Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics

Cellular and Molecular Neurobiology

Volumn 37, Issue 4, 2017, Pages 571-585

  Pearn, Matthew L ^a,b   Niesman, Ingrid R ^c,d   Egawa, Junji ^a,b   Sawada, Atsushi ^a,b   Almenar Queralt, Angels ^c,d   Shah, Sameer B ^a   Duckworth, Josh L ^e   Head, Brian P ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b University of California at San Diego   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d SANFORD CONSORTIUM FOR REGENERATIVE MEDICINE   (United States)

^e Uniformed Services University of the Health Sciences   (United States)

Author keywords

Biologics; Blood brain barrier; Caveolin; Membrane lipid rafts; Neuroinflammation; Traumatic brain injury

Indexed keywords

BIOLOGICAL PRODUCT; CAVEOLIN;

BLOOD BRAIN BARRIER; BRAIN CONTUSION; BRAIN HEMORRHAGE; COMBAT SPORT; DIFFUSE AXONAL INJURY; DRUG THERAPY; FALLING; GUNSHOT INJURY; HUMAN; IN VIVO STUDY; INJURY SEVERITY; LIPID RAFT; NERVE CELL PLASTICITY; NERVE REGENERATION; NERVOUS SYSTEM INFLAMMATION; NON INVASIVE PROCEDURE; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; TRAFFIC ACCIDENT; TRAUMATIC BRAIN INJURY; WOUND; ANIMAL; BRAIN INJURIES, TRAUMATIC; DISEASE MODEL; DRUG EFFECTS; INFLAMMATION; METABOLISM; TREATMENT OUTCOME;

ANIMALS; BLOOD-BRAIN BARRIER; BRAIN INJURIES, TRAUMATIC; CAVEOLINS; DISEASE MODELS, ANIMAL; HUMANS; INFLAMMATION; TREATMENT OUTCOME;

EID: 84978174415     PISSN: 02724340     EISSN: 15736830     Source Type: Journal    
DOI: 10.1007/s10571-016-0400-1     Document Type: Review

References (133)

1. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37(1):13–25. doi:10.1016/j.nbd.2009.07.030
2. Abdul-Muneer PM, Schuetz H, Wang F, Skotak M, Jones J, Gorantla S, Zimmerman MC, Chandra N, Haorah J (2013) Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast. Free Radic Biol Med 60:282–291. doi:10.1016/j.freeradbiomed.2013.02.029
3. Atkins CM, Oliva AA Jr, Alonso OF, Pearse DD, Bramlett HM, Dietrich WD (2007) Modulation of the cAMP signaling pathway after traumatic brain injury. Exp Neurol 208(1):145–158. doi:10.1016/j.expneurol.2007.08.011
4. Atkins CM, Falo MC, Alonso OF, Bramlett HM, Dietrich WD (2009) Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury. Neurosci Lett 459(2):52–56. doi:10.1016/j.neulet.2009.04.064
5. Atkins CM, Cepero ML, Kang Y, Liebl DJ, Dietrich WD (2013) Effects of early rolipram treatment on histopathological outcome after controlled cortical impact injury in mice. Neurosci Lett 532:1–6. doi:10.1016/j.neulet.2012.10.019
6. Aungst SL, Kabadi SV, Thompson SM, Stoica BA, Faden AI (2014) Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 34(7):1223–1232. doi:10.1038/jcbfm.2014.75
7. Ayling LJ, Briddon SJ, Halls ML, Hammond GR, Vaca L, Pacheco J, Hill SJ, Cooper DM (2012) Adenylyl cyclase AC8 directly controls its micro-environment by recruiting the actin cytoskeleton in a cholesterol-rich milieu. J Cell Sci 125(Pt 4):869–886. doi:10.1242/jcs.091090
8. Besson VC, Chen XR, Plotkine M, Marchand-Verrecchia C (2005) Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, exerts neuroprotective effects in traumatic brain injury. Neurosci Lett 388(1):7–12. doi:10.1016/j.neulet.2005.06.019
9. Blaya MO, Tsoulfas P, Bramlett HM, Dietrich WD (2014) Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury. Exp Neurol 264C:67–81. doi:10.1016/j.expneurol.2014.11.014
10. Bonnelle V, Ham TE, Leech R, Kinnunen KM, Mehta MA, Greenwood RJ, Sharp DJ (2012) Salience network integrity predicts default mode network function after traumatic brain injury. Proc Natl Acad Sci USA 109(12):4690–4695. doi:10.1073/pnas.1113455109
