Pharmacological Neuroprotection in Severe Traumatic Brain Injury

  • Niklas Marklund


The basic pathophysiology of TBI consists of an initial, primary injury including rapid deformation of brain tissue with destruction of brain parenchyma and blood vessels and acute loss of neuronal and glial cells. A key concept in the management of TBI is that not all cell death occurs at the time of primary injury; instead, a cascade of molecular and neurochemical secondary events occur during the initial hours and days with a complex temporal profile. Ultimately, this secondary injury cascade markedly exacerbates the primary injury. Pharmacological attenuation of this secondary injury cascade with the aim of neuroprotection using, e.g. reactive oxygen species scavengers, glutamate receptor modulator, endocannabinoids, hypothermia or magnesium sulphate, has received much attention over several decades in numerous preclinical publications. To date, more than 20 phase III clinical trials have been conducted, and several trials are ongoing (Maas et al. 2010, Unfortunately, these trials all failed to demonstrate clinical efficacy, and there is no neuroprotective compound currently available for TBI patients. So is neuroprotection for TBI a dead concept not to be pursued clinically or experimentally? Arguably, no. There are likely numerous reasons for the failure of neuroprotective compounds used in clinical trials for TBI, including heterogeneous patient samples and general neurointensive care management. With few exceptions, the pharmacological and hypothermia TBI trials conducted to date have been rather small and have been frequently criticised in terms of study design, route of administration, time window and patient selection (e.g. Marklund and Hillered 2011; Maas et al. 2010). It should be emphasised that TBI is not one disease; instead, all the different subtypes of TBI may require markedly different treatments. Lack of early mechanistic or established surrogate endpoints and the insensitivity of the rather global outcome measures are specific problems in clinical TBI research. It is also obvious that numerous mistakes have been made in the past when attempting to translate preclinical information into the complex human situation. Such shortcomings of preclinical studies include the use of rodent TBI models reaching at most a moderate level of injury, and additionally, only rarely are pharmacological compounds administered beyond the first post-injury hours. Important lessons for future trials include improved patient classification, knowledge of brain penetration and action of the evaluated compound and more carefully defined and detailed outcome measures. Likely, future pharmacological management of TBI patients needs to combine neuroprotective drugs with compounds enhancing regeneration. Until such pharmacological treatment options are developed, neuroprotection for patients suffering from severe TBI is best provided by improved neurointensive care management with the avoidance, detection and treatment of avoidable factors such as seizures, fever, hypotension, hypoxemia, hyper- and hypoglycaemia, low CPP and high ICP. The present chapter reviews important aspects of pharmacological neuroprotection in severe traumatic brain injury. Hypothermia-induced neuroprotection is discussed in another chapter of this book ( Chap. 61).


