Emerging treatments for traumatic brain injury

Expert Opinion on Emerging Drugs

Volumn 14, Issue 1, 2009, Pages 67-84

  Xiong, Ye ^a   Mahmood, Asim ^a   Chopp, Michael ^a,b  

^a HENRY FORD HEALTH SYSTEM   (United States)

^b OAKLAND UNIVERSITY   (United States)

Author keywords

Clinical trials; Neurogenesis; Neuroprotection; Neurorestoration; Pharmacological; Traumatic brain injury

Indexed keywords

AMANTADINE; AMINO ACID RECEPTOR BLOCKING AGENT; AMPHETAMINE; ANATIBANT; ATORVASTATIN; BARBITURIC ACID DERIVATIVE; CALCIUM CHANNEL BLOCKING AGENT; CORTICOSTEROID; DEXAMETHASONE; DEXANABINOL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LACTATE SODIUM; MAGNESIUM; MANNITOL; METHYLPHENIDATE; METHYLPREDNISOLONE; NEUROPROTECTIVE AGENT; NIMODIPINE; NOVEL ERYTHROPOIESIS STIMULATING PROTEIN; OMEGA CONOTOXIN MVIIA; PEGORGOTEIN; PENTOBARBITAL; PLACEBO; PROGESTERONE; RECOMBINANT BLOOD CLOTTING FACTOR 7A; RECOMBINANT ERYTHROPOIETIN; ROSUVASTATIN; SCAVENGER; SNX 185; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ABSENCE OF SIDE EFFECTS; ADRENAL DISEASE; ANGIOGENESIS; BEHAVIOR; BRAIN DAMAGE; BRAIN EDEMA; BRAIN HEMATOMA; BRAIN VASOSPASM; CLINICAL STUDY; CLINICAL TRIAL; COGNITION; COGNITIVE DEFECT; CONTINUOUS INFUSION; CRANIOTOMY; DECOMPRESSION SURGERY; DEEP VEIN THROMBOSIS; DISABILITY; DRUG EFFICACY; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG SAFETY; EXERCISE; FUNCTIONAL STATUS; HUMAN; HYPOTENSION; INDUCED HYPOTHERMIA; INTRACRANIAL HYPERTENSION; INTRACRANIAL PRESSURE; LOW DRUG DOSE; MEMORY; MORBIDITY; MORTALITY; NERVOUS SYSTEM DEVELOPMENT; NEUROLOGIC DISEASE; NEUROPROTECTION; NONHUMAN; PATHOPHYSIOLOGY; REVIEW; RISK REDUCTION; SINGLE DRUG DOSE; STROMA CELL; SUBARACHNOID HEMORRHAGE; SYNAPTOGENESIS; TRAUMATIC BRAIN INJURY; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; VEGETATIVE STAGE; ANIMAL; BRAIN INJURY; DRUG DELIVERY SYSTEM; DRUG SCREENING; KINESIOTHERAPY; METHODOLOGY; STEM CELL TRANSPLANTATION;

ANIMALS; BRAIN INJURIES; CLINICAL TRIALS AS TOPIC; DRUG DELIVERY SYSTEMS; DRUG EVALUATION, PRECLINICAL; EXERCISE THERAPY; HUMANS; NEUROPROTECTIVE AGENTS; STEM CELL TRANSPLANTATION; TREATMENT OUTCOME;

EID: 65649110094     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728210902769601     Document Type: Review

References (190)

1. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil 2006;21:375-378 (Pubitemid 44413110)
2. Tagliaferri F, Compagnone C, Korsic M, et al. A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien) 2006;148:255-68 • A detailed account of TBI epidemiology in Europe.
3. Schofield PW, Logroscino G, Andrews HF, et al. An association between head circumference and Alzheimer's disease in a population-based study of aging and dementia. Neurology 1997;49:30-37 (Pubitemid 27328678)
4. Rehabilitation of persons with traumatic brain injury. NIH consensus statement 1998;16:1-41
5. Consensus conference. Rehabilitation of persons with traumatic brain injury. NIH consensus development panel on rehabilitation of persons with traumatic brain injury. JAMA 1999;282:974-983
6. Narayan RK, Michel ME, Ansell B, et al. Clinical trials in head injury. J Neurotrauma 2002;19:503-57 •• An important review article describing the TBI clinical trials.
7. Royo NC, Shimizu S, Schouten JW, et al. Pharmacology of traumatic brain injury. Curr Opin Pharmacol 2003;3:27-32 (Pubitemid 36131323)
8. Beauchamp K, Mutlak H, Smith WR, et al. Pharmacology of traumatic brain injury: where is the 'golden bullet'? Mol Med 2008;14:731-40 •• An important review article describing the published prospective clinical trials on pharmacological treatment modalities for TBI patients and outlining future promising therapeutic avenues in the field.