11. Bowles DE, Rabinowitz JE, Sumulski RJ (2006) The genus dependovirus. In: Kerr JR, Cotmore SF, Bloom ME, Linden RM, Parrish CR (eds) Parvoviruses. Edward Arnold Ltd., New York
12. Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M (2005) Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci 29(3):381–393. doi:10.1016/j.mcn.2005.03.005
13. Bye N, Habgood MD, Callaway JK, Malakooti N, Potter A, Kossmann T, Morganti-Kossmann MC (2007) Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol 204(1):220–233. doi:10.1016/j.expneurol.2006.10.013
14. Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M, Heinemann U, Friedman A, Kaufer D (2009) Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci: Off J Soc Neurosci 29(28):8927–8935. doi:10.1523/JNEUROSCI.0430-09.2009
15. Cai D, Qiu J, Cao Z, McAtee M, Bregman BS, Filbin MT (2001) Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J Neurosci: Off J Soc Neurosci 21(13):4731–4739
16. Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ (2012) Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain: J Neurol 135(Pt 4):1224–1236. doi:10.1093/brain/aws072
17. Ceyhan O, Birsoy K, Hoffman CS (2012) Identification of biologically active PDE11-selective inhibitors using a yeast-based high-throughput screen. Chem Biol 19(1):155–163. doi:10.1016/j.chembiol.2011.12.010
18. 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(7):1119–1131. doi:10.1089/neu.2006.0216
19. Cheng G, Kong RH, Zhang LM, Zhang JN (2012) Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol 167(4):699–719. doi:10.1111/j.1476-5381.2012.02025.x
20. Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflamm 3:27. doi:10.1186/1742-2094-3-27
21. Cramer SC, Sur M, Dobkin BH, O’Brien C, Sanger TD, Trojanowski JQ, Rumsey JM, Hicks R, Cameron J, Chen D, Chen WG, Cohen LG, deCharms C, Duffy CJ, Eden GF, Fetz EE, Filart R, Freund M, Grant SJ, Haber S, Kalivas PW, Kolb B, Kramer AF, Lynch M, Mayberg HS, McQuillen PS, Nitkin R, Pascual-Leone A, Reuter-Lorenz P, Schiff N, Sharma A, Shekim L, Stryker M, Sullivan EV, Vinogradov S (2011) Harnessing neuroplasticity for clinical applications. Brain: J Neurol 134(Pt 6):1591–1609. doi:10.1093/brain/awr039
22. Das M, Mohapatra S, Mohapatra SS (2012) New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuroinflamm 9:236. doi:10.1186/1742-2094-9-236
23. Das M, Wang C, Bedi R, Mohapatra SS, Mohapatra S (2014) Magnetic micelles for DNA delivery to rat brains after mild traumatic brain injury. Nanomed Nanotechnol Biol Med 10(7):1539–1548. doi:10.1016/j.nano.2014.01.003
24. David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D, Friedman A (2009) Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J Neurosci: Off J Soc Neurosci 29(34):10588–10599. doi:10.1523/JNEUROSCI.2323-09.2009
25. de Kreuk BJ, Nethe M, Fernandez-Borja M, Anthony EC, Hensbergen PJ, Deelder AM, Plomann M, Hordijk PL (2011) The F-BAR domain protein PACSIN2 associates with Rac1 and regulates cell spreading and migration. J Cell Sci 124(Pt 14):2375–2388. doi:10.1242/jcs.080630
26. DeKosky ST, Blennow K, Ikonomovic MD, Gandy S (2013) Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol 9(4):192–200. doi:10.1038/nrneurol.2013.36
27. Del Pozo MA, Schwartz MA (2007) Rac, membrane heterogeneity, caveolin and regulation of growth by integrins. Trends Cell Biol 17(5):246–250. doi:10.1016/j.tcb.2007.03.001
28. Denny JB (2006) Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43. Curr Neuropharmacol 4(4):293–304
29. Dent EW, Gupton SL, Gertler FB (2011) The growth cone cytoskeleton in axon outgrowth and guidance. Cold Spring Harb Perspect Biol. doi:10.1101/cshperspect.a001800
30. DeWitt DS, Prough DS (2009) Blast-induced brain injury and posttraumatic hypotension and hypoxemia. J Neurotrauma 26(6):877–887. doi:10.1089/neu.2007.0439
