Potential Neuroprotective Strategies for Traumatic Brain Injury



Traumatic brain injury (TBI) is caused by physical trauma to the brain tissue that temporarily or permanently impairs brain function. According to Centers for Disease Control and Prevention about 2 million people sustain a TBI in the USA each year, of which approximately 70,000–90,000 suffer from long-term disability (Nolan, 2005). Symptoms and severity of a TBI can be mild, moderate, or severe depending on the intensity of impact and extent of the damage to the brain. Some TBI symptoms appear immediately, while others do not appear until several days or weeks. Mild TBI symptoms include headache, confusion, lightheadedness, dizziness, blurred vision, fatigue, and trouble with memory (Bahraini et al., 2009). Moderate TBI produces a headache that gets worse with time, seizures, inability to awaken from sleep, dilation of one or both pupils of the eyes, slurred speech, loss of coordination, increased confusion.


Traumatic Brain Injury Spinal Cord Injury Progesterone Receptor Traumatic Brain Injury Patient Secondary Brain Injury 


  1. Abrahamson EE, Ikonomovic MD, Dixon CE, DeKosky ST (2009) Simvastatin therapy prevents brain trauma-induced increases in beta-amyloid peptide levels. Ann Neurol 66:407–414PubMedCrossRefGoogle Scholar
  2. Adibhatla RM, Hatcher JF, Dempsey RJ (2002) Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 80:12–23PubMedCrossRefGoogle Scholar
  3. Adibhatla RM, Hatcher JF (2003) Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. J Neurosci Res 73:308–315PubMedCrossRefGoogle Scholar
  4. Amarenco P (2005) Effect of statins in stroke prevention. Curr Opin Lipidol 16:614–618PubMedCrossRefGoogle Scholar
  5. Andersen M, Overgaard K, Meden P, Boysen G (1999) Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Stroke 30:1464–1470PubMedCrossRefGoogle Scholar
  6. Atif F, Sayeed I, Ishrat T, Stein DG (2009) Progesterone with vitamin D affords better neuroprotection against excitotoxicity in cultured cortical neurons than progesterone alone. Mol Med 15:328–336PubMedCrossRefGoogle Scholar
  7. Bahraini NH, Brenner LA, Harwood JE, Homaifar BY, Ladley-O’Brien SE, Filley CM, Kelly JP, Adler LE (2009) Utility of the trauma symptom inventory for the assessment of post-traumatic stress symptoms in veterans with a history of psychological trauma and/or brain injury. Mil Med 174:1005–1009PubMedGoogle Scholar
  8. Bayir H, Andelson PD, Wisniewski SR, Shore P, Lai Y, Brown D, Janesko KL, Kagan VE, Kochanek PM (2009) Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children. Crit Care Med 37:689–695PubMedCrossRefGoogle Scholar
  9. Bazan NG (2006) The onset of brain injury and neurodegeneration triggers the synthesis of docosanoid neuroprotective signaling. Cell Mol Neurobiol 26:901–913PubMedCrossRefGoogle Scholar
  10. Bazan NG (2007) Omega-3 fatty acids, pro-inflammatory signaling and neuroprotection. Curr Opin Clin Nutr Metab Care 10:136–141Google Scholar
  11. Boonyaratanakomkit V, Bi Y, Rudd M, Edwards DP (2008) The role and mechanism of progesterone receptor activation of extra-nuclear signaling pathways in regulating gene transcription and cell cycle progression. Steroids 73:922–928CrossRefGoogle Scholar
  12. Bösel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC, Megow D, Dirnagl U, Hörtnagl H, Fink KB, Endres M (2005) Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 92:1386–1398PubMedCrossRefGoogle Scholar