9. Hovda DA, Fu K, Badie H, et al. Administration of an omega-conopeptide one hour following traumatic brain injury reduces 45calcium accumulation. Acta Neurochir Suppl (Wien) 1994;60:521-523
10. Xiong Y, Gu Q, Peterson PL, et al. Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 1997;14:23-34 (Pubitemid 27100278)
11. Kontos HA, Povlishock JT. Oxygen radicals in brain injury. Cent Nerv Syst Trauma 1986;3:257-263 (Pubitemid 17055007)
12. Hall ED. Lipid antioxidants in acute central nervous system injury. Ann Emerg Med 1993;22:1022-1027
13. Smith SL, Andrus PK, Zhang JR, Hall ED. Direct measurement of hydroxyl radicals, lipid peroxidation, and blood-brain barrier disruption following unilateral cortical impact head injury in the rat. J Neurotrauma 1994;11:393-404 (Pubitemid 24304691)
14. Singh IN, Sullivan PG, Deng Y, et al. Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy. J Cereb Blood Flow Metab 2006;26:1407-1418 (Pubitemid 44629888)
15. Mbye LH, Singh IN, Sullivan PG, et al. Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a nonimmunosuppressive cyclosporin A analog. Exp Neurol 2008;209:243-253
16. Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth 2007;99:4-9 (Pubitemid 47072553)
17. Schouten JW. Neuroprotection in traumatic brain injury: a complex struggle against the biology of nature. Curr Opin Crit Care 2007;13:134-142 (Pubitemid 46328326)
18. Bullock MR, Povlishock JT. Guidelines for the management of severe traumatic brain injury: editor's commentary. J Neurotrauma 2007;24 (Suppl 1):2 p preceding S1
19. Doppenberg EM, Choi SC, Bullock R. Clinical trials in traumatic brain injury: lessons for the future. J Neurosurg Anesthesiol 2004;16:87-94 • This review article provides lessons for future TBI clinical trials.
20. Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 2007;(1):CD001049 (Pubitemid 351820497)
21. Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: a systematic review and meta-analysis. J Neurotrauma 2008;25:62-71 (Pubitemid 351161073)
22. Marmarou A. Increased intracranial pressure in head injury and influence of blood volume. J Neurotrauma 1992;9 (Suppl 1):S327-32
23. Sahuquillo J, Arikan F. Decompressive craniectomy for the treatment of refractory high intracranial pressure in traumatic brain injury. Cochrane Database Syst Rev 2006;(1):CD003983
24. ClinicalTrials.gov. Available from: http://www.clinicaltrials.gov/
25. Wang KK, Larner SF, Robinson G, Hayes RL. Neuroprotection targets after traumatic brain injury. Curr Opin Neurol 2006;19:514-9 • This article describes targets for TBI treatment.
26. Lu D, Mahmood A, Qu C, et al. Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma 2005;22:1011-1017 (Pubitemid 41362067)
27. Xiong Y, Lu D, Qu C, et al. Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. J Neurosurg 2008;109:510-521
28. Hastings NB, Gould E. Rapid extension of axons into the CA3 region by adult-generated granule cells. J Comp Neurol 1999;413:146-154 (Pubitemid 29409757)
29. Emery DL, Fulp CT, Saatman KE, et al. Newly born granule cells in the dentate gyrus rapidly extend axons into the hippocampal CA3 region following experimental brain injury. J Neurotrauma 2005;22:978-988 (Pubitemid 41362064)
30. Xiong Y, Mahmood A, Lu D, et al. Role of gender in outcome after traumatic brain injury and therapeutic effect of erythropoietin in mice. Brain Res 2007;1185:301-312 (Pubitemid 350166319)
31. Kleindienst A, McGinn MJ, Harvey HB, et al. Enhanced hippocampal neurogenesis by intraventricular S100B infusion is associated with improved cognitive recovery after traumatic brain injury. J Neurotrauma 2005;22:645-655 (Pubitemid 40840380)
32. Mahmood A, Lu D, Chopp M. Marrow stromal cell transplantation after traumatic brain injury promotes cellular proliferation within the brain. Neurosurgery 2004;55:1185-1193 (Pubitemid 39525223)
33. Gaulke LJ, Horner PJ, Fink AJ, et al. Environmental enrichment increases progenitor cell survival in the dentate gyrus following lateral fluid percussion injury. Brain Res Mol Brain Res 2005;141:138-150 (Pubitemid 41608694)
34. Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol 2002;1:92-100 (Pubitemid 37163494)
35. Wieloch T, Nikolich K. Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol 2006;16:258-264 (Pubitemid 43949227)