31. Di Giovanni S, Movsesyan V, Ahmed F, Cernak I, Schinelli S, Stoica B, Faden AI (2005) Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci USA 102(23):8333–8338. doi:10.1073/pnas.0500989102
32. Duckworth JL, Grimes J, Ling GS (2013) Pathophysiology of battlefield associated traumatic brain injury. Pathophysiol: Off J Int Soc Pathophysiol/ISP 20(1):23–30. doi:10.1016/j.pathophys.2012.03.001
33. Engelhardt B, Sorokin L (2009) The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31(4):497–511. doi:10.1007/s00281-009-0177-0
34. Evans MA, Golomb BA (2009) Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy 29(7):800–811. doi:10.1592/phco.29.7.800
35. Feeney DM, Boyeson MG, Linn RT, Murray HM, Dail WG (1981) Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res 211(1):67–77
36. Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, Schwam E, Schindler R, Hey-Hadavi J, DeMicco DA, Breazna A, Investigators LE (2010) Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 74(12):956–964. doi:10.1212/WNL.0b013e3181d6476a
37. Friess SH, Ichord RN, Ralston J, Ryall K, Helfaer MA, Smith C, Margulies SS (2009) Repeated traumatic brain injury affects composite cognitive function in piglets. J Neurotrauma 26(7):1111–1121. doi:10.1089/neu.2008-0845
38. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM (2002) Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA 99(18):11854–11859. doi:10.1073/pnas.182412299
39. Gensel JC, Zhang B (2015) Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res. doi:10.1016/j.brainres.2014.12.045
40. Goldstein LS (2012) Axonal transport and neurodegenerative disease: can we see the elephant? Prog Neurobiol 99(3):186–190. doi:10.1016/j.pneurobio.2012.03.006
41. Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, Upreti C, Kracht JM, Ericsson M, Wojnarowicz MW, Goletiani CJ, Maglakelidze GM, Casey N, Moncaster JA, Minaeva O, Moir RD, Nowinski CJ, Stern RA, Cantu RC, Geiling J, Blusztajn JK, Wolozin BL, Ikezu T, Stein TD, Budson AE, Kowall NW, Chargin D, Sharon A, Saman S, Hall GF, Moss WC, Cleveland RO, Tanzi RE, Stanton PK, McKee AC (2012) Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 4(134):134ra160. doi:10.1126/scitranslmed.3003716
42. Grande-Garcia A, del Pozo MA (2008) Caveolin-1 in cell polarization and directional migration. Eur J Cell Biol 87(8–9):641–647. doi:10.1016/j.ejcb.2008.02.001
43. Guirland C, Zheng JQ (2007) Membrane lipid rafts and their role in axon guidance. Adv Exp Med Biol 621:144–155. doi:10.1007/978-0-387-76715-4_11
44. Gyoneva S, Ransohoff RM (2015) Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci. doi:10.1016/j.tips.2015.04.003
45. Hall A, Lalli G (2010) Rho and Ras GTPases in axon growth, guidance, and branching. Cold Spring Harb Perspect Biol 2(2):a001818. doi:10.1101/cshperspect.a001818
46. Harmon BT, Aly AE, Padegimas L, Sesenoglu-Laird O, Cooper MJ, Waszczak BL (2014) Intranasal administration of plasmid DNA nanoparticles yields successful transfection and expression of a reporter protein in rat brain. Gene Ther 21(5):514–521. doi:10.1038/gt.2014.28
47. Harrington AW, St Hillaire C, Zweifel LS, Glebova NO, Philippidou P, Halegoua S, Ginty DD (2011) Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146(3):421–434. doi:10.1016/j.cell.2011.07.008
48. Head BP, Hu Y, Finley JC, Saldana MD, Bonds JA, Miyanohara A, Niesman IR, Ali SS, Murray F, Insel PA, Roth DM, Patel HH, Patel PM (2011) Neuron-targeted caveolin-1 protein enhances signaling and promotes arborization of primary neurons. J Biol Chem 286(38):33310–33321. doi:10.1074/jbc.M111.255976
49. Head BP, Patel HH, Insel PA (2013) Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta. doi:10.1016/j.bbamem.2013.07.018
