Download PDF
Seminars in Neurosurgery 2003; 14(2): 147-158
DOI: 10.1055/s-2003-42770
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

The Future Impact of Translational Research in Traumatic Brain Injury

Anders Lewén, Pelle Nilsson, Per Enblad
  • Department of Neuroscience, Neurosurgery, Uppsala University Hospital, Uppsala, Sweden
Further Information

Publication History

Publication Date:
02 October 2003 (online)

    Permissions and Reprints

ABSTRACT

The outcome after traumatic brain injury (TBI) has improved during the past three decades. This has mainly been accomplished through improved neurointensive care. Neuroprotective drugs have been disappointing in past clinical trials, and TBI remains one of few common severe illnesses completely without specific pharmacological therapy. One of the biggest challenges for brain trauma research is finding a way to translate preclinical results to the clinical care of the patients. It is hoped that advances in the understanding of basic molecular injury mechanisms and the possible association of genetic profile with outcome after TBI will soon provide better opportunities for drug development. In this review, we summarize some of the pathophysiological pathways targeted for pharmacological intervention in TBI patients. In order to achieve therapeutic success in the future, the advancement in basic science must develop in concert with standardized methods for monitoring and analyzing neurointensive care data between different trauma centers. The European collaboration BrainIT is a first step in this direction. With this type of approach, neuroprotective drugs may also prove to be beneficial in the clinical setting.

KEYWORDS

Apoptosis - necrosis - neuroprotection - neurointensive care - traumatic brain injury