36. Maeda T, Lee SM, Hovda DA. Restoration of cerebral vasoreactivity by an L-type calcium channel blocker following fluid percussion brain injury. J Neurotrauma 2005;22:763-771 (Pubitemid 40995308)
37. Kostron H, Twerdy K, Stampfl G, et al. Treatment of the traumatic cerebral vasospasm with the calcium channel blocker nimodipine: a preliminary report. Neurol Res 1984;6:29-32 (Pubitemid 14031304)
38. Bailey I, Bell A, Gray J, et al. A trial of the effect of nimodipine on outcome after head injury. Acta Neurochir (Wien) 1991;110:97-105
39. European Study Group on Nimodipine in Severe Head Injury. A multicenter trial of the efficacy of nimodipine on outcome after severe head injury. J Neurosurg 1994;80:797-804 (Pubitemid 24129673)
40. Langham J, Goldfrad C, Teasdale G, et al. Calcium channel blockers for acute traumatic brain injury. Cochrane Database Syst Rev 2003;(4):CD000565
41. Vergouwen MD, Vermeulen M, Roos YB. Effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage: a systematic review. Lancet Neurol 2006;5:1029-1032 (Pubitemid 44709966)
42. Samii A, Badie H, Fu K, et al. Effects of an N-type calcium channel antagonist (SNX 111; Ziconotide) on calcium-45 accumulation following fluid-percussion injury. J Neurotrauma 1999;16:879-892 (Pubitemid 29491760)
43. Lee LL, Galo E, Lyeth BG, et al. Neuroprotection in the rat lateral fluid percussion model of traumatic brain injury by SNX-185, an N-type voltage-gated calcium channel blocker. Exp Neurol 2004;190:70-78 (Pubitemid 39335707)
44. Verweij BH, Muizelaar JP, Vinas FC, et al. Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury. J Neurosurg 2000;93:829-834 (Pubitemid 32803407)
45. Buchan AM, Gertler SZ, Li H, et al. A selective N-type Ca(2+)-channel blocker prevents CA1 injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia. J Cereb Blood Flow Metab 1994;14:903-910
46. Gudeman SK, Miller JD, Becker DP. Failure of high-dose steroid therapy to influence intracranial pressure in patients with severe head injury. J Neurosurg 1979;51:301-306 (Pubitemid 9255003)
47. Alderson P, Roberts I. Corticosteroids for acute traumatic brain injury. Cochrane Database Syst Rev 2005;15:CD000196
48. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury: outcomes at 6 months. Lancet 2005;365:1957-1959 (Pubitemid 40797505)
49. Bareyre F, Wahl F, McIntosh TK, Stutzmann JM. Time course of cerebral edema after traumatic brain injury in rats: effects of riluzole and mannitol. J Neurotrauma 1997;14:839-849 (Pubitemid 28007568)
50. Soustiel JF, Vlodavsky E, Zaaroor M. Relative effects of mannitol and hypertonic saline on calpain activity, apoptosis and polymorphonuclear infiltration in traumatic focal brain injury. Brain Res 2006;1101:136-144 (Pubitemid 44036774)
51. Sorani MD, Morabito D, Rosenthal G, et al. Characterizing the dose-response relationship between mannitol and intracranial pressure in traumatic brain injury patients using a high-frequency physiological data collection system. J Neurotrauma 2008;25:291-298
52. Ichai C, Armando G, Orban JC, et al. Sodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain-injured patients. Intensive Care Med 2009;35:471-479
53. van den Heuvel C, Vink R. The role of magnesium in traumatic brain injury. Clin Calcium 2004;14:9-14
54. Vink R, O'Connor CA, Nimmo AJ, Heath DL. Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats. Neurosci Lett 2003;336:41-44 (Pubitemid 35454117)
55. Barbre AB, Hoane MR. Magnesium and riboflavin combination therapy following cortical contusion injury in the rat. Brain Res Bull 2006;69:639-646 (Pubitemid 44250800)
56. Hoane MR. Assessment of cognitive function following magnesium therapy in the traumatically injured brain. Magn Res 2007;20:229-236
57. Hoane MR, Knotts AA, Akstulewicz SL, et al. The behavioral effects of magnesium therapy on recovery of function following bilateral anterior medial cortex lesions in the rat. Brain Res Bull 2003;60:105-114 (Pubitemid 36506458)
58. Turkoglu OF, Eroglu H, Okutan O, et al. A comparative study of treatment for brain edema: magnesium sulphate versus dexamethasone sodium phosphate. J Clin Neurosci 2008;15:60-65 (Pubitemid 350192259)
59. Arango MF, Bainbridge D. Magnesium for acute traumatic brain injury. Cochrane Database Syst Rev 2008;14:CD005400
60. Temkin NR, Anderson GD, Winn HR, et al. Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol 2007;6:29-38 (Pubitemid 44880259)