50. Hilton GD, Stoica BA, Byrnes KR, Faden AI (2008) Roscovitine reduces neuronal loss, glial activation, and neurologic deficits after brain trauma. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 28(11):1845–1859. doi:10.1038/jcbfm.2008.75
51. Huot P, Johnston TH, Lewis KD, Koprich JB, Reyes MG, Fox SH, Piggott MJ, Brotchie JM (2014) UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances l-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset. Neuropharmacology. doi:10.1016/j.neuropharm.2014.01.012
52. Hurtado-Alvarado G, Cabanas-Morales AM, Gomez-Gonzalez B (2014) Pericytes: brain-immune interface modulators. Front Integr Neurosci 7:80. doi:10.3389/fnint.2013.00080
53. Johnson VE, Stewart W, Smith DH (2013) Axonal pathology in traumatic brain injury. Exp Neurol 246:35–43. doi:10.1016/j.expneurol.2012.01.013
54. Kabadi SV, Faden AI (2014) Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci 15(1):1216–1236. doi:10.3390/ijms15011216
55. Kabadi SV, Stoica BA, Byrnes KR, Hanscom M, Loane DJ, Faden AI (2012) Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 32(1):137–149. doi:10.1038/jcbfm.2011.117
56. Kamiguchi H (2006) The region-specific activities of lipid rafts during axon growth and guidance. J Neurochem 98(2):330–335. doi:10.1111/j.1471-4159.2006.03888.x
57. Kaminska K, Golembiowska K, Rogoz Z (2013) Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine, serotonin and noradrenaline in the rat frontal cortex. Pharmacol Rep: PR 65(5):1144–1151
58. Kane MJ, Angoa-Perez M, Briggs DI, Viano DC, Kreipke CW, Kuhn DM (2012) A mouse model of human repetitive mild traumatic brain injury. J Neurosci Methods 203(1):41–49. doi:10.1016/j.jneumeth.2011.09.003
59. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci: Off J Soc Neurosci 29(43):13435–13444. doi:10.1523/JNEUROSCI.3257-09.2009
60. Kleim JA, Kleim ED, Cramer SC (2007) Systematic assessment of training-induced changes in corticospinal output to hand using frameless stereotaxic transcranial magnetic stimulation. Nat Protoc 2(7):1675–1684. doi:10.1038/nprot.2007.206
61. Kline AE, Leary JB, Radabaugh HL, Cheng JP, Bondi CO (2016) Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: is more better? Prog Neurobiol. doi:10.1016/j.pneurobio.2016.05.002
62. Kuhle J, Gaiottino J, Leppert D, Petzold A, Bestwick JP, Malaspina A, Lu CH, Dobson R, Disanto G, Norgren N, Nissim A, Kappos L, Hurlbert J, Yong VW, Giovannoni G, Casha S (2015) Serum neurofilament light chain is a biomarker of human spinal cord injury severity and outcome. J Neurol Neurosurg Psychiatry 86(3):273–279. doi:10.1136/jnnp-2013-307454
63. Kumar A, Loane DJ (2012) Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun 26(8):1191–1201. doi:10.1016/j.bbi.2012.06.008
64. Liao GP, Harting MT, Hetz RA, Walker PA, Shah SK, Corkins CJ, Hughes TG, Jimenez F, Kosmach SC, Day MC, Tsao K, Lee DA, Worth LL, Baumgartner JE, Cox CS Jr (2015) Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children. Pediatr Crit Care Med: J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc 16(3):245–255. doi:10.1097/PCC.0000000000000324
65. Loane DJ, Stoica BA, Tchantchou F, Kumar A, Barrett JP, Akintola T, Xue F, Conn PJ, Faden AI (2014) Novel mGluR5 positive allosteric modulator improves functional recovery, attenuates neurodegeneration, and alters microglial polarization after experimental traumatic brain injury. Neurother: J Am Soc Exp Neurother 11(4):857–869. doi:10.1007/s13311-014-0298-6
66. Luan Z, Qu S, Du K, Liu W, Yang Y, Wang Z, Cui Y, Du Q (2013) Neural stem/progenitor cell transplantation for cortical visual impairment in neonatal brain injured patients. Cell Transplant 22(Suppl 1):S101–S112. doi:10.3727/096368913X672163