REFERENCES

  • 1 Laurer H L, McIntosh T K. Pharmacologic therapy in traumatic brain injury: update on experimental treatment strategies.  Curr Pharm Des . 2001;  7 1505-1516
    CrossrefPubMedGoogle Scholar
  • 2 McIntosh T K, Juhler M, Wieloch T. Novel pharmacologic strategies in the treatment of experimental traumatic brain injury: 1998.  J Neurotrauma . 1998;  15 731-769
    PubMedGoogle Scholar
  • 3 Narayan R K, Michel M E, Ansell B. et al . Clinical trials in head injury.  J Neurotrauma . 2002;  19 503-557
    CrossrefPubMedGoogle Scholar
  • 4 Kerr J F, Wyllie A H, Currie A R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.  Br J Cancer . 1972;  26 239-257
    CrossrefPubMedGoogle Scholar
  • 5 Horvitz H R. Genetic control of programmed cell death in the nematode Caenorhabditis elegans Cancer Res .  1999;  59 (suppl 7) S1701-S1706
    PubMedGoogle Scholar
  • 6 Choi D, Maulucci-Gedde M, Kriegstein A. Glutamate neurotoxicity in cortical cell culture.  J Neurosci . 1987;  7 357-368
    PubMedGoogle Scholar
  • 7 Faden A I, Demediuk P, Panter S S, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury.  Science . 1989;  244 798-800
    CrossrefPubMedGoogle Scholar
  • 8 Nilsson P, Hillered L, Pontén U. et al . Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats.  J Cereb Blood Flow Metab . 1990;  10 631-637
    PubMedGoogle Scholar
  • 9 Persson L, Hillered L. Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis.  J Neurosurg . 1992;  76 72-80
    PubMedGoogle Scholar
  • 10 McIntosh T K, Vink R, Soares H, Hayes R, Simon R. Effects of the N-methyl-D-aspartate receptor blocker MK-801 on neurologic function after experimental brain injury.  J Neurotrauma . 1989;  6 247-259
    PubMedGoogle Scholar
  • 11 Gill R, Foster A C, Woodruff G N. Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil.  J Neurosci . 1987;  7 3343-3349
    PubMedGoogle Scholar
  • 12 Rao V L, Dogan A, Todd K G, Bowen K K, Dempsey R J. Neuroprotection by memantine, a non-competitive NMDA receptor antagonist after traumatic brain injury in rats.  Brain Res . 2001;  911 96-100
    CrossrefPubMedGoogle Scholar
  • 13 Lewén A, Matz P, Chan P. Free radical pathways in CNS injury.  J Neurotrauma . 2000;  17 871-890
    PubMedGoogle Scholar
  • 14 Bondy S C, LeBel C P. The relationship between excitotoxicity and oxidative stress in the central nervous system.  Free Radic Biol Med . 1993;  14 633-642
    CrossrefPubMedGoogle Scholar
  • 15 Dugan L L, Sensi S L, Canzoniero L M. et al . Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate.  J Neurosci . 1995;  15 6377-6388
    PubMedGoogle Scholar
  • 16 Cheng Y, Sun A Y. Oxidative mechanisms involved in kainate-induced cytotoxicity in cortical neurons.  Neurochem Res . 1994;  19 1557-1564
    CrossrefPubMedGoogle Scholar
  • 17 Lafon Cazal M, Pietri S, Culcasi M, Bockaert J. NMDA-dependent superoxide production and neurotoxicity.  Nature . 1993;  364 535-537
    CrossrefPubMedGoogle Scholar
  • 18 Pellegrini Giampietro E D, Cherici G, Alesiani M, Carla V, Moroni F. Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemia-induced neuronal damage.  J Neurosci . 1990;  10 1035-1041
    PubMedGoogle Scholar
  • 19 Sengpiel B, Preis E, Krieglstein J, Prehn J H. NMDA-induced superoxide production and neurotoxicity in cultured rat hippocampal neurons: role of mitochondria.  Eur J Neurosci . 1998;  10 1903-1910
    CrossrefPubMedGoogle Scholar
  • 20 Kowaltowski A J, Vercesi A E. Mitochondrial damage induced by conditions of oxidative stress.  Free Radic Biol Med . 1999;  26 463-471
    CrossrefPubMedGoogle Scholar
  • 21 Kowaltowski A J, Castilho R F, Vercesi A E. Ca(2+)-induced mitochondrial membrane permeabilization: role of coenzyme Q redox state.  Am J Physiol . 1995;  269 C141-C147
    PubMedGoogle Scholar
  • 22 Weisiger R A, Fridovich I. Superoxide dismutase organelle specificity.  J Biol Chem . 1973;  248 4793-4796
    PubMedGoogle Scholar
  • 23 Fridovich I. Superoxide dismutases.  Annu Rev Biochem . 1975;  44 147-159
    CrossrefPubMedGoogle Scholar
  • 24 Oury T D, Card J P, Klann E. Localization of extracellular superoxide dismutase in adult mouse brain.  Brain Res . 1999;  850 96-103
    CrossrefPubMedGoogle Scholar
  • 25 Gardner A M, Xu F H, Fady C. et al . Apoptotic versus nonapoptotic cytotoxicity induced by hydrogen peroxide.  Free Radic Biol Med . 1997;  22 73-83
