. J Neurotrauma 11:499–506

    Article  CAS  PubMed  Google Scholar 

  • Dai SS, Li W, An JH, Wang H, Yang N, Chen XY, Zhao Y, Li P, Liu P, Chen JF, Zhou YG (2010) Adenosine A2A receptors in both bone marrow cells and non-bone marrow cells contribute to traumatic brain injury. J Neurochem 113:1536–1544

    CAS  PubMed  Google Scholar 

  • Dai SS, Zhou YG (2011) Adenosine 2A receptor: a crucial neuromodulator with bidirectional effect in neuroinflammation and brain injury. Rev Neurosci 22:231–239

    PubMed  Google Scholar 

  • DeKosky ST, Ikonomovic MD, Gandy S (2010) Traumatic brain injury―football, warfare, and long-term effects. N Engl J Med 363:1293–1296

    Article  CAS  PubMed  Google Scholar 

  • Del Prete MJ, Robles MS, Guao A, Martinez-A C, Izquierdo M, Garcia-Sanz JA (2002) Degradation of cellular mRNA is a general early apoptosis-induced event. FASEB J 16:2003–2005

    PubMed  Google Scholar 

  • Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL (1991) A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 39:253–262

    PubMed  Google Scholar 

  • Fedele DE, Gouder N, Güttinger M, Gabernet L, Scheurer L, Rülicke T, Crestani F, Boison D (2005) Astrogliosis in epilepsy leads to overexpression of adenosine kinase, resulting in seizure aggravation. Brain 128:2383–2395

    Article  PubMed  Google Scholar 

  • Foley LM, Hitchens TK, Ho C, Janesko-Feldman KL, Melick JA, Bayir H, Kochanek PM (2009) Magnetic resonance imaging assessment of macrophage accumulation in mouse brain after experimental traumatic brain injury. J Neurotrauma 26:1509–1519

    Article  PubMed  Google Scholar 

  • Franklin PH, Zhang G, Tripp ED, Murray TF (1989) Adenosine A1 receptor activation mediates suppression of (-) bicuculline methiodide-induced seizures in rat prepiriform cortex. J Pharmacol Exp Ther 251:1229–1236

    CAS  PubMed  Google Scholar 

  • Gopinath SP, Robertson CS, Contant CF, Hayes C, Feldman Z, Narayan RK, Grossman RG (1994) Jugular venous desaturation and outcome after head injury. J Neurol Neurosurg Psychiatry 57:717–723

    CAS  PubMed  Google Scholar 

  • Gouder N, Scheurer L, Fritschy JM, Boison D (2004) Overexpression of adenosine kinase in epileptic hippocampus contributes to epileptogenesis. J Neurosci 24:692–701

    Article  CAS  PubMed  Google Scholar 

  • Hall ED, Sullivan PG, Gibson TR, Pavel KM, Thompson BM, Scheff SW (2005) Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: more than a focal brain injury. J Neurotrauma 22:252–265

    Article  CAS  PubMed  Google Scholar 

  • Haselkorn ML, Shellington DK, Jackson EK, Vagni VA, Janesko-Feldman K, Dubey RK, Gillespie DG, Cheng D, Bell MJ, Jenkins LW, Homanics GE, Schnermann J, Kochanek PM (2010) Adenosine A1 receptor activation as a brake on the microglial response after experimental traumatic brain injury in mice. J Neurotrauma 27:901–910

    Article  PubMed  Google Scholar 

  • Hendrich KS, Kochanek PM, Williams DS, Schiding JK, Marion DW, Ho C (1999) Early perfusion after controlled cortical impact in rats: quantification by arterial spin-labeled MRI and the influence of spin-lattice relaxation time heterogeneity. Magn Reson Med 42:673–681

    Article  CAS  PubMed  Google Scholar 

  • Hovda DA, Lee SM, Smith ML, Von Stuck S, Bergsneider M, Kelly D, Shalmon E, Martin N, Caron M, Mazziotta J et al (1995) The neurochemical and metabolic cascade following brain injury: moving from animal models to man. J Neurotrauma 12:903–906

    Article  CAS  PubMed  Google Scholar 

  • Jackson EK, Gillespie DG, Dubey RK (2011a) 2′-AMP and 3′-AMP inhibit proliferation of preglomerular vascular smooth muscle cells and glomerular mesangial cells via A2B receptors. J Pharmacol Exp Ther 337:444–450

    Article  CAS  PubMed  Google Scholar 

  • Jackson EK, Ren J, Cheng D, Mi Z (2011b) Extracellular cAMP-adenosine pathways in the mouse kidney. Am J Physiol Renal Physiol 301(3):F565–F573

    Article  CAS  PubMed  Google Scholar 

  • Jackson EK, Ren J, Gillespie DG (2011c) 2′,3′-cAMP, 3′-AMP and 2′-AMP inhibit human aortic and coronary vascular smooth muscle cell proliferation via A2B receptors. Am J Physiol Heart Circ Physiol 301(2):H391–H401