  13. Brewer LD, Thibault V, Chen KC, Langub MC, Landfield PW, Porter NM (2001) Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J Neurosci 21:98–108PubMedGoogle Scholar
  14. Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J (2008) Progesterone receptors: form and function in brain. Front Neuroendocrinol 29:313–339PubMedCrossRefGoogle Scholar
  15. Cekic M, Sayeed I, Stein DG (2009a) Combination treatment with progesterone and vitamin D hormone may be more effective than monotherapy for nervous system injury and disease. Front Neuroendocrinol 30:158–172PubMedCrossRefGoogle Scholar
  16. Cekic M, Culter SM, Vanlandingham JW, Stein DG (2009b) Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats. Neurobiol Aging DOI:  http://10.1016/j.neurobiolaging.2009.04.017, May 29. [Epub ahead of print]
  17. Chen XR, Besson VC, Palmier B, Garcia Y, Plotkine M, Marchand-Leroux C (2007) Neurological recovery-promoting, anti-inflammatory, and anti-oxidative effects afforded by fenofibrate, a PPAR alpha agonist, in traumatic brain injury. J Neurotrauma 24:1119–1131PubMedCrossRefGoogle Scholar
  18. Chen G, Shi J, Wei Jin W, Wang L, Xie W, Sun J, Hang C (2008a) Progesterone administration modulates TLRs/NF-κB signaling pathway in rat brain after cortical contusion. Ann Clin Lab Sci 38:65–74PubMedGoogle Scholar
  19. Chen XR, Besson VC, Beziand T, Plotkine M, Marchand-Leroux C (2008b) Combination therapy with fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on experimental traumatic brain injury. J Pharmacol Exp Ther 326:966–974PubMedCrossRefGoogle Scholar
  20. Chen G, Zhang S, Shi J, Ai J, Qi M, Hang C (2009) Simvastatin reduces secondary brain injury caused by cortical contusion in rats: possible involvement of TLR4/NF-kappaB pathway. Exp Neurol 216:398–406PubMedCrossRefGoogle Scholar
  21. Cherian L, Goodman JC, Robertson C (2007) Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J Pharmacol Exp Ther 322:789–794PubMedCrossRefGoogle Scholar
  22. Childers SR, Breivogel CS (1998) Cannabis and endogenous cannabinoid systems. Drug Alcohol Dependence 51:173–187CrossRefGoogle Scholar
  23. Chun KA, Manley GT, Stiver SI, Aiken AH, Phan N, Wang V, Meeker M, Cheng SC, Gean AD, Wintermark M (2009) Interobserver Variability in the Assessment of CT Imaging Features of Traumatic Brain Injury. J Neurotrauma 2009 Nov 6 [Epub ahead of print]Google Scholar
  24. Crack PJ, Gould J, Bye N, Ross S, Ali U, Habgood MD, Morganti-Kossman C, Saunders NR, Hertzog PJ Victorian Neurotrauma Research Group (2009) The genomic profile of the cerebral cortex after closed head injury in mice: effects of minocycline. J Neural Transm 116:1–12PubMedCrossRefGoogle Scholar
  25. Dempsey RJ, Rao VLR (2003) Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. J Neurosurg 98:867–873PubMedCrossRefGoogle Scholar
  26. Delerive P, De Bosscher K, Vanden Berghe W, Fruchart JC, Haegeman G, Staels B (2002) DNA binding-independent induction of IkappaBalpha gene transcription by PPARalpha. Mol Endocrinol 16:1029–1039PubMedCrossRefGoogle Scholar
  27. De Nicola AF, Labombarada F, Deniselle MC, Gonzalez SL, Garay L, Meyer M, Gargiulo G, Guennoun R, Schumacher M (2009) Progesterone neuroprotection in traumatic CNS injury and motoneuron degeneration. Front Neuroendocrinol 30:173–187PubMedCrossRefGoogle Scholar
  28. De Spiegelaere W, Cornillie P, Van den Broeck W (2009) Localization of erythropoietin in and around growing cartilage. Mol Cell Biochem 2009 Nov 12 [Epub ahead of print]Google Scholar