    CrossrefPubMedGoogle Scholar
  • 26 Lewén A, Sugawara T, Gasche Y, Fujimura M, Chan P H. Oxidative cellular damage and the reduction of APE/Ref-1 expression after traumatic brain injury.  Neurobiol Dis . 2001;  8 380-390
    CrossrefPubMedGoogle Scholar
  • 27 Lewén A, Fujimura M, Sugawara T, Matz P, Copin J C, Chan P H. Oxidative stress-dependent release of mitochondrial cytochrome c after traumatic brain injury.  J Cereb Blood Flow Metab . 2001;  21 914-920
    PubMedGoogle Scholar
  • 28 Lewén A, Skoglösa Y, Clausen F. et al . Paradoxical increase in neuronal DNA fragmentation after neuroprotective free radical scavenger treatment in experimental traumatic brain injury.  J Cereb Blood Flow Metab . 2001;  21 344-350
    PubMedGoogle Scholar
  • 29 Nicotera P, Leist M, Ferrando-May E. Intracellular ATP, a switch in the decision between apoptosis and necrosis.  Toxicol Lett . 1998;  102-103 139-142
    CrossrefPubMedGoogle Scholar
  • 30 Leist M, Single B, Castoldi A F, Kuhnle S, Nicotera P. Intracellular adenosine trisphosphate (ATP) concentration: a switch in the decision between apoptosis or necrosis.  J Exp Med . 1997;  185 1481-1486
    CrossrefPubMedGoogle Scholar
  • 31 Eliasson M J, Sampei K, Mandir A S. et al . Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia.  Nat Med . 1997;  3 1089-1095
    CrossrefPubMedGoogle Scholar
  • 32 Shi Y. Mechanisms of caspase activation and inhibition during apoptosis.  Mol Cell . 2002;  9 459-470
    CrossrefPubMedGoogle Scholar
  • 33 Reed J C. Apoptosis-regulating proteins as targets for drug discovery.  Trends Mol Med . 2001;  7 314-319
    CrossrefPubMedGoogle Scholar
  • 34 Enari M, Sakahira H, Yooyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD.  Nature . 1998;  391 43-50
    CrossrefPubMedGoogle Scholar
  • 35 Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis.  Cell . 1997;  89 175-184
    CrossrefPubMedGoogle Scholar
  • 36 Liu X, Kim C N, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirements for dATP and cytochrome c.  Cell . 1996;  86 147-157
    CrossrefPubMedGoogle Scholar
  • 37 Hakem R, Hakem A, Duncan G S. et al . Differential requirement for caspase 9 in apoptotic pathways in vivo.  Cell . 1998;  94 339-352
    CrossrefPubMedGoogle Scholar
  • 38 Zou H, Henzel W J, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C elegans CED-4, participates in cytochrome c-dependent activation of caspase-3.   Cell . 1997;  90 405-413
    CrossrefPubMedGoogle Scholar
  • 39 Kuida K, Haydar T F, Kuan C Y. et al . Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9.  Cell . 1998;  94 325-337
    CrossrefPubMedGoogle Scholar
  • 40 Slee E A, Harte M T, Kluck R M. et al . Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner.  J Cell Biol . 1999;  144 281-292
    CrossrefPubMedGoogle Scholar
  • 41 Fujimura M, Morita-Fujimura Y, Murakami K, Kawase M, Chan P H. Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats.  J Cereb Blood Flow Metab . 1998;  18 1239-1247
    PubMedGoogle Scholar
  • 42 Sugawara T, Fujimura M, Morita-Fujimura Y, Kawase M, Chan P H. Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global ischemia.  J Neurosci . 1999;  19 RC39(1-6)
    PubMedGoogle Scholar
  • 43 Buki A, Okonkwo D O, Wang K K, Povlishock J T. Cytochrome c release and caspase activation in traumatic axonal injury.  J Neurosci . 2000;  20 2825-2834
    PubMedGoogle Scholar
  • 44 Fujimura M, Morito-Fujimora Y, Noshita N, Sugawara T, Kawase M, Chan P H. The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrome c in ischemic brain after transient focal cerebral ischemia in mice.  J Neurosci . 2000;  20 2817-2824
    PubMedGoogle Scholar
  • 45 Cai J, Jones D P. Superoxide in apoptosis. Mitochondrial generation triggered by cytochrome c loss.  J Biol Chem . 1998;  273 11401-11404
    CrossrefPubMedGoogle Scholar
  • 46 Jurgensmeier J M, Xie Z, Deveraux Q, Ellerby L, Bredersen D, Reed J C. Bax directly induces release of cytochrome c from isolated mitochondria.  Proc Natl Acad Sci U S A . 1998;  95 4997-5002
    CrossrefPubMedGoogle Scholar
  • 47 Narita M, Shimizu S, Ito T. et al . Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria.  Proc Natl Acad Sci U S A . 1998;  95 14681-14686
    CrossrefPubMedGoogle Scholar