    Article  CAS  PubMed  Google Scholar 

  • Jackson EK, Ren J, Gillespie DG, Dubey RK (2010) Extracellular 2′,3′-cyclic adenosine 5′-monophosphate is a potent inhibitor of preglomerular vascular smooth muscle cell and mesangial cell growth. Hypertension 56:151–158

    Article  CAS  PubMed  Google Scholar 

  • Jackson EK, Ren J, Mi Z (2009) Extracellular 2′,3′-cAMP is a source of adenosine. J Biol Chem 284:33097–33106

    Article  CAS  PubMed  Google Scholar 

  • Kochanek PM, Clark RS, Ruppel RA, Adelson PD, Bell MJ, Whalen MJ, Robertson CL, Satchell MA, Seidberg NA, Marion DW, Jenkins LW (2000) Biochemical, cellular, and molecular mechanisms in the evolution of secondary damage after severe traumatic brain injury in infants and children: lessons learned from the bedside. Pediatr Crit Care Med 1:4–19

    Article  PubMed  Google Scholar 

  • Kochanek PM, Hendrich KS, Jackson EK, Wisniewski SR, Melick JA, Shore PM, Janesko KL, Zacharia L, Ho C (2005) Characterization of the effects of adenosine receptor agonists on cerebral blood flow in uninjured and traumatically injured rat brain using continuous arterial spin-labeled magnetic resonance imaging. J Cereb Blood Flow Metab 25:1596–1612

    Article  CAS  PubMed  Google Scholar 

  • Kochanek PM, Vagni VA, Janesko KL, Washington CB, Crumrine PK, Garman RH, Jenkins LW, Clark RS, Homanics GE, Dixon CE, Schnermann J, Jackson EK (2006) Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury. J Cereb Blood Flow Metab 26:565–575

    Article  CAS  PubMed  Google Scholar 

  • Kusano Y, Echeverry G, Miekisiak G, Kulik TB, Aronhime SN, Chen JF, Winn HR (2010) Role of adenosine A2 receptors in regulation of cerebral blood flow during induced hypotension. J Cereb Blood Flow Metab 30:808–815

    Article  CAS  PubMed  Google Scholar 

  • Laghi Pasini F, Guideri F, Picano E, Parenti G, Petersen C, Varga A, Di Perri T (2000) Increase in plasma adenosine during brain ischemia in man: a study during transient ischemic attacks, and stroke. Brain Res Bull 51:327–330

    Article  CAS  PubMed  Google Scholar 

  • Lalancette-Hébert M, Gowing G, Simard A, Weng YC, Kriz J (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27:2596–2605

    Article  PubMed  Google Scholar 

  • Li W, Dai S, An J, Li P, Chen X, Xiong R, Liu P, Wang H, Zhao Y, Zhu M, Liu X, Zhu P, Chen JF, Zhou Y (2008) Chronic but not acute treatment with caffeine attenuates traumatic brain injury in the mouse cortical impact model. Neuroscience 151:1198–1207

    Article  CAS  PubMed  Google Scholar 

  • Li W, Dai S, An J, Xiong R, Li P, Chen X, Zhao Y, Liu P, Wang H, Zhu P, Chen J, Zhou Y (2009) Genetic inactivation of adenosine A2A receptors attenuates acute traumatic brain injury in the mouse cortical impact model. Exp Neurol 215:69–76

    Article  CAS  PubMed  Google Scholar 

  • Lu G, Zhou QX, Kang S, Li QL, Zhao LC, Chen JD, Sun JF, Cao J, Wang YJ, Chen J, Chen XY, Zhong DF, Chi ZQ, Xu L, Liu JG (2010) Chronic morphine treatment impaired hippocampal long-term potentiation and spatial memory via accumulation of extracellular adenosine acting on adenosine A1 receptors. J Neurosci 30:5058–5070

    Article  CAS  PubMed  Google Scholar 

  • McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP, Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee HS, Kubilus CA, Daneshvar DH, Wulff M, Budson AE (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69:918–929

    Article  CAS  PubMed  Google Scholar 

  • Miller LP, Hsu C (1992) Therapeutic potential for adenosine receptor activation in ischemic brain injury. J Neurotrauma 9 (Suppl 2): S563–S577

    Article  CAS  PubMed  Google Scholar 

  • Ngai AC, Coyne EF, Meno JR, West GA, Winn HR (2001) Receptor subtypes mediating adenosine-induced dilation of cerebral arterioles. Am J Physiol Heart Circ Physiol 280:H2329–H2335

    CAS  PubMed  Google Scholar 

  • RAND invisible wounds of war study. http://www.rand.org/multi/military/veterans.html. Accessed 26 June 2011

  • Ren J, Mi Z, Stewart NA, Jackson EK (2009) Identification and quantification of 2′,3′-cAMP release by the kidney. J Pharmacol Exp Ther 328:855–865

    Article  CAS  PubMed  Google Scholar 

  • Robertson CL, Bell MJ, Kochanek PM, Adelson PD, Ruppel RA, Carcillo JA, Wisniewski SR, Mi Z, Janesko KL, Clark RS, Marion DW, Graham SH, Jackson EK (2001) Increased adenosine in cerebrospinal fluid after severe traumatic brain injury in infants and children: association with severity of injury and excitotoxicity. Crit Care Med 29:2287–2293