61. Saxena M, Andrews PJ, Cheng A. Modest cooling therapies (35 degrees C to 37.5 degrees C) for traumatic brain injury. Cochrane Database Syst Rev 2008;(3):CD006811
62. Markgraf CG, Clifton GL, Moody MR. Treatment window for hypothermia in brain injury. J Neurosurg 2001;95:979-983 (Pubitemid 33123855)
63. Ma M, Matthews BT, Lampe JW, et al. Immediate short-duration hypothermia provides long-term protection in an in vivo model of traumatic axonal injury. Exp Neurol 2009;215:119-127
64. Baranova AI, Wei EP, Ueda Y, et al. Cerebral vascular responsiveness after experimental traumatic brain injury: the beneficial effects of delayed hypothermia combined with superoxide dismutase administration. J Neurosurg 2008;109:502-509
65. Sahuquillo J, Vilalta A. Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury. Curr Pharm Des 2007;13:2310-2322 (Pubitemid 47317037)
66. Christian E, Zada G, Sung G, Giannotta SL. A review of selective hypothermia in the management of traumatic brain injury. Neurosurg Focus 2008;25:E9
67. Rutigliano D, Egnor MR, Priebe CJ, et al. Decompressive craniectomy in pediatric patients with traumatic brain injury with intractable elevated intracranial pressure. J Pediatr Surg 2006;41:83-87 (Pubitemid 43067497)
68. Plesnila N. Decompression craniectomy after traumatic brain injury: recent experimental results. Prog Brain Res 2007;161:393-400 (Pubitemid 47017417)
69. Zweckberger K, Eros C, Zimmermann R, et al. Effect of early and delayed decompressive craniectomy on secondary brain damage after controlled cortical impact in mice. J Neurotrauma 2006;23:1083-1093 (Pubitemid 44162713)
70. Hickenbottom SL, Grotta J. Neuroprotective therapy. Semin Neurol 1998;18:485-492 (Pubitemid 29058860)
71. Gentile NT, McIntosh TK. Antagonists of excitatory amino acids and endogenous opioid peptides in the treatment of experimental central nervous system injury. Ann Emerg Med 1993;22:1028-1034 (Pubitemid 23163046)
72. Duhaime AC. Exciting your neurons to death: can we prevent cell loss after brain injury? Pediatr Neurosurg 1994;21:117-122
73. Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil 2002;17:300-313 (Pubitemid 34809595)
74. Meythaler JM, Peduzzi JD, Eleftheriou E, Novack TA. Current concepts: diffuse axonal injury-associated traumatic brain injury. Arch Phys Med Rehabil 2001;82:1461-1471 (Pubitemid 32952371)
75. Sawyer E, Mauro LS, Ohlinger MJ. Amantadine enhancement of arousal and cognition after traumatic brain injury. Ann Pharmacother 2008;42:247-252 (Pubitemid 351238573)
76. Maas AI, Murray G, Henney H, et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol 2006;5:38-45 (Pubitemid 41790694)
77. Hellal F, Pruneau D, Palmier B, et al. Detrimental role of bradykinin B2 receptor in a murine model of diffuse brain injury. J Neurotrauma 2003;20:841-851 (Pubitemid 37159066)
78. Marmarou A, Guy M, Murphey L, et al. A single dose, three-arm, placebo-controlled, phase I study of the bradykinin B2 receptor antagonist Anatibant (LF16-0687Ms) in patients with severe traumatic brain injury. J Neurotrauma 2005;22:1444-1455 (Pubitemid 43122359)
79. Ker K, Blackhall K. Beta-2 receptor antagonists for acute traumatic brain injury. Cochrane Database Syst Rev 2008;(1):CD006686 (Pubitemid 351807751)
80. Roberts I. Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev 2000;(2):CD000033
81. Llompart-Pou JA, Perez-Barcena J, Raurich JM, et al. Effect of barbiturate coma on adrenal response in patients with traumatic brain injury. J Endocrinol Invest 2007;30:393-398 (Pubitemid 47098234)
82. Goss CW, Hoffman SW, Stein DG. Behavioral effects and anatomic correlates after brain injury: a progesterone dose-response study. Pharmacol Biochem Behav 2003;76:231-242 (Pubitemid 37329844)
83. Stein DG, Wright DW, Kellermann AL. Does progesterone have neuroprotective properties? Ann Emerg Med 2008;51:164-172
84. Wright DW, Kellermann AL, Hertzberg VS, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 2007;49:391-402 (Pubitemid 46413419)
85. Xiao G, Wei J, Yan W, et al. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 2008;12:R61 (Pubitemid 351650165)
86. Vandromme M, Melton SM, Kerby JD. Progesterone in traumatic brain injury: time to move on to phase III trials. Crit Care 2008;12:153 abstract.