  • 48 Cassarino D S, Parks J K, Parker Jr D W, Bennett Jr P J. The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism.  Biochim Biophys Acta . 1999;  1453 49-62
    PubMedGoogle Scholar
  • 49 Ghafourifar P, Schenk U, Klein S D, Richter C. Mitochondrial nitric-oxide synthase stimulation causes cytochrome c release from isolated mitochondria: evidence for intramitochondrial peroxynitrite formation.  J Biol Chem . 1999;  274 31185-31188
    CrossrefPubMedGoogle Scholar
  • 50 Deveraux Q L, Reed J C. IAP family proteins-suppressors of apoptosis.  Genes Dev . 1999;  13 239-252
    CrossrefPubMedGoogle Scholar
  • 51 Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death.  Mol Cell . 2001;  8 613-621
    CrossrefPubMedGoogle Scholar
  • 52 Cande C, Cecconi F, Dessen P, Kroemer G. Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death?.  J Cell Sci . 2002;  115(Pt 24) 4727-4734
    CrossrefPubMedGoogle Scholar
  • 53 Clark R S, Kochanek P M, Watkins S C. et al . Caspase-3 mediated neuronal death after traumatic brain injury in rats.  J Neurochem . 2000;  74 740-753
    CrossrefPubMedGoogle Scholar
  • 54 Keane R W, Kraydieh S, Lotocki G, Alonso O F, Aldana P, Dietrich W D. Apoptotic and antiapoptotic mechanisms after traumatic brain injury.  J Cereb Blood Flow Metab . 2001;  21 1189-1198
    PubMedGoogle Scholar
  • 55 Fink K B, Andrews L J, Butler W E. et al . Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade.  Neuroscience . 1999;  94 1213-1218
    CrossrefPubMedGoogle Scholar
  • 56 Beer R, Franz G, Schopf M. et al . Expression of Fas and Fas ligand after experimental traumatic brain injury in the rat.  J Cereb Blood Flow Metab . 2000;  20 669-677
    PubMedGoogle Scholar
  • 57 Knoblach S M, Nikolaeva M, Huang X. et al . Multiple caspases are activated after traumatic brain injury: evidence for involvement in functional outcome.  J Neurotrauma . 2002;  19 1155-1170
    CrossrefPubMedGoogle Scholar
  • 58 Zhang X, Chen J, Graham S H. et al . Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite.  J Neurochem . 2002;  82 181-191
    CrossrefPubMedGoogle Scholar
  • 59 Beer R, Franz G, Krajewski S. et al . Temporal and spatial profile of caspase 8 expression and proteolysis after experimental traumatic brain injury.  J Neurochem . 2001;  78 862-873
    CrossrefPubMedGoogle Scholar
  • 60 Franz G, Beer R, Intemann D. et al . Temporal and spatial profile of Bid cleavage after experimental traumatic brain injury.  J Cereb Blood Flow Metab . 2002;  22 951-958
    PubMedGoogle Scholar
  • 61 Yakovlev A G, Knoblach S M, Fan L, Fox G B, Goodnight R, Faden A I. Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury.  J Neurosci . 1997;  17 7415-7424
    PubMedGoogle Scholar
  • 62 Skoglösa Y, Lewén A, Takei N, Hillered L, Lindholm D. Regulation of pituitary adenylate cyclase activating polypeptide and its receptor type 1 after traumatic brain injury: comparison with brain derived neurotrophic factor and the induction of neuronal cell death.  Neuroscience . 1999;  90 235-247
    CrossrefPubMedGoogle Scholar
  • 63 Noshita N, Sugawara T, Hayashi T, Lewen A, Omar G, Chan P H. Copper/zinc superoxide dismutase attenuates neuronal cell death by preventing extracellular signal-regulated kinase activation after transient focal cerebral ischemia in mice.  J Neurosci . 2002;  22 7923-7930
    PubMedGoogle Scholar
  • 64 Segal R A, Greenberg M E. Intracellular signaling pathways activated by neurotrophic factors.  Annu Rev Neurosci . 1996;  19 463-489
    PubMedGoogle Scholar
  • 65 Chang L, Karin M. Mammalian MAP kinase signalling cascades.  Nature . 2001;  410 37-40
    CrossrefPubMedGoogle Scholar
  • 66 Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new concepts of activation.  Biol Cell . 2001;  93 53-62
    CrossrefPubMedGoogle Scholar
  • 67 Alessandrini A, Namura S, Moskowitz M A, Bonventre J V. MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia.  Proc Natl Acad Sci U S A . 1999;  96 12866-12869
    CrossrefPubMedGoogle Scholar
  • 68 Mori T, Wang X, Jung J C. et al . Mitogen-activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects.  J Cereb Blood Flow Metab . 2002;  22 444-452
    PubMedGoogle Scholar
  • 69 Wang X, Mori T, Jung J C, Fini M E, Lo E H. Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase.  J Neurotrauma . 2002;  19 615-625