    Article  CAS  PubMed  Google Scholar 

  • Saatman KE, Duhaime AC, Bullock R, Maas AI, Valadka A, Manley GT, Workshop Scientific Team and Advisory Panel Members (2008) Classification of traumatic brain injury for targeted therapies. J Neurotrauma 25:719–738

    Article  PubMed  Google Scholar 

  • Sachse KT, Jackson EK, Wisniewski SR, Gillespie DG, Puccio AM, Clark RS, Dixon CE, Kochanek PM (2008) Increases in cerebrospinal fluid caffeine concentration are associated with favorable outcome after severe traumatic brain injury in humans. J Cereb Blood Flow Metab 28:395–401

    Article  CAS  PubMed  Google Scholar 

  • Saharan RS, Nantwi KD (2006) Changes in the biochemical profiles of mid-cervically located adenosine A1 receptors after repeated theophylline administration in adult rats. J Spinal Cord Med 29:520–526

    PubMed  Google Scholar 

  • Sinz EH, Kochanek PM, Heyes MP, Wisniewski SR, Bell MJ, Clark RS, DeKosky ST, Blight AR, Marion DW (1998) Quinolinic acid is increased in CSF and associated with mortality after traumatic brain injury in humans. J Cereb Blood Flow Metab 18:610–615

    Article  CAS  PubMed  Google Scholar 

  • Sprinkle TJ (1989) 2′,3′-cyclic nucleotide 3′-phosphodiesterase, an oligodendrocyte-Schwann cell and myelin-associated enzyme of the nervous system. Crit Rev Neurobiol 4:235–301

    CAS  PubMed  Google Scholar 

  • Synowitz M, Glass R, Färber K, Markovic D, Kronenberg G, Herrmann K, Schnermann J, Nolte C, van Rooijen N, Kiwit J, Kettenmann H (2006) A1 adenosine receptors in microglia control glioblastoma-host interaction. Cancer Res 66:8550–8557

    Article  CAS  PubMed  Google Scholar 

  • Tsutsui S, Schnermann J, Noorbakhsh F, Henry S, Yong VW, Winston BW, Warren K, Power C (2004) A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci 24:1521–1529

    Article  CAS  PubMed  Google Scholar 

  • Varma MR, Dixon CE, Jackson EK, Peters GW, Melick JA, Griffith RP, Vagni VA, Clark RS, Jenkins LW, Kochanek PM (2002) Administration of adenosine receptor agonists or antagonists after controlled cortical impact in mice: effects on function and histopathology. Brain Res 951:191–201

    Article  CAS  PubMed  Google Scholar 

  • Verrier JD, Exo JL, Jackson TC, Ren J, Gillespie DG, Dubey RK, Kochanek PM, Jackson EK (2011) Robust expression of the 2′,3′-cAMP-adenosine pathway, but not the 3′,5′-cAMP-adenosine pathway, in microglia. J Neurochem 118:979–987

    Google Scholar 

  • Vespa PM, Miller C, McArthur D, Eliseo M, Etchepare M, Hirt D, Glenn TC, Martin N, Hovda D (2007) Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis. Crit Care Med 35:2830–2836

    Article  PubMed  Google Scholar 

  • Wagner AK, Miller MA, Scanlon J, Ren D, Kochanek PM, Conley YP (2010) Adenosine A1 receptor gene variants associated with post-traumatic seizures after severe TBI. Epilepsy Res 90:259–272

    Article  CAS  PubMed  Google Scholar 

  • Yu L, Huang Z, Mariani J, Wang Y, Moskowitz M, Chen JF (2004) Selective inactivation or reconstitution of adenosine A2A receptors in bone marrow cells reveals their significant contribution to the development of ischemic brain injury. Nat Med 10:1081–1087

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

We thank the National Institutes of Neurological Disorders and Stroke NS070003 (PMK, EKJ) and the American Heart Association (JDV) for support.

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Authors and Affiliations

  1. Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15260, USA

    Patrick M. Kochanek M.D., M.C.C.M.

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15217, USA

    Jonathan D. Verrier Ph.D. & Edwin K. Jackson Ph.D.

  3. Department of Physical Medicine & Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Amy K. Wagner M.D.

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  1. Patrick M. Kochanek M.D., M.C.C.M.
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  2. Jonathan D. Verrier Ph.D.
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  3. Amy K. Wagner M.D.
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  4. Edwin K. Jackson Ph.D.
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Correspondence to Patrick M. Kochanek M.D., M.C.C.M. .

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Editors and Affiliations

  1. Trinity College, 300 Summit Street, LSC 208, Hartford, 06106, USA

    Susan Masino

  2. Legacy Research Institute, Portland, OR,, 1225 NE 2nd Avenue, Portland, 97232, USA

    Detlev Boison

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Kochanek, P.M., Verrier, J.D., Wagner, A.K., Jackson, E.K. (2013). The Many Roles of Adenosine in Traumatic Brain Injury. In: Masino, S., Boison, D. (eds) Adenosine. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3903-5_15

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