87. Cutler SM, Vanlandingham JW, Murphy AZ, Stein DG. Slow-release and injected progesterone treatments enhance acute recovery after traumatic brain injury. Pharmacol Biochem Behav 2006;84:420-428 (Pubitemid 44292244)
88. Siddall OM. Use of methylphenidate in traumatic brain injury. Ann Pharmacother 2005;39:1309-1313 (Pubitemid 40943185)
89. Forsyth RJ, Jayamoni B, Paine TC. Monoaminergic agonists for acute traumatic brain injury. Cochrane Database Syst Rev 2006;(4):CD003984
90. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-785 (Pubitemid 40271172)
91. Narayan RK, Maas AI, Marshall LF, et al. Recombinant factor VIIA in traumatic intracerebral hemorrhage: results of a dose-escalation clinical trial. Neurosurgery 2008;62:776-786
92. Stein DM, Dutton RP, Kramer ME, et al. Recombinant factor VIIa: decreasing time to intervention in coagulopathic patients with severe traumatic brain injury. J Trauma 2008;64:620-627
93. Hall ED. Free radicals and CNS injury. Crit Care Clin 1989;5:793-805
94. Hall ED, Braughler JM. Free radicals in CNS injury. Res Publ Assoc Res Nerv Ment Dis 1993;71:81-105
95. Muizelaar JP, Marmarou A, Young HF, 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 (Pubitemid 23073205)
96. Young B, Runge JW, Waxman KS, et al. Effects of pegorgotein on neurologic outcome of patients with severe head injury. A multicenter, randomized controlled trial. JAMA 1996;276:538-543
97. Yunoki M, Kawauchi M, Ukita N, et al. Effects of lecithinized superoxide dismutase on neuronal cell loss in CA3 hippocampus after traumatic brain injury in rats. Surg Neurol 2003;59:156-160 (Pubitemid 36390200)
98. Wojchowski DM, Gregory RC, Miller CP, et al. Signal transduction in the erythropoietin receptor system. Exp Cell Res 1999;253:143-156
99. Naranda T, Kaufman RI, Li J, et al. Activation of erythropoietin receptor through a novel extracellular binding site. Endocrinology 2002;143:2293-2302 (Pubitemid 34521576)
100. Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol 2004;207 (Pt 18):3233-3242 (Pubitemid 39275297)
101. Grasso G, Sfacteria A, Cerami A, Brines M. Erythropoietin as a tissue-protective cytokine in brain injury: what do we know and where do we go? Neuroscientist 2004;10:93-98
102. Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000;97:10526-31 • This paper first time demonstrates that EPO is neuroprotective in vivo.
103. Wang L, Zhang Z, Wang Y, et al. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004;35:1732-1737 (Pubitemid 38823656)
104. Bartesaghi S, Marinovich M, Corsini E, et al. Erythropoietin: a novel neuroprotective cytokine. Neurotoxicology 2005;26:923-928 (Pubitemid 41427532)
105. Siren AL, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 2001;98:4044-4049 (Pubitemid 32249895)
106. Wang L, Zhang ZG, Zhang RL, et al. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci 2006;26:5996-6003 (Pubitemid 44318365)
107. Ransome MI, Turnley AM. Systemically delivered Erythropoietin transiently enhances adult hippocampal neurogenesis. J Neurochem 2007;102:1953-1965 (Pubitemid 47329277)
108. Mahmood A, Lu D, Qu C, et al. Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin. J Neurosurg 2007;107:392-397 (Pubitemid 47219384)
109. Wang L, Zhang ZG, Gregg SR, et al. The Sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem 2007;282:32462-32470 (Pubitemid 350106478)
110. Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci USA 2008;105:10925-30 • An important paper demonstrates that short peptides from EPO are tissue-protective in vitro and in vivo.
