Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Cell Death and Recovery in Traumatic Brain Injury

  • 7 Accesses

Abstract

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. Although TBI leads to mechanical damage during initial impact, secondary damage also occurs as results from delayed neurochemical process and intracellular signaling pathways. Accumulated animal and human studies demonstrated that apoptotic mechanism contributes to overall pathology of TBI. Apoptotic cell death has been identified within contusional brain lesion at acute phase of TBI and in region remote from the site directly injured in days to weeks after trauma. TBI is also dynamic conditions that cause neuronal decline overtime and is likely due to neurodegenerative mechanisms years after trauma. Current studies have even suggested association of neuronal damage through apoptotic pathway with mild TBI, which contributes chronic persistent neurological symptoms and cognitive deficits. Thus, a better understanding of the acute and chronic consequences of apoptosis following TBI is required. The purpose of this review is to describe (1) neuronal apoptotic pathway following TBI, (2) contribution of apoptosis to acute and chronic phase of TBI, and (3) current treatment targeting on apoptotic pathway.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths - United States, 2007 and 2013. MMWR Surveill Summ 2017;66:1–16.

  2. 2.

    Loane DJ, Faden AI. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci 2010;31:596–604.

  3. 3.

    Bramlett HM, Dietrich WD, Green EJ, Busto R. Chronic histopathological consequences of fluid-percussion brain injury in rats: effects of post-traumatic hypothermia. Acta Neuropathol 1997;93:190–199.

  4. 4.

    Colicos MA, Dixon CE, Dash PK. Delayed, selective neuronal death following experimental cortical impact injury in rats: possible role in memory deficits. Brain Res 1996;739:111–119.

  5. 5.

    Dietrich WD, Alonso O, Halley M. Early microvascular and neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats. J Neurotrauma 1994;11:289–301.

  6. 6.

    Hicks R, Soares H, Smith D, McIntosh T. Temporal and spatial characterization of neuronal injury following lateral fluid-percussion brain injury in the rat. Acta Neuropathol 1996;91:236–246.

  7. 7.

    Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 1992;119:493–501.

  8. 8.

    Nakamura M, Raghupathi R, Merry DE, Scherbel U, Saatman KE, Mcintosh TK. Overexpression of Bcl-2 is neuroprotective after experimental brain injury in transgenic mice. J Comp Neurol 1999;412:681–692.

  9. 9.

    Raghupathi R, Fernandez SC, Murai H, et al. BCL-2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice. J Cereb Blood Flow Metab 1998;18:1259–1269.

  10. 10.

    Conti AC, Raghupathi R, Trojanowski JQ, McIntosh TK. Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period. J Neurosci 1998;18:5663–5672.

  11. 11.

    Clark RS, Chen J, Watkins SC, et al. Apoptosis-suppressor gene bcl-2 expression after traumatic brain injury in rats. J Neurosci 1997;17:9172–9182.

  12. 12.

    Kaya SS, Mahmood A, Li Y, Yavuz E, Göksel M, Chopp M. Apoptosis and expression of p53 response proteins and cyclin D1 after cortical impact in rat brain. Brain Res 1999;818:23–33.

  13. 13.

    Fox GB, Fan L, Levasseur RA, Faden AI. Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse. J Neurotrauma 1998;15:599–614.

  14. 14.

    Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL. A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 1991;39:253–262.

  15. 15.

    Hamm RJ, Dixon CE, Gbadebo DM, et al. Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J Neurotrauma 1992;9:11–20.

  16. 16.

    Clark RS, Kochanek PM, Chen M, et al. Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB J 1999;13:813–821.

  17. 17.

    Smith FM, Raghupathi R, MacKinnon MA, et al. TUNEL-positive staining of surface contusions after fatal head injury in man. Acta Neuropathol 2000;100:537–545.

  18. 18.

    Dressler J, Hanisch U, Kuhlisch E, Geiger KD. Neuronal and glial apoptosis in human traumatic brain injury. Int J Legal Med 2007;121:365–375.

  19. 19.

    Fowler J, MacKinnon MA, Raghupathi R, Saatman KE, McIntosh TK, Graham DI. Age does not influence DNA fragmentation in the hippocampus after fatal traumatic brain injury in young and aged humans compared with controls. Clin Neuropathol 2002;21:156–162.

  20. 20.

    Niizuma K, Yoshioka H, Chen H, et al. Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta 2010;1802:92–99.

  21. 21.

    Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: lessons from animal models. Metab Brain Dis 2004;19:151–167.

  22. 22.

    Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999;22:391–397.