  29. Di Marzo V, De Petrocellis L, Sugiura T, Waku K (1996) Potential biosynthetic connections between the two cannabimimetic eicosanoids, anandamide and 2-arachidonoyl-glycerol, in mouse neuroblastoma cells. Biochem and Biophys Res Commun 227:281–288CrossRefGoogle Scholar
  30. Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG (2005) The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma 22:106–118PubMedCrossRefGoogle Scholar
  31. Eckartdt KU, Kurtz A (2005) Regulation of erythropoietin production. Eur J Clin Invest 35(Suppl 3):13–19CrossRefGoogle Scholar
  32. Endres M (2005) Statins and stroke. J Cereb Blood Flow Metab 25:1093–1110PubMedCrossRefGoogle Scholar
  33. Endres M (2006) Statins: potential new indications in inflammatory conditions. Atheroscler Suppl 7:31–35PubMedCrossRefGoogle Scholar
  34. Eshhar N, Striem S, Kohen R, Tirosh O, Biegon A (1995) Neuroprotectant and antioxidant activities of HU-211, a novel NMDA receptor antagonist. Eur J Pharmacol 283:19–29PubMedCrossRefGoogle Scholar
  35. Faden AI, Salzman SK (1994) Experimental pharmacology. In: Salzman SK, Faden AI (eds) The neurobiology of central nervous system trauma. Oxford University Press, New York, Oxford, pp 227–244Google Scholar
  36. Faden AI, Fox GB, Fan L, Araldi GL, Qiao L, Wang S, Kozikowski AP (1999) Novel TRH analog improves motor and cognitive recovery after traumatic brain injury in rodents. Am J Physiol 277:R1196–R1204PubMedGoogle Scholar
  37. Faden AI (2002) Neuroprotection and traumatic brain injury:theoretical option or realistic proposition. Curr Opin Neurol 15:707–712PubMedCrossRefGoogle Scholar
  38. Faden AI, Movsesyan VA, Knoblach SM, Ahmed F, Cernak I (2005) Neuroprotective effects of novel small peptides in vitro and after brain injury. Neuropharmacology 49:410–424PubMedCrossRefGoogle Scholar
  39. Farooqui AA, Ong WY, Horrocks LA (2004) Biochemical aspects of neurodegeneration in human brain: involvement of neural membrane phospholipids and phospholipases A2. Neurochem Res 29:1961–1977PubMedCrossRefGoogle Scholar
  40. Farooqui AA, Horrocks, LA (2009) Glutamate and cytokine-mediated alterations of phospholipids in head injury and spinal cord trauma. In: Banik NK, Ray SK (eds) Handbook of Neurochemistry and Molecular Neurobiology vol 24, 3rd edn. Springer, New York, NY, pp 71–89Google Scholar
  41. Farooqui AA (2009a) Hot topics in neural membrane lipidology. Springer, New York, NYCrossRefGoogle Scholar
  42. Farooqui AA (2009b) Beneficial effects of fish oil on human brain. Springer, New York, NYCrossRefGoogle Scholar
  43. Feigenbaum JJ, Bergmann F, Richmond SA, Mechoulam R, Nadler V, Kloog Y, Sokolovsky M (1989) Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker. Proc Natl Acad Sci USA 86:9584–9587PubMedCrossRefGoogle Scholar
  44. Garcia-Martinez EM, Sanz-Blasco S, Karachitos A, Bandez MJ, Fernandez-Gomez FJ, Perez-Alvarez S, de Mera RM, Jordan MJ, Aguirre N, Galindo MF, Villalobos C, Navarro A, Kmita H, Jordán J (2010) Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells. Biochem Pharmacol 79:239–2350PubMedCrossRefGoogle Scholar
  45. Gervois P, Kleemann R, Pilon A, Percevault F, Koenig W, Staels B, Kooistra T (2004) Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate. J Biol Chem 279:16154–16160PubMedCrossRefGoogle Scholar
  46. Gonzalez SL, Labombarda F, Gonzalez Deniselle MC, Guennoun R, Schumacher M, De Nicola AF (2004) Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cord. Neuroscience 125:605–614PubMedCrossRefGoogle Scholar