67. Lv Q, Fan X, Xu G, Liu Q, Tian L, Cai X, Sun W, Wang X, Cai Q, Bao Y, Zhou L, Zhang Y, Ge L, Guo R, Liu X (2013) Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats. Brain Res 1493:80–89. doi:10.1016/j.brainres.2012.11.028
68. Ma H, Yu B, Kong L, Zhang Y, Shi Y (2012) Neural stem cells over-expressing brain-derived neurotrophic factor (BDNF) stimulate synaptic protein expression and promote functional recovery following transplantation in rat model of traumatic brain injury. Neurochem Res 37(1):69–83. doi:10.1007/s11064-011-0584-1
69. Ma J, Zhang Z, Su Y, Kang L, Geng D, Wang Y, Luan F, Wang M, Cui H (2013) Magnetic stimulation modulates structural synaptic plasticity and regulates BDNF-TrkB signal pathway in cultured hippocampal neurons. Neurochem Int 62(1):84–91. doi:10.1016/j.neuint.2012.11.010
70. MacDonald E, Van der Lee H, Pocock D, Cole C, Thomas N, VandenBerg PM, Bourtchouladze R, Kleim JA (2007) A novel phosphodiesterase type 4 inhibitor, HT-0712, enhances rehabilitation-dependent motor recovery and cortical reorganization after focal cortical ischemia. Neurorehabil Neural Repair 21(6):486–496. doi:10.1177/1545968307305521
71. Mandrekar-Colucci S, Sauerbeck A, Popovich PG, McTigue DM (2013) PPAR agonists as therapeutics for CNS trauma and neurological diseases. ASN Neuro 5(5):e00129. doi:10.1042/AN20130030
72. Mandyam CD, Schilling JM, Cui W, Egawa J, Niesman IR, Kellerhals SE, Staples MC, Busija AR, Risbrough VB, Posadas E, Grogman GC, Chang JW, Roth DM, Patel PM, Patel HH, Head BP (2015) Neuron-targeted caveolin-1 improves molecular signaling, plasticity, and behavior dependent on the hippocampus in adult and aged mice. Biol Psychiatry. doi:10.1016/j.biopsych.2015.09.020
73. Maningat PD, Sen P, Rijnkels M, Hadsell DL, Bray MS, Haymond MW (2011) Short-term administration of rhGH increases markers of cellular proliferation but not milk protein gene expression in normal lactating women. Physiol Genomics 43(8):381–391. doi:10.1152/physiolgenomics.00079.2010
74. Marmarou A, Foda MA, van den Brink W, Campbell J, Kita H, Demetriadou K (1994) A new model of diffuse brain injury in rats. Part I: pathophysiology and biomechanics. J Neurosurg 80(2):291–300. doi:10.3171/jns.1994.80.2.0291
75. Ming GL, Song HJ, Berninger B, Holt CE, Tessier-Lavigne M, Poo MM (1997) cAMP-dependent growth cone guidance by netrin-1. Neuron 19(6):1225–1235
76. Mouhieddine TH, Kobeissy FH, Itani M, Nokkari A, Wang KK (2014) Stem cells in neuroinjury and neurodegenerative disorders: challenges and future neurotherapeutic prospects. Neural Regen Res 9(9):901–906. doi:10.4103/1673-5374.133129
77. Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB (2004) Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med 117(11):823–829. doi:10.1016/j.amjmed.2004.07.041
78. Murlidharan G, Samulski RJ, Asokan A (2014) Biology of adeno-associated viral vectors in the central nervous system. Front Mol Neurosci 7:76. doi:10.3389/fnmol.2014.00076
79. Murray AJ, Tucker SJ, Shewan DA (2009) cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A. J Neurosci: Off J Soc Neurosci 29(49):15434–15444. doi:10.1523/JNEUROSCI.3071-09.2009
80. Neggers SF, Langerak TR, Schutter DJ, Mandl RC, Ramsey NF, Lemmens PJ, Postma A (2004) A stereotactic method for image-guided transcranial magnetic stimulation validated with fMRI and motor-evoked potentials. Neuroimage 21(4):1805–1817. doi:10.1016/j.neuroimage.2003.12.006
81. Nichol A, French C, Little L, Presneill J, Cooper DJ, Haddad S, Duranteau J, Huet O, Skrifvars M, Arabi Y, Bellomo R, Investigators E-T, the A, New Zealand Intensive Care Society Clinical Trials G (2015) G2015Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial. Trials 16(1):39. doi:10.1186/s13063-014-0528-6