111. Chen J, Chopp M. Neurorestorative treatment of stroke: cell and pharmacological approaches. NeuroRx 2006;3:466-73 • This review article provides readers with details of neuroprotective treatment of stroke. (Pubitemid 44443015)
112. Lu D, Goussev A, Chen J, et al. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. J Neurotrauma 2004;21:21-32 (Pubitemid 38141799)
113. Wu H, Lu D, Jiang H, et al. Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J Neurotrauma 2008;25:130-139 (Pubitemid 351252578)
114. Chen SF, Hung TH, Chen CC, et al. Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury. Life Sci 2007;81:288-298 (Pubitemid 47030572)
115. Wang H, Lynch JR, Song P, et al. Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury. Exp Neurol 2007;206:59-69 (Pubitemid 46935123)
116. Lu D, Qu C, Goussev A, et al. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma 2007;24:1132-1146
117. Tapia-Perez JH, Sanchez-Aguilar M, Torres-Corzo JG, et al. Effect of rosuvastatin on amnesia and disorientation after traumatic brain injury (NCT003229758). J Neurotrauma 2008;25:1011-1017
118. Mahmood A, Lu D, Qu C, et al. Treatment of traumatic brain injury with a combination therapy of marrow stromal cells and atorvastatin in rats. Neurosurgery 2007;60:546-53; discussion 53-54 (Pubitemid 46339204)
119. Lee OK, Ko YC, Kuo TK, et al. Fluvastatin and lovastatin but not pravastatin induce neuroglial differentiation in human mesenchymal stem cells. J Cell Biochem 2004;93:917-928 (Pubitemid 44264147)
120. Cardenas A, Moro MA, Hurtado O, et al. Dual role of nitric oxide in adult neurogenesis. Brain Res Brain Res Rev 2005;50:1-6 (Pubitemid 41607511)
121. Sun Y, Jin K, Childs JT, et al. Neuronal nitric oxide synthase and ischemia-induced neurogenesis. J Cereb Blood Flow Metab 2005;25:485-492 (Pubitemid 40502998)
122. Zhang R, Zhang L, Zhang Z, et al. A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol 2001;50:602-611 (Pubitemid 33021918)
123. Gibbs SM. Regulation of neuronal proliferation and differentiation by nitric oxide. Mol Neurobiol 2003;27:107-120 (Pubitemid 36724515)
124. Chen J, Zhang ZG, Li Y, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 2003;53:743-751 (Pubitemid 36622511)
125. Firestein BL, Bredt DS. Regulation of sensory neuron precursor proliferation by cyclic GMP-dependent protein kinase. J Neurochem 1998;71:1846-1853 (Pubitemid 28491539)
126. Chen J, Zacharek A, Zhang C, et al. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci 2005;25:2366-2375 (Pubitemid 40322278)
127. Chen J, Li Y, Zhang R, et al. Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. Brain Res 2004;1005:21-28 (Pubitemid 38388396)
128. Luo CX, Zhu XJ, Zhou QG, et al. Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression. J Neurochem 2007;103:1872-1882 (Pubitemid 350126636)
129. Lu D, Mahmood A, Zhang R, Copp M. Upregulation of neurogenesis and reduction in functional deficits following administration of DEtA/NONOate, a nitric oxide donor, after traumatic brain injury in rats. J Neurosurg 2003;99:351-361 (Pubitemid 36900130)
130. Zhang R, Wang L, Zhang L, et al. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 2003;92:308-313 (Pubitemid 36258553)
131. Heizmann CW, Fritz G, Schafer BW. S100 proteins: structure, functions and pathology. Front Biosci 2002;7:d1356-68
132. Wunderlich MT, Wallesch CW, Goertler M. Release of neurobiochemical markers of brain damage is related to the neurovascular status on admission and the site of arterial occlusion in acute ischemic stroke. J Neurol Sci 2004;227:49-53 (Pubitemid 39491125)
133. Van Eldik LJ, Wainwright MS. The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restor Neurol Neurosci 2003;21:97-108 (Pubitemid 37330251)
134. Hayakata T, Shiozaki T, Tasaki O, et al. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock 2004;22:102-107 (Pubitemid 40228186)
135. Goncalves CA, Concli Leite M, Nardin P. Biological and methodological features of the measurement of S100B, a putative marker of brain injury. Clin Biochem 2008;41:755-763
136. Pelinka LE, Kroepfl A, Leixnering M, et al. GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome. J Neurotrauma 2004;21:1553-1561 (Pubitemid 39525165)
137. Piazza O, Storti MP, Cotena S, et al. S100B is not a reliable prognostic index in paediatric TBI. Pediatr Neurosurg 2007;43:258-264 (Pubitemid 47056593)