  47. Grände PO, Reinstrup P, Romner B (2009) Active cooling in traumatic brain-injured patients: a questionable therapy? Acta Anaesthesiol Scand 53:1233–1238 Epub 2009 Aug 13PubMedCrossRefGoogle Scholar
  48. Grasso G, Sfacteria A, Meli F, Fodale V, Buemi M, Iacopino DG (2007) Neuroprotection by erythropoietin administration after experimental traumatic brain injury. Brain Res 1182:99–105PubMedCrossRefGoogle Scholar
  49. Hansen HH, Schmid PC, Bittigau P, Lastres-Becker I, Berrendero F, Manzanares J, Ikonomidou C, Schmid HH, Fernández-Ruiz JJ, Hansen HS (2001a) Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J Neurochem 78:1415–1427PubMedCrossRefGoogle Scholar
  50. Hansen HH, Ikonomidou C, Bittigau P, Hansen SH, Hansen HS (2001b) Accumulation of the anandamide precursor and other N-acylethanolamine phospholipids in infant rat models of in vivo necrotic and apoptotic neuronal death. J Neurochem 76:39–46PubMedCrossRefGoogle Scholar
  51. Hansen HS, Moesgaard B, Petersen G, Hansen HH (2002) Putative neuroprotective actions of N-acyl-ethanolamines. Pharmacol Ther 95:119–126PubMedCrossRefGoogle Scholar
  52. He J, Evans CO, Hoffman SW, Oyesiku MN, Stein DG (2004) Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp Neurol 189:404–412PubMedCrossRefGoogle Scholar
  53. Homayoun P, Parkins NE, Soblosky J, Carey ME, Rodriguez de Turco EB, Bazan NG (2000) Cortical impact injury in rats promotes a rapid and sustained increase in polyunsaturated free fatty acids and diacylglycerols. Neurochem Res 25:269–276PubMedCrossRefGoogle Scholar
  54. Homayoun P, Rodriguez de Turco EB, Parkins NE, Lane DC, Soblosky J, Carey ME, Bazan NG (1997) Delayed phospholipid degradation in rat brain after traumatic brain injury. J Neurochem 69:199–205PubMedCrossRefGoogle Scholar
  55. Homsi S, Federico F, Croci N, Palmier B, Plotkine M, Marchand-Leroux C, Jafarian-Tehrani M (2009) Minocycline effects on cerebral edema: relations with inflammatory and oxidative stress markers following traumatic brain injury in mice. Brain Res 1291:122–132PubMedCrossRefGoogle Scholar
  56. Hou ST, Jiang SX, Smith RA (2008) Permissive and repulsive cues and signalling pathways of axonal outgrowth and regeneration. Int Rev Cell Mol Biol 267:125–181PubMedCrossRefGoogle Scholar
  57. Hu Z, Li Y, Fang M, Wai MS, Yew DT (2009) Exogenous progesterone: a potential therapeutic candidate in CNS injury and neurodegeneration. Curr Med Chem 16:1418–1425PubMedCrossRefGoogle Scholar
  58. Hua XY, Svensson CI, Matsui T, Fitzsimmons B, Yaksh TL, Webb M (2005) Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci 22:2431–2440PubMedCrossRefGoogle Scholar
  59. Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Ann Rev Biochem 72:609–642PubMedCrossRefGoogle Scholar
  60. Huang T, Solano J, He D, Loutfi M, Dietrich WD, Kuluz JW (2009) Traumatic injury activates MAP kinases in astrocytes: mechanisms of hypothermia and hyperthermia. J Neurotrauma 26:1535–1545PubMedCrossRefGoogle Scholar
  61. Huh JW, And Raghupathi R (2009) New concepts in treatment of pediatric traumatic brain injury. Anesthesiol Clin 27:213–240PubMedCrossRefGoogle Scholar
  62. Hutchison JS, Ward RE, Lacroix J, Hébert PC, Barnes MA, Bohn DJ, Dirks PB, Doucette S, Fergusson D, Gottesman R et al (2008) Hypothermia therapy after traumatic brain injury in children. N Engl J Med 358:2447–2456PubMedCrossRefGoogle Scholar