82. Niesman IR, Schilling JM, Shapiro LA, Kellerhals SE, Bonds JA, Kleschevnikov AM, Cui W, Voong A, Krajewski S, Ali SS, Roth DM, Patel HH, Patel PM, Head BP (2014) Traumatic brain injury enhances neuroinflammation and lesion volume in caveolin deficient mice. J Neuroinflamm 11(1):39. doi:10.1186/1742-2094-11-39
83. Niethammer P, Delling M, Sytnyk V, Dityatev A, Fukami K, Schachner M (2002) Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis. J Cell Biol 157(3):521–532. doi:10.1083/jcb.200109059
84. Norton L, Hutchison RM, Young GB, Lee DH, Sharpe MD, Mirsattari SM (2012) Disruptions of functional connectivity in the default mode network of comatose patients. Neurology 78(3):175–181. doi:10.1212/WNL.0b013e31823fcd61
85. Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19(12):1584–1596. doi:10.1038/nm.3407
86. Padala KP, Padala PR, McNeilly DP, Geske JA, Sullivan DH, Potter JF (2012) The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer’s dementia: a prospective withdrawal and rechallenge pilot study. Am J Geriatr Pharmacother 10(5):296–302. doi:10.1016/j.amjopharm.2012.08.002
87. Peng W, Xing Z, Yang J, Wang Y, Wang W, Huang W (2014) The efficacy of erythropoietin in treating experimental traumatic brain injury: a systematic review of controlled trials in animal models. J Neurosurg 121(3):653–664. doi:10.3171/2014.6.JNS132577
88. Perlson E, Maday S, Fu MM, Moughamian AJ, Holzbaur EL (2010) Retrograde axonal transport: pathways to cell death? Trends Neurosci 33(7):335–344. doi:10.1016/j.tins.2010.03.006
89. Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci: Off J Soc Neurosci 27(40):10714–10721. doi:10.1523/JNEUROSCI.1922-07.2007
90. Presneill J, Little L, Nichol A, French C, Cooper DJ, Haddad S, Duranteau J, Huet O, Skrifvars M, Arabi Y, Bellomo R (2014) Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury. Trials 15(1):501. doi:10.1186/1745-6215-15-501
91. Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X, Samulski RJ (2002) Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 76(2):791–801
92. Reneer DV, Hisel RD, Hoffman JM, Kryscio RJ, Lusk BT, Geddes JW (2011) A multi-mode shock tube for investigation of blast-induced traumatic brain injury. J Neurotrauma 28(1):95–104. doi:10.1089/neu.2010.1513
93. Rizvanov AA, Guseva DS, Salafutdinov II, Kudryashova NV, Bashirov FV, Kiyasov AP, Yalvac ME, Gazizov IM, Kaligin MS, Sahin F, Mukhamedyarov MA, Palotas A, Islamov RR (2011) Genetically modified human umbilical cord blood cells expressing vascular endothelial growth factor and fibroblast growth factor 2 differentiate into glial cells after transplantation into amyotrophic lateral sclerosis transgenic mice. Exp Biol Med 236(1):91–98. doi:10.1258/ebm.2010.010172
94. Saatman KE, Creed J, Raghupathi R (2010) Calpain as a therapeutic target in traumatic brain injury. Neurother: J Am Soc Exp Neurother 7(1):31–42. doi:10.1016/j.nurt.2009.11.002
95. Sabirzhanov B, Zhao Z, Stoica BA, Loane DJ, Wu J, Borroto C, Dorsey SG, Faden AI (2014) Downregulation of miR-23a and miR-27a following experimental traumatic brain injury induces neuronal cell death through activation of proapoptotic Bcl-2 proteins. J Neurosci: Off J Soc Neurosci 34(30):10055–10071. doi:10.1523/JNEUROSCI.1260-14.2014
96. Sabirzhanova I, Liu C, Zhao J, Bramlett H, Dietrich WD, Hu B (2013) Changes in the GEF-H1 pathways after traumatic brain injury. J Neurotrauma 30(16):1449–1456. doi:10.1089/neu.2012.2673
97. Sauerbeck A, Gao J, Readnower R, Liu M, Pauly JR, Bing G, Sullivan PG (2011) Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury. Exp Neurol 227(1):128–135. doi:10.1016/j.expneurol.2010.10.003