138. Kleindienst A, Hesse F, Bullock MR, Buchfelder M. The neurotrophic protein S100B: value as a marker of brain damage and possible therapeutic implications. Prog Brain Res 2007;161:317-325 (Pubitemid 47017412)
139. Kleindienst A, Ross Bullock M. A critical analysis of the role of the neurotrophic protein S100B in acute brain injury. J Neurotrauma 2006;23:1185-1200 (Pubitemid 44681474)
140. Korfias S, Stranjalis G, Boviatsis E, et al. Serum S-100B protein monitoring in patients with severe traumatic brain injury. Intensive Care Med 2007;33:255-260 (Pubitemid 46221230)
141. Kassem M, Abdallah BM. Human bone-marrow-derived mesenchymal stem cells: biological characteristics and potential role in therapy of degenerative diseases. Cell Tissue Res 2008;331:157-163 (Pubitemid 350265499)
142. Greco SJ, Rameshwar P. Enhancing effect of IL-1alpha on neurogenesis from adult human mesenchymal stem cells: implication for inflammatory mediators in regenerative medicine. J Immunol 2007;179:3342-3350
143. Deng J, Petersen BE, Steindler DA, et al. Mesenchymal stem cells spontaneously express neural proteins in culture and are neurogenic after transplantation. Stem Cells 2006;24:1054-1064 (Pubitemid 44464738)
144. Shih CC, Fu L, Zhu L, et al. Derivation of neural stem cells from mesenchymal stem cells: evidence for a bipotential stem cell population. Stem Cells Dev 2008;17:1109-1122
145. Wislet-Gendebien S, Hans G, Leprince P, et al. Plasticity of cultured mesenchymal stem cells: switch from nestin-positive to excitable neuron-like phenotype. Stem Cells 2005;23:392-402 (Pubitemid 40404458)
146. Lu D, Li Y, Wang L, et al. Intraarterial administration of marrow stromal cells in a rat model of traumatic brain injury. J Neurotrauma 2001;18:813-819 (Pubitemid 32769777)
147. Mahmood A, Lu D, Yi L, et al. Intracranial bone marrow transplantation after traumatic brain injury improving functional outcome in adult rats. J Neurosurg 2001;94:589-595 (Pubitemid 32799652)
148. Mahmood A, Lu D, Wang L, Chopp M. Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury. J Neurotrauma 2002;19:1609-1617 (Pubitemid 36026216)
149. Lu D, Mahmood A, Wang L, et al. Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 2001;12:559-563 (Pubitemid 32173965)
150. Mahmood A, Lu D, Qu C, et al. Human marrow stromal cell treatment provides long-lasting benefit after traumatic brain injury in rats. Neurosurgery 2005;57:1026-1031 (Pubitemid 41579737)
151. Mahmood A, Lu D, Qu C, et al. Long-term recovery after bone marrow stromal cell treatment of traumatic brain injury in rats. J Neurosurg 2006;104:272-277 (Pubitemid 43304326)
152. Qu C, Mahmood A, Lu D, et al. Treatment of traumatic brain injury in mice with marrow stromal cells. Brain Res 2008;1208:234-239
153. Chen X, Katakowski M, Li Y, et al. Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J Neurosci Res 2002;69:687-691 (Pubitemid 34966882)
154. Mahmood A, Lu D, Chopp M. Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. J Neurotrauma 2004;21:33-39 (Pubitemid 38141800)
155. Yoshimura S, Teramoto T, Whalen MJ, et al. FGF-2 regulates neurogenesis
156. Jin K, Zhu Y, Sun Y, et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 2002;99:11946-11950 (Pubitemid 34994504)
157. Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 2002;82:1367-1375
158. Zhang C, Li Y, Chen J, et al. Bone marrow stromal cells upregulate expression of bone morphogenetic proteins 2 and 4, gap junction protein connexin-43 and synaptophysin after stroke in rats. Neuroscience 2006;141:687-695 (Pubitemid 44066656)
159. Li Y, Chen J, Zhang CL, et al. Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia 2005;49:407-417 (Pubitemid 40222918)
160. Lu D, Mahmood A, Qu C, et al. Collagen scaffolds populated with human marrow stromal cells reduce lesion volume and improve functional outcome after traumatic brain injury. Neurosurgery 2007;61:596-602 (Pubitemid 47442659)
161. Zhang ZX, Guan LX, Zhang K, et al. A combined procedure to deliver autologous mesenchymal stromal cells to patients with traumatic brain injury. Cytotherapy 2008;10:134-139
162. Stahel PF, Barnum SR. The role of the complement system in CNS inflammatory diseases. Expert Rev Clin Immunol 2006;2:445-456 (Pubitemid 44355575)
163. Roberts I, Yates D, Sandercock P, et al. 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 2004;364:1321-1328 (Pubitemid 39335823)