  63. Hyong A, Jadhav V, Lee S, Tong W, Rowe J, Zhang JH, Tang J (2008) Rosiglitazone, a PPAR gamma agonist, attenuates inflammation after surgical brain injury in rodents. Brain Res 1215:218–224PubMedCrossRefGoogle Scholar
  64. Jain KK (2009) Cell therapy for CNS trauma. Mol Biotechnol 2009 Mar 28 [Epub ahead of print]Google Scholar
  65. Johnson-Anuna LN, Eckert GP, Franke C, Igbavboa U, Müller WE, Wood WG (2007) Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein. J Neurochem 101:77–86PubMedCrossRefGoogle Scholar
  66. Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, Schubert-Zsilavecz M, Karas M, Müller WE, Wood WG (2005) Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther 312:786–793PubMedCrossRefGoogle Scholar
  67. Kochanek PM, Bayir H, Jenkins LW (2008) Molecular biology of brain injury. In: Nichols D (ed) Textbook of pediatric intensive care, 4th edn. Lippincott Williams & Wilkins, Pennsylvania, PA, pp 826–845Google Scholar
  68. Kim HS, Suh YH (2009) Minocycline and neurodegenerative diseases. Behav Brain Res 196:168–179PubMedCrossRefGoogle Scholar
  69. Kirsch C, Eckert GP, Muller EE (2003) Brain cholesterol, statins and Alzheimer’s Disease. Pharmacopsychiatry 36(Suppl 2):S113–S119PubMedGoogle Scholar
  70. Knoller N, Levi L, Shoshan I, Reichenthal E, Razon N, Rappaport ZH, Biegon A (2002) Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Crit Care Med 30:548–554PubMedCrossRefGoogle Scholar
  71. Lenzlinger PM, Saatman K, Raghupathi R (2001) Overview of basic mechanisms underlying neuropathological consequences of head trauma. In: Miller G, Hayes R (eds) Head trauma – basic, preclinical, and clinical directions. Wiley-Liss, Hoboken, NJ, pp 3–36Google Scholar
  72. Leonhardt SA, Boonyaratanakornkit V, Edwards DP (2003) Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids 68:761–770PubMedCrossRefGoogle Scholar
  73. Longhi L, Zanier ER, Royo N, Stocchetti N, McIntosh TK (2005) Stem cell transplantation as a therapeutic strategy for traumatic brain injury. Transpl Immunol 15:143–148PubMedCrossRefGoogle Scholar
  74. Lu D, Qu C, Goussev A, Jiang H, Lu C, Schallert T, Mahmood A, Chen J, Li Y, Chopp M (2007) 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 24:1132–1146PubMedCrossRefGoogle Scholar
  75. Maas AI (2001) Neuroprotective agents in traumatic brain injury. Expert Opin Investig Drugs 10:753–767PubMedCrossRefGoogle Scholar
  76. 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
  77. Machado LS, Kozak A, Erqul A, Hess DC, Borlougan CV, Fagan SC (2006) Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC 7:56Google Scholar
  78. Maegele M, Schaefer U (2008) Stem cell-based cellular replacement strategies following traumatic brain injury (TBI). Minim Invasive Ther Allied Technol 17:119–131PubMedCrossRefGoogle Scholar
  79. Marchand F, Tsantoulas C, Singh D, Grist J, Clark AK, Bradbury EJ, McMahon SB (2009) Effects of Etanercept and Minocycline in a rat model of spinal cord injury. Eur J Pain 13:673–681PubMedCrossRefGoogle Scholar
  80. MacNevin CJ, Atif F, Sayeed I, Stein DG, Liotta DC (2009) Development and screening of water-soluble analogues of progesterone and allopregnanolone in models of brain injury. J Med Chem 52:6012–6023PubMedCrossRefGoogle Scholar
  81. Mahmood A, Gousser A, Kazmi H, Qu C, Lu D, Chopp M (2009a) Long-term benefits after treatment of traumatic brain injury with simvastatin in rats. Neurosurg 65:187–191CrossRefGoogle Scholar