98. Schilling JM, Cui W, Godoy JC, Risbrough VB, Niesman IR, Roth DM, Patel PM, Drummond JC, Patel HH, Zemljic-Harpf AE, Head BP (2014) Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry. Behav Brain Res 267:6–11. doi:10.1016/j.bbr.2014.03.014
99. Sharp DJ (2014) The association of traumatic brain injury with rate of progression of cognitive and functional impairment in a population-based cohort of Alzheimer’s disease: the Cache County dementia progression study by Gilbert et al. Late effects of traumatic brain injury on dementia progression. Int Psychogeriatr/IPA 26(10):1591–1592. doi:10.1017/S1041610214001689
100. Sharp DJ, Scott G, Leech R (2014) Network dysfunction after traumatic brain injury. Nat Rev Neurol 10(3):156–166. doi:10.1038/nrneurol.2014.15
101. Shetty AK, Mishra V, Kodali M, Hattiangady B (2014) Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves. Front Cell Neurosci 8:232. doi:10.3389/fncel.2014.00232
102. Shewan D, Dwivedy A, Anderson R, Holt CE (2002) Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway. Nat Neurosci 5(10):955–962. doi:10.1038/nn919
103. Shlosberg D, Benifla M, Kaufer D, Friedman A (2010) Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6(7):393–403. doi:10.1038/nrneurol.2010.74
104. Shultz SR, MacFabe DF, Foley KA, Taylor R, Cain DP (2011) A single mild fluid percussion injury induces short-term behavioral and neuropathological changes in the Long-Evans rat: support for an animal model of concussion. Behav Brain Res 224(2):326–335. doi:10.1016/j.bbr.2011.06.012
105. Shultz SR, Bao F, Omana V, Chiu C, Brown A, Cain DP (2012) Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioral impairments, neuroinflammation, and cortical loss in an animal model of repeated concussion. J Neurotrauma 29(2):281–294. doi:10.1089/neu.2011.2123
106. Song HJ, Poo MM (1999) Signal transduction underlying growth cone guidance by diffusible factors. Curr Opin Neurobiol 9(3):355–363
107. Sridharan D, Levitin DJ, Menon V (2008) A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc Natl Acad Sci USA 105(34):12569–12574. doi:10.1073/pnas.0800005105
108. Taylor SR, Smith C, Harris BT, Costine BA, Duhaime AC (2013) Maturation-dependent response of neurogenesis after traumatic brain injury in children. J Neurosurg Pediatr 12(6):545–554. doi:10.3171/2013.8.PEDS13154
109. Thal SC, Heinemann M, Luh C, Pieter D, Werner C, Engelhard K (2011) Pioglitazone reduces secondary brain damage after experimental brain trauma by PPAR-gamma-independent mechanisms. J Neurotrauma 28(6):983–993. doi:10.1089/neu.2010.1685
110. Thau-Zuchman O, Shohami E, Alexandrovich AG, Leker RR (2012) Combination of vascular endothelial and fibroblast growth factor 2 for induction of neurogenesis and angiogenesis after traumatic brain injury. J Mol Neurosci: MN 47(1):166–172. doi:10.1007/s12031-012-9706-8
111. Thompson HJ, Lifshitz J, Marklund N, Grady MS, Graham DI, Hovda DA, McIntosh TK (2005) Lateral fluid percussion brain injury: a 15-year review and evaluation. J Neurotrauma 22(1):42–75. doi:10.1089/neu.2005.22.42
112. Tian L, Guo R, Yue X, Lv Q, Ye X, Wang Z, Chen Z, Wu B, Xu G, Liu X (2012) Intranasal administration of nerve growth factor ameliorate beta-amyloid deposition after traumatic brain injury in rats. Brain Res 1440:47–55. doi:10.1016/j.brainres.2011.12.059
113. Titus DJ, Furones C, Kang Y, Atkins CM (2013a) Age-dependent alterations in cAMP signaling contribute to synaptic plasticity deficits following traumatic brain injury. Neuroscience 231:182–194. doi:10.1016/j.neuroscience.2012.12.002
114. Titus DJ, Sakurai A, Kang Y, Furones C, Jergova S, Santos R, Sick TJ, Atkins CM (2013b) Phosphodiesterase inhibition rescues chronic cognitive deficits induced by traumatic brain injury. J Neurosci: Off J Soc Neurosci 33(12):5216–5226. doi:10.1523/JNEUROSCI.5133-12.2013