164. Leinhase I, Rozanski M, Harhausen D, et al. Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice. J Neuroinflammation 2007;4:13 (Pubitemid 46767754)
165. Harris CL, Fraser DA, Morgan BP. Tailoring anti-complement therapeutics. Biochem Soc Trans 2002;30:1019-1026 (Pubitemid 36002399)
166. Leinhase I, Schmidt OI, Thurman JM, et al. Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury. Exp Neurol 2006;199:454-464 (Pubitemid 44202458)
167. Rus H, Cudrici C, David S, Niculescu F. The complement system in central nervous system diseases. Autoimmunity 2006;39:395-402 (Pubitemid 44269617)
168. van Beek J, Elward K, Gasque P. Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann NY Acad Sci 2003;992:56-71 (Pubitemid 36706637)
169. Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 2006;7:179-193 (Pubitemid 43292464)
170. Kempermann G, Gast D, Gage FH. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol 2002;52:135-143 (Pubitemid 34810592)
171. Brown J, Cooper-Kuhn CM, Kempermann G, et al. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci 2003;17:2042-2046 (Pubitemid 36713965)
172. Williams BM, Luo Y, Ward C, et al. Environmental enrichment: effects on spatial memory and hippocampal CREB immunoreactivity. Physiol Behav 2001;73:649-658 (Pubitemid 32728467)
173. Lippert-Gruener M, Maegele M, Garbe J, Angelov DN. Late effects of enriched environment (EE) plus multimodal early onset stimulation (MEOS) after traumatic brain injury in rats: ongoing improvement of neuromotor function despite sustained volume of the CNS lesion. Exp Neurol 2007;203:82-94 (Pubitemid 44821166)
174. Olson AK, Eadie BD, Ernst C, Christie BR. Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 2006;16:250-260
175. Rossi C, Angelucci A, Costantin L, et al. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur J Neurosci 2006;24:1850-1856 (Pubitemid 44583469)
176. During MJ, Cao L. VEGF, a mediator of the effect of experience on hippocampal neurogenesis. Curr Alzheimer Res 2006;3:29-33
177. Bruel-jungerman E, Laroche S, Rampon C. New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 2005;21:513-521 (Pubitemid 40204254)
178. Fan Y, Liu Z, Weinstein PR, et al. Environmental enrichment enhances neurogenesis and improves functional outcome after cranial irradiation. Eur J Neurosci 2007;25:38-46 (Pubitemid 46096221)
179. Will B, Galani R, Kelche C, Rosenzweig MR. Recovery from brain injury in animals: relative efficacy of environmental enrichment, physical exercise or formal training (1990-2002). Prog Neurobiol 2004;72:167-182 (Pubitemid 38591294)
180. Hoffman AN, Malena RR, Westergom BP, et al. Environmental enrichment-mediated functional improvement after experimental traumatic brain injury is contingent on task-specific neurobehavioral experience. Neurosci Lett 2008;431:226-230
181. Kline AE, Wagner AK, Westergom BP, et al. Acute treatment with the 5-HT(1A) receptor agonist 8-OH-DPAT and chronic environmental enrichment confer neurobehavioral benefit after experimental brain trauma. Behav Brain Res 2007;177:186-194 (Pubitemid 46149919)
182. Wagner AK, Kline AE, Sokoloski J, et al. Intervention with environmental enrichment after experimental brain trauma enhances cognitive recovery in male but not female rats. Neurosci Lett 2002;334:165-168 (Pubitemid 35346850)
183. van Praag H. Neurogenesis and exercise: past and future directions. Neuromolecular Med 2008;10:128-140
184. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 2007;30:464-472
185. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002;25:295-301 (Pubitemid 34667010)
186. van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999;2:266-270 (Pubitemid 30491298)
187. Yasuhara T, Hara K, Maki M, et al. Lack of exercise, via hindlimb suspension, impedes endogenous neurogenesis. Neuroscience 2007;149:182-191 (Pubitemid 47488660)
188. Lou SJ, Liu JY, Chang H, Chen PJ. Hippocampal neurogenesis and gene expression depend on exercise intensity in juvenile rats. Brain Res 2008;1210:48-55
189. Hellweg S, Johannes S. Physiotherapy after traumatic brain injury: a systematic review of the literature. Brain Inj 2008;22:365-373 (Pubitemid 351541325)
190. Carney NA, Ghajar J. Guidelines for the management of severe traumatic brain injury. Introduction. J Neurotrauma 2007;24 (Suppl 1):S1-2 .