  82. Mahmood A, Lu D, Qu C, Goussev A, Zhang Y, Chopp M (2009b) Treatment of traumatic brain injury in rats with erythropoietin and carbamylated erythropoietin. J Neurosurg 107:392–397Google Scholar
  83. Mani S (2008) Progestin receptor subtypes in the brain: the known and the unknown. Endocrinology 149:2750–2756PubMedCrossRefGoogle Scholar
  84. Marx N, Sukhova GK, Collins T, Libby P, Plutzky J (1999) PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 99:3125–3131PubMedCrossRefGoogle Scholar
  85. Matis GK, Birbillis TA (2009) Erythropoietin in spinal cord injury. Eur Spine J 18:314–323PubMedCrossRefGoogle Scholar
  86. McIntosh TK, Saatman KE, Raghupathi R, Graham DI, Smith DH, Lee VM, Trojanowski JQ (1998) The Dorothy Russell Memorial Lecture. The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms. Neuropathol Appl Neurobiol 24:251–267PubMedCrossRefGoogle Scholar
  87. McKenna NJ, O’Malley BW (2002) Minireview: nuclear receptor coactivators—an update. Endocrinology 143:2461–2465PubMedCrossRefGoogle Scholar
  88. Mir C, Clotet J, Aledo R, Durany N, Argemi J, Lozano R, Cervos-Navarro J, Casals N (2003) CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons. J Mol Neurosci 20:53–59PubMedCrossRefGoogle Scholar
  89. Monga V, Meena CL, Kaura N, Jain R (2008) Chemistry and biology of thyrotropin-releasing hormone (TRH) and its analogs. Curr Med Chem 15:2718–2733PubMedCrossRefGoogle Scholar
  90. Nakazawa T, Takahashi H, Nishijima K, Shimura M, Fuse N, Tamai M, Hafezi-Moghadam A, Nishida K (2007) Pitavastatin prevents NMDA-induced retinal ganglion cell death by suppressing leukocyte recruitment. J Neurochem 100:1018–1031PubMedCrossRefGoogle Scholar
  91. Nilsen J, Brinton RD (2002) Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology 143:205–212PubMedCrossRefGoogle Scholar
  92. Noguchi CT, Asavaritikrai P, Teng R, Jia Y (2007) Role of erythropoietin in the brain. Crit Rev Oncol Hematol 64:159–171PubMedCrossRefGoogle Scholar
  93. Nolan S (2005) Traumatic brain injury: a review. Ctrt Care Nurse 28:188–194Google Scholar
  94. O’Connor CA, Cernak I, Vink R (2005) Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res 1062:171–174PubMedCrossRefGoogle Scholar
  95. Owen GI, Richer JK, Tung L, Takimoto G, Horwitz KB (1998) Progesterone regulates transcription of the p21(WAF1) cyclindependent kinase inhibitor gene through Sp1 and CBP/p300. J Biol Chem 273(1998):10696–10701PubMedCrossRefGoogle Scholar
  96. Oz M (2006) Receptor-independent effects of endocannabinoids on ion channels. Curr Pharm Design 12:227–239CrossRefGoogle Scholar
  97. Pettus EH, Wright DW, Stein DG, Hoffman SW (2005) Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res 1049:112–119PubMedCrossRefGoogle Scholar
  98. Philips MF, Muir JK, Saatman KE, Raghupathi R, Lee VM, Trojanowski JQ, McIntosh TK (1999) Survival and integration of transplanted postmitotic human neurons following experimental brain injury in immunocompetent rats. J Neurosurg 90:116–124PubMedCrossRefGoogle Scholar
  99. Povlishock JT, Christman CW (1995) The pathobiology of traumatically induced axonal injury in animals and humans: a review of current thoughts. J Neurotrauma 12:555–564PubMedCrossRefGoogle Scholar
  100. Pratt WB (1998) The hsp90-based chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors, Proc. Soc Exp Biol Med 217:420–434Google Scholar
  101. Rajanikant GK, Zemke D, Kassab M, Majid A (2007) The therapeutic potential of statins in neurological disorders. Curr Med Chem 14:103–112PubMedCrossRefGoogle Scholar