Severe Traumatic Brain Injury Magnesium Sulphate Primary Injury Traumatic Axonal Injury Pharmacological Treatment Option 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Bramlett HM, Dietrich WD (2002) Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathol 103(6):607–614PubMedCrossRefGoogle Scholar
  2. Buki A, Povlishock JT (2006) All roads lead to disconnection? – Traumatic axonal injury revisited. Acta Neurochir (Wien) 148:181–193; discussion 193–194CrossRefGoogle Scholar
  3. Chen SF, Richards HK, Smielewski P, Johnström P, Salvador R, Pickard JD, Harris NG (2004) Relationship between flow-metabolism uncoupling and evolving axonal injury after experimental traumatic brain injury. J Cereb Blood Flow Metab 24:1025–1036PubMedCrossRefGoogle Scholar
  4. Clausen F, Hånell A, Björk M, Hillered L, Mir AK, Gram H, Marklund N (2009) Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice. Eur J Neurosci 30:385–396PubMedCrossRefGoogle Scholar
  5. Faden AI, Demediuk P, Panter SS, Vink R (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800PubMedCrossRefGoogle Scholar
  6. Ferrand-Drake M, Zhu C, Gidö G, Hansen AJ, Karlsson JO, Bahr BA, Zamzami N, Kroemer G, Chan PH, Wieloch T, Blomgren K (2003) Cyclosporin A prevents calpain activation despite increased intracellular calcium concentrations, as well as translocation of apoptosis-inducing factor, cytochrome c and caspase-3 activation in neurons exposed to transient hypoglycemia. J Neurochem 85:1431–1442PubMedCrossRefGoogle Scholar
  7. Gonzenbach RR, Schwab ME (2008) Disinhibition of neurite growth to repair the injured adult CNS: focusing on Nogo. Cell Mol Life Sci 65:161–176PubMedCrossRefGoogle Scholar
  8. Graham DI, Adams JH, Murray LS, Jennett B (2005) Neuropathology of the vegetative state after head injury. Neuropsychol Rehabil 15:198–213PubMedCrossRefGoogle Scholar
  9. Huh JW, Raghupathi R (2009) New concepts in treatment of pediatric brain injury. Anesthesiol Clin 27(2):213–240PubMedCrossRefGoogle Scholar
  10. Israelsson C, Bengtsson H, Kylberg A, Kullander K, Lewen A, Hillered L, Ebendal T (2008) Distinct cellular patterns of upregulated chemokine expression supporting a prominent inflammatory role in traumatic brain injury. J Neurotrauma 25:959–974PubMedCrossRefGoogle Scholar
  11. Lenzlinger PM, Morganti-Kossmann MC, Laurer HL, McIntosh TK (2001) The duality of the inflammatory response to traumatic brain injury. Mol Neurobiol 24:169–181PubMedCrossRefGoogle Scholar
  12. Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–890PubMedCrossRefGoogle Scholar
  13. Lifshitz J, Sullivan PG, Hovda DA, Wieloch T, McIntosh TK (2004) Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondrion 4:705–713PubMedCrossRefGoogle Scholar
  14. Maas AI, Murray G, Henney H 3rd, Kassem N, Legrand V, Mangelus M, Muizelaar JP, Stocchetti N, Knoller N, Pharmos TBI Investigators (2006) Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol 5:38–45PubMedCrossRefGoogle Scholar
  15. Maas AI, Roozenbeek B, Manley GT (2010) Clinical trials in traumatic brain injury: past experience and current developments. Neurotherapeutics 7:115–126PubMedCrossRefGoogle Scholar
  16. Marklund N, Hillered L (2011) Animal modeling of traumatic brain injury in pre-clinical drug development – where do we go from here? Br J Pharmacol 164(4):1207–1229PubMedCrossRefGoogle Scholar
  17. Marklund N, Lewander T, Clausen F, Hillered L (2001) Effects of the nitrone radical scavengers PBN and S-PBN on in vivo trapping of reactive oxygen species after traumatic brain injury in rats. J Cereb Blood Flow Metab 21:1259–1267PubMedCrossRefGoogle Scholar
  18. Mazzeo AT, Beat A, Singh A, Bullock MR (2009) The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI. Exp Neurol 218:363–370PubMedCrossRefGoogle Scholar
  19. Nilsson P, Hillered L, Ponten U, Ungerstedt U (1990) Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J Cereb Blood Flow Metab 10:631–637PubMedCrossRefGoogle Scholar
  20. Nilsson P, Hillered L, Olsson Y, Sheardown MJ, Hansen AJ (1993) Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats. J Cereb Blood Flow Metab 13:183–192PubMedCrossRefGoogle Scholar
  21. Roberts I, Yates D, Sandercock P, Farrell B, Wasserberg J, Lomas G, Cottingham R, Svoboda P, Brayley N, Mazairac G, Laloë V, Muñoz-Sánchez A, Arango M, Hartzenberg B, Khamis H, Yutthakasemsunt S, Komolafe E, Olldashi F, Yadav Y, Murillo-Cabezas F, Shakur H, Edwards P, CRASH trial collaborators (2004) Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet 364:1321–1328PubMedCrossRefGoogle Scholar
  22. Saatman KE, Feeko KJ, Pape RL, Raghupathi R (2006) Differential behavioral and histopathological responses to graded cortical impact injury in mice. J Neurotrauma 23(8):1241–1253PubMedCrossRefGoogle Scholar
  23. Sandvig A, Berry M, Barrett LB, Butt A, Logan A (2004) Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration. Glia 46:225–251PubMedCrossRefGoogle Scholar
  24. Schmidt OI, Heyde CE, Ertel W, Stahel PF (2005) Closed head injury – an inflammatory disease? Brain Res Brain Res Rev 48:388–399PubMedCrossRefGoogle Scholar
  25. Shiozaki T, Akai H, Taneda M, Hayakata T, Aoki M, Oda J, Tanaka H, Hiraide A, Shimazu T, Sugimoto H (2001) Delayed hemispheric neuronal loss in severely head-injured patients. J Neurotrauma 18:665–674PubMedCrossRefGoogle Scholar
  26. Singleton RH, Stone JR, Okonkwo DO, Pellicane AJ, Povlishock JT (2001) The immunophilin ligand FK506 attenuates axonal injury in an impact-acceleration model of traumatic brain injury. J Neurotrauma 18:607–614PubMedCrossRefGoogle Scholar
  27. Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, Lucas T, Newell DW, Mansfield PN, Machamer JE, Barber J, Dikmen SS (2007) Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol 6:29–38PubMedCrossRefGoogle Scholar
  28. Vergouwen MD, Vermeulen M, Roos YB (2006) Effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage: a systematic review. Lancet Neurol 5:1029–1032PubMedCrossRefGoogle Scholar
  29. Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP (2000) Impaired cerebral mitochondrial function after traumatic brain injury in humans. J Neurosurg 93:815–820PubMedCrossRefGoogle Scholar
  30. Walmsley AR, Mir AK (2007) Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury. Curr Pharm Des 13:2470–2484PubMedCrossRefGoogle Scholar
  31. Whitney NP, Eidem TM, Peng H, Huang Y, Zheng JC (2009) Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem 108:1343–1359PubMedCrossRefGoogle Scholar
  32. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG (2007) ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 49:391–402, 402:391–392PubMedCrossRefGoogle Scholar
  33. Xiao G, Wei J, Yan W et al (2008) Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 12:R61PubMedCrossRefGoogle Scholar
  34. Ziebell JM, Morganti-Kossmann MC (2010) Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 7:22–30PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of NeurosurgeryUppsala University HospitalUppsalaSweden

Personalised recommendations