    CrossrefPubMedGoogle Scholar
  • 70 Namura S, Iihara K, Takami S. et al . Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia.  Proc Natl Acad Sci U S A . 2001;  98 11569-11574
    CrossrefPubMedGoogle Scholar
  • 71 Yuan J, Yankner B A. Apoptosis in the nervous system.  Nature . 2000;  407 802-809
    CrossrefPubMedGoogle Scholar
  • 72 Noshita N, Lewen A, Sugawara T, Chan P H. Evidence of phosphorylation of Akt and neuronal survival after transient focal cerebral ischemia in mice.  J Cereb Blood Flow Metab . 2001;  21 1442-1450
    PubMedGoogle Scholar
  • 73 Noshita N, Lewen A, Sugawara T, Chan P H. Akt phosphorylation and neuronal survival after traumatic brain injury in mice.  Neurobiol Dis . 2002;  9 294-304
    CrossrefPubMedGoogle Scholar
  • 74 Gill R, Soriano M, Blomgren K. et al . Role of caspase-3 activation in cerebral ischemia-induced neurodegeneration in adult and neonatal brain.  J Cereb Blood Flow Metab . 2002;  22 420-430
    PubMedGoogle Scholar
  • 75 Loetscher H, Niederhauser O, Kemp J, Gill R. Is caspase-3 inhibition a valid therapeutic strategy in cerebral ischemia?.  Drug Discov Today . 2001;  6 671-680
    CrossrefPubMedGoogle Scholar
  • 76 Chen J, Nagayama T, Jin K. et al . Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia.  J Neurosci . 1998;  18 4914-4928
    PubMedGoogle Scholar
  • 77 Loddick S A, MacKenzie A, Rothwell N J. An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat.  Neuroreport . 1996;  7 1465-1468
    PubMedGoogle Scholar
  • 78 Endres M, Namura S, Shimizu-Sasamata M. et al . Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family.  J Cereb Blood Flow Metab . 1998;  18 238-247
    PubMedGoogle Scholar
  • 79 Endres M, Wang Z Q, Namura S, Waeber C, Moskowitz M A. Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase.  J Cereb Blood Flow Metab . 1997;  17 1143-1151
    PubMedGoogle Scholar
  • 80 Abdelkarim G E, Gertz K, Harms C. et al . Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke.  Int J Mol Med . 2001;  7 255-260
    PubMedGoogle Scholar
  • 81 LaPlaca M C, Zhang J, Raghupathi R. et al . Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats.  J Neurotrauma . 2001;  18 369-376
    CrossrefPubMedGoogle Scholar
  • 82 Muizelaar J P, Marmarou A, Young H F. et al . Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a phase II trial.  J Neurosurg . 1993;  78 375-382
    PubMedGoogle Scholar
  • 83 Young B, Runge J W, Waxman K S. et al . Effects of pegorgotein on neurologic outcome of patients with severe head injury. A multicenter, randomized controlled trial.  JAMA . 1996;  276 538-543
    CrossrefPubMedGoogle Scholar
  • 84 Sydserff S G, Borelli A R, Green A R, Cross A J. Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window.  Br J Pharmacol . 2002;  135 103-112
    PubMedGoogle Scholar
  • 85 Kuroda S, Tsuchidate R, Smith M L, Maples K R, Siesjo B K. Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat.  J Cereb Blood Flow Metab . 1999;  19 778-787
    PubMedGoogle Scholar
  • 86 Zhao Z, Cheng M, Maples K R, Ma J Y, Buchan A M. NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat.  Brain Res . 2001;  909 46-50
    CrossrefPubMedGoogle Scholar
  • 87 Marshall J W, Duffin K J, Green A R, Ridley R M. NXY-059, a free radical-trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species.  Stroke . 2001;  32 190-198
    PubMedGoogle Scholar
  • 88 Marklund N, Clausen F, McIntosh T K, Hillered L. Free radical scavenger posttreatment improves functional and morphological outcome after fluid percussion injury in the rat.  J Neurotrauma . 2001;  18 821-832
    CrossrefPubMedGoogle Scholar
  • 89 Zhao Q, Pahlmark K, Smith M L, Siesjo B K. Delayed treatment with the spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats.  Acta Physiol Scand . 1994;  152 349-350
    PubMedGoogle Scholar
  • 90 Naritomi H. Neuroprotective therapy for the treatment of acute ischemic stroke.  Rinsho Shinkeigaku . 2001;  41 1060-1063
    PubMedGoogle Scholar
  • 91 Friberg H, Wieloch T. Mitochondrial permeability transition in acute neurodegeneration.  Biochimie . 2002;  84 241-250
    CrossrefPubMedGoogle Scholar
  • 92 Friberg H, Connern C, Halestrap A P, Wieloch T. Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability.  J Neurochem . 1999;  72 2488-2497