  102. Rao JS, Ertley RN, Lee H-J, DeMar JC Jr, Arnold JT, Repoport SI, Bazinet RP (2007) N-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MARK-dependent mechanism. Mol Psychiatry 12:36–46PubMedCrossRefGoogle Scholar
  103. Roof RL, Duvdevani R, Stein DG (1992) Progesterone treatment attenuates brain edema following contusion injury in male and female rats. Restor Neurol Neurosci 4:425–427PubMedGoogle Scholar
  104. Roof RL, Hoffman SW, Stein DG (1997) Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol 31:1–11PubMedCrossRefGoogle Scholar
  105. Rupprecht R, Holsboer F (1999) Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 22:410–416PubMedCrossRefGoogle Scholar
  106. Sahuguillo J, Bietro A, Amoros S, Poca MA, Baguena M, Ibanez J, Noguer M, Garnacho A (2001) The use of moderate hypothermia in the treatment of patients with severe craniocerebral trauma. Neurocirgia (Astur) 12:23–35Google Scholar
  107. Sahuguillo J, Vilalta A (2009) Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury. Curr Pharm Des 13:2310–2322CrossRefGoogle Scholar
  108. Salim A, Hadjizacharea P, Brown C, Inaba K, Teixeira PG, Chan L, Rhee P, Demetriades D (2008) Significance of troponin elevation after severe traumatic brain injury. J Trauma 64:46–57PubMedCrossRefGoogle Scholar
  109. Sayeed I, Stein DG (2009) Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Prog Brain Res 175:219–237PubMedCrossRefGoogle Scholar
  110. Schumacher M, Sitruk-ware R, De Nicola AF (2008) Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 8:740–746PubMedCrossRefGoogle Scholar
  111. Sensi SL, Jeng JM (2004) Rethinking the excitotoxic ionic milieu: the emerging role of Zn2+ in ischemic neuronal injury. Curr Mol Med 4:87–111PubMedCrossRefGoogle Scholar
  112. Serhan CN (2005a) Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes, and neuroprotectins. Curr Opin Clin Nutr Metab Care 8:115–121PubMedCrossRefGoogle Scholar
  113. Serhan CN (2005b) Novel ω-3-derived local mediators in anti-inflammation and resolution. Pharmacol Ther 105:7–21PubMedCrossRefGoogle Scholar
  114. Shin BS, Won SJ, Yoo BH, Kauppinen TM, Suh SW (2009) Prevention of hypoglycemia-induced neuronal death by hypothermia. J Cereb Blood Flow Metab 2009 Oct 28 [Epub ahead of print]Google Scholar
  115. Shohami E, Novikov M, Mechoulam R (1993) A nonpsychotropic cannabinoid, HU-211, has cerebrovascular effects after closed head injury in the rat. J Neurotrauma 10:109–119PubMedCrossRefGoogle Scholar
  116. Shohami E, Beit-Yannai E, Horowitz M, Kohen R (1997) Oxidative stress in closed-head injury: brain antioxidant capacity as an indicator of functional outcome. J Cereb Blood Flow Metab 17:1007–1019PubMedCrossRefGoogle Scholar
  117. Siren AL, Fasshauer T, Bartels C, Ehrenreich H (2009) Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics 6:108–127PubMedCrossRefGoogle Scholar
  118. Skaper SD, Moore SE, Walsh FS (2001) Cell signalling cascades regulating neuronal growth-promoting and inhibitory cues. Prog Neurobiol 65:593–608PubMedCrossRefGoogle Scholar
  119. Stockmann C, Fandrey J (2006) Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression. Clin Exp Pharmacol Physiol 33:968–979PubMedCrossRefGoogle Scholar
  120. Stoica BA, Byrnes KR, Faden AI (2009) Cell cycle activation and CNS injury. Neurotox Res 16:221–237PubMedCrossRefGoogle Scholar