115. Vandenberghe LH, Wilson JM, Gao G (2009) Tailoring the AAV vector capsid for gene therapy. Gene Ther 16(3):311–319. doi:10.1038/gt.2008.170
116. Vang AG, Ben-Sasson SZ, Dong H, Kream B, DeNinno MP, Claffey MM, Housley W, Clark RB, Epstein PM, Brocke S (2010) PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER. PLoS One 5(8):e12011. doi:10.1371/journal.pone.0012011
117. Villamar MF, Santos Portilla A, Fregni F, Zafonte R (2012) Noninvasive brain stimulation to modulate neuroplasticity in traumatic brain injury. Neuromodul: J Int Neuromodul Soc 15(4):326–338. doi:10.1111/j.1525-1403.2012.00474.x
118. Villapol S, Yaszemski AK, Logan TT, Sanchez-Lemus E, Saavedra JM, Symes AJ (2012) Candesartan, an angiotensin II AT(1)-receptor blocker and PPAR-gamma agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol 37(13):2817–2829. doi:10.1038/npp.2012.152
119. Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM (2003) Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 23(7):871–880
120. Wang Y, Neumann M, Hansen K, Hong SM, Kim S, Noble-Haeusslein LJ, Liu J (2011) Fluoxetine increases hippocampal neurogenesis and induces epigenetic factors but does not improve functional recovery after traumatic brain injury. J Neurotrauma 28(2):259–268. doi:10.1089/neu.2010.1648
121. Wang S, Cheng H, Dai G, Wang X, Hua R, Liu X, Wang P, Chen G, Yue W, An Y (2013) Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain Res 1532:76–84. doi:10.1016/j.brainres.2013.08.001
122. Wang L, Wang X, Su H, Han Z, Yu H, Wang D, Jiang R, Liu Z, Zhang J (2015) Recombinant human erythropoietin improves the neurofunctional recovery of rats following traumatic brain injury via an increase in circulating endothelial progenitor cells. Transl Stroke Res 6(1):50–59. doi:10.1007/s12975-014-0362-x
123. Wetherington J, Serrano G, Dingledine R (2008) Astrocytes in the epileptic brain. Neuron 58(2):168–178. doi:10.1016/j.neuron.2008.04.002
124. Willmann R, Pun S, Stallmach L, Sadasivam G, Santos AF, Caroni P, Fuhrer C (2006) Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscular junction. The EMBO J 25(17):4050–4060. doi:10.1038/sj.emboj.7601288
125. Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH (2001) Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels. J Neurosci: Off J Soc Neurosci 21(6):1923–1930
126. Xiao X, Xiao W, Li J, Samulski RJ (1997) A novel 165-base-pair terminal repeat sequence is the sole cis requirement for the adeno-associated virus life cycle. J Virol 71(2):941–948
127. Xiao X, Li J, Samulski RJ (1998) Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol 72(3):2224–2232
128. Xiong Y, Mahmood A, Chopp M (2013) Animal models of traumatic brain injury. Nat Rev Neurosci 14(2):128–142. doi:10.1038/nrn3407
129. Yi JH, Park SW, Brooks N, Lang BT, Vemuganti R (2008) PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. Brain Res 1244:164–172. doi:10.1016/j.brainres.2008.09.074
130. Yonutas HM, Sullivan PG (2013) Targeting PPAR isoforms following CNS injury. Curr Drug Targets 14(7):733–742
131. Yuan Y, Zhu F, Pu Y, Wang D, Huang A, Hu X, Qin S, Sun X, Su Z, He C (2015) Neuroprotective effects of nitidine against traumatic CNS injury via inhibiting microglia activation. Brain Behav Immun. doi:10.1016/j.bbi.2015.04.008
132. Zetterberg H, Smith DH, Blennow K (2013) Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat Rev Neurol 9(4):201–210. doi:10.1038/nrneurol.2013.9
133. Zonta B, Minichiello L (2013) Synaptic membrane rafts: traffic lights for local neurotrophin signaling? Front Synaptic Neurosci 5:9. doi:10.3389/fnsyn.2013.00009