    CrossrefPubMedGoogle Scholar
  • 93 Okonkwo D O, Buki A, Siman R, Povlishock J T. Cyclosporin A limits calcium-induced axonal damage following traumatic brain injury.  Neuroreport . 1999;  10 353-358
    CrossrefPubMedGoogle Scholar
  • 94 Okonkwo D O, Povlishock J T. An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury.  J Cereb Blood Flow Metab . 1999;  19 443-451
    PubMedGoogle Scholar
  • 95 Scheff S W, Sullivan P G. Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents.  J Neurotrauma . 1999;  16 783-792
    CrossrefPubMedGoogle Scholar
  • 96 Riess P, Bareyre F M, Saatman K E. et al . Effects of chronic, post-injury cyclosporin A administration on motor and sensorimotor function following severe, experimental traumatic brain injury.  Restor Neurol Neurosci . 2001;  18 1-8
    PubMedGoogle Scholar
  • 97 Sullivan P G, Rabchevsky A G, Hicks R R, Gibson T R, Fletcher-Turner A, Scheff S W. Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats.  Neuroscience . 2000;  101 289-295
    CrossrefPubMedGoogle Scholar
  • 98 Sadamoto Y, Igase K, Sakanaka M. et al . Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery.  Biochem Biophys Res Commun . 1998;  253 26-32
    CrossrefPubMedGoogle Scholar
  • 99 Bernaudin M, Marti H H, Roussel S. et al . A potential role for erythropoietin in focal permanent cerebral ischemia in mice.  J Cereb Blood Flow Metab . 1999;  19 643-651
    PubMedGoogle Scholar
  • 100 Buemi M, Grasso G, Corica F. et al . In vivo evidence that erythropoietin has a neuroprotective effect during subarachnoid hemorrhage.  Eur J Pharmacol . 2000;  392 31-34
    CrossrefPubMedGoogle Scholar
  • 101 Siren A L, Fratelli M, Brines M. et al . Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress.  Proc Natl Acad Sci U S A . 2001;  98 4044-4049
    CrossrefPubMedGoogle Scholar
  • 102 Brines M L, Ghezzi P, Keenan S. et al . Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury.  Proc Natl Acad Sci U S A . 2000;  97 10526-10531
    CrossrefPubMedGoogle Scholar
  • 103 Gorio A, Gokmen N, Erbayraktar S. et al . Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma.  Proc Natl Acad Sci U S A . 2002;  99 9450-9455
    CrossrefPubMedGoogle Scholar
  • 104 Digicaylioglu M, Lipton S A. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades.  Nature . 2001;  412 641-647
    CrossrefPubMedGoogle Scholar
  • 105 Wen T C, Sadamoto Y, Tanaka J. et al . Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression.  J Neurosci Res . 2002;  67 795-803
    CrossrefPubMedGoogle Scholar
  • 106 Ehrenreich H, Hasselblatt M, Dembowski C. et al . Erythropoietin therapy for acute stroke is both safe and beneficial.  Mol Med . 2002;  8 495-505
    PubMedGoogle Scholar
  • 107 Reilly P L, Graham D I, Adams J H, Jennett B. Patients with head injury who talk and die.  Lancet . 1975;  2 375-377
    PubMedGoogle Scholar
  • 108 Rose J, Valtonen S, Jennett B. Avoidable factors contributing to death after head injury.  Br Med J . 1977;  2 615-618
    PubMedGoogle Scholar
  • 109 Graham D I, Adams J H, Doyle D. Ischaemic brain damage in fatal non-missile head injuries.  J Neurol Sci . 1978;  39 213-234
    CrossrefPubMedGoogle Scholar
  • 110 Graham D I, Ford I, Adams J H. et al . Ischaemic brain damage is still common in fatal non-missile head injury.  J Neurol Neurosurg Psychiatry . 1989;  52 346-350
    CrossrefPubMedGoogle Scholar
  • 111 Elf K, Nilsson P, Enblad P. Outcome after traumatic brain injury improved by an organized secondary insult program and standardized neurointensive care.  Crit Care Med . 2002;  30 2129-2134
    PubMedGoogle Scholar
  • 112 Jones P A, Andrews P J, Midgley S. et al . Measuring the burden of secondary insults in head-injured patients during intensive care.  J Neurosurg Anesthesiol . 1994;  6 4-14
    PubMedGoogle Scholar
  • 113 Signorini D F, Andrews P J, Jones P A, Wardlaw J M, Miller J D. Adding insult to injury: the prognostic value of early secondary insults for survival after traumatic brain injury.  J Neurol Neurosurg Psychiatry . 1999;  66 26-31
    PubMedGoogle Scholar
  • 114 Chambers I R, Treadwell L, Mendelow A D. The cause and incidence of secondary insults in severely head-injured adults and children.  Br J Neurosurg . 2000;  14 424-431
    CrossrefPubMedGoogle Scholar