  121. Sun H, Huang Y, Yu X, Li Y, Yang J, Li R, Deng Y, Zhao G (2008) Peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, suppresses CD40 expression and attenuates inflammatory responses after lithium pilocarpine-induced status epilepticus in rats. Int J Neurosci 26:505–515CrossRefGoogle Scholar
  122. Ueda N, Okamoto Y, Tsuboi K (2005) Endocannabinoid-related enzymes as drug targets with special reference to N-acylphosphatidylethanolamine-hydrolyzing phospholipase D. Curr Med Chem 2005(12):1413–1422CrossRefGoogle Scholar
  123. Vaughan CJ (2003) Prevention of stroke and dementia with statins: effects beyond lipid lowering. Am J Cardiol 91:23B–29BPubMedCrossRefGoogle Scholar
  124. Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590PubMedCrossRefGoogle Scholar
  125. Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ (2006) Statins of different brain penetrability differentially affect CSFPLTP activity. Dement Geriatr Cogn Disord 22:392–398PubMedCrossRefGoogle Scholar
  126. Wu A, Molteni R, Ying Z, Gomez-Pinilla F (2003) A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor. Neuroscience 119:365–375PubMedCrossRefGoogle Scholar
  127. Wu A, Ying Z, Gomez-Pinilla F (2004a) Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma 21:1457–1467PubMedCrossRefGoogle Scholar
  128. Wu A, Ying Z, Gomez-Pinilla F (2004b) The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci 19:1699–1707PubMedCrossRefGoogle Scholar
  129. Wu A, Ying Z, Gomez-Pinilla F (2005) Omega-3 fatty acids supplementation restores homeostatic mechanisms disrupted by traumatic brain injury. J Neurotrauma 22:1212Google Scholar
  130. Wu H, Jiang H, Xiong Y, Qu C, Li B, Mahmood A, Zhou D, Chopp M (2008) 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 25:130–139PubMedCrossRefGoogle Scholar
  131. Wu J, Yang S, Xi G, Fu G, Keep RF, Hua Y (2009) Minocycline reduces intracerebral hemorrhage-induced brain injury. Neurol Res 31:183–188PubMedCrossRefGoogle Scholar
  132. Xiong Y, Lu D, Qu C (2008) Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. J Neurosurg 109:510–521PubMedCrossRefGoogle Scholar
  133. Xiong Y, Mahmood A, Meng Y, Zhang Y, Qu C, Schallert T, Chopp M (2009) Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose. J Neurosurg 2009 Oct 9 [Epub ahead of print]Google Scholar
  134. Yamashita T (2007) Molecular mechanism and regulation of axon growth inhibition. Brain Nerve 59:1347–1353PubMedGoogle Scholar
  135. Yang D, Xie P, Guo S, Li H (2009) Induction of MAPK phosphatase-1 by hypothermia inhibits TNF-{alpha}-induced endothelial barrier dysfunction and apoptosis. Cardiovasc Res Oct 22 [Epub ahead of print]Google Scholar
  136. Yao XL, Liu J, Lee E, Ling GS, McCabe JT (2005) Progesterone differentially regulates pro- and anti-apoptotic gene expression in cerebral cortex following traumatic brain injury in rats. J Neurotrauma 22:656–668PubMedCrossRefGoogle Scholar
  137. Zafonte R, Friedewald WT, Lee SM, Levin B, Diaz-Arrastia R, Ansel B, Eisenberg H, Timmons SD, Temkin N, Novack T, Ricker J, Merchant R, Jallo J (2009) The citicoline brain injury treatment (COBRIT) trial: design and methods. J Neurotrauma 26:2207–2216PubMedCrossRefGoogle Scholar
  138. Zhu L, Wang HD, Yu XG, Jin W, Qiao L, Lu TJ, Hu ZL, Zhou J (2009) Erythropoietin prevents zinc accumulation and neuronal death after traumatic brain injury in rat hippocampus: in vitro and in vivo studies. Brain Res 1289:96–105PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Molecular and Cellular BiochemistryThe Ohio State UniversityColumbusUSA

Personalised recommendations