  23. 23.

    Culmsee C, Zhu C, Landshamer S, et al. Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 2005;25:10262–10272.

  24. 24.

    Love S. Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:267–282.

  25. 25.

    Wang KK. Calpain and caspase: can you tell the difference. Trends Neurosci 2000;23:20–26.

  26. 26.

    Yamada KH, Kozlowski DA, Seidl SE, et al. Targeted gene inactivation of calpain-1 suppresses cortical degeneration due to traumatic brain injury and neuronal apoptosis induced by oxidative stress. J Biol Chem 2012;287:13182–13193.

  27. 27.

    Toescu EC. Apoptosis and cell death in neuronal cells: where does Ca2+ fit in. Cell Calcium 1998;24:387–403.

  28. 28.

    Weber JT. Altered calcium signaling following traumatic brain injury. Front Pharmacol 2012;3:60.

  29. 29.

    Kim H, Rafiuddin-Shah M, Tu HC, et al. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 2006;8:1348–1358.

  30. 30.

    Kamada H, Nito C, Endo H, Chan PH. Bad as a converging signaling molecule between survival PI3-K/Akt and death JNK in neurons after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2007;27:521–533.

  31. 31.

    Okuno S, Saito A, Hayashi T, Chan PH. The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 2004;24:7879–7887.

  32. 32.

    Endo H, Kamada H, Nito C, Nishi T, Chan PH. Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci 2006;26:7974–7983.

  33. 33.

    Niizuma K, Endo H, Nito C, Myer DJ, Chan PH. Potential role of PUMA in delayed death of hippocampal CA1 neurons after transient global cereb ral ischemia. Stroke 2009;40:618–625.

  34. 34.

    Fujimura M, Morita-Fujimura Y, Kawase M, et al. Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. J Neurosci 1999;19:3414–3422.

  35. 35.

    Kirkland RA, Windelborn JA, Kasprzak JM, Franklin JL. A Bax-induced pro-oxidant state is critical for cytochrome c release during programmed neuronal death. J Neurosci 2002;22:6480–6490.

  36. 36.

    Saito A, Hayashi T, Okuno S, Ferrand-Drake M, Chan PH. Interaction between XIAP and Smac/DIABLO in the mouse brain after transient focal cerebral ischemia. J Cereb Blood Flow Metab 2003;23:1010–1019.

  37. 37.

    Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci 1997;20:245–267.

  38. 38.

    Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479–489.

  39. 39.

    Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-depe ndent activation of caspase-3. Cell 1997;90:405–413.

  40. 40.

    LaPlaca MC, Raghupathi R, Verma A, et al. Temporal patterns of poly(ADP-ribose) polymerase activation in the cortex following experimental brain injury in the rat. J Neurochem 1999;73:205–213.

  41. 41.

    Chaitanya GV, Babu PP. Differential PARP cleavage: an indication of heterogeneous forms of cell death and involvement of multiple proteases in the infarct of focal cerebral ischemia in rat. Cell Mol Neurobiol 2009;29:563–573.

  42. 42.

    Greenberg DS. Medicine and public affairs. FDA: poor marks for its self-investigation. N Engl J Med 1976;294:1465–1466.

  43. 43.

    Zhang X, Chen J, Graham SH, et al. Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. J Neurochem 2002;82:181–191.

  44. 44.

    Cregan SP, Dawson VL, Slack RS. Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 2004;23:2785–2796.

  45. 45.

    Candé C, Vahsen N, Garrido C, Kroemer G. Apoptosis-inducing factor (AIF): caspase-independent after all. Cell Death Differ 2004;11:591–595.

  46. 46.

    Whalen MJ, Clark RS, Dixon CE, et al. Reduction of cognitive and motor deficits after traumatic brain injury in mice deficient in poly(ADP-ribose) polymerase. J Cereb Blood Flow Metab 1999;19:835–842.

  47. 47.

    Galat A. Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity--targets--functions. Curr Top Med Chem 2003;3:1315–1347.

  48. 48.

    Candé C, Vahsen N, Kouranti I, et al. AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene 2004;23:1514–1521.

  49. 49.

    Parcellier A, Gurbuxani S, Schmitt E, Solary E, Garrido C. Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways. Biochem Biophys Res Commun 2003;304:505–512.

  50. 50.

    Gurbuxani S, Schmitt E, Cande C, et al. Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 2003;22:6669–6678.

  51. 51.

    Matsumori Y, Hong SM, Aoyama K, et al. Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. J Cereb Blood Flow Metab 2005;25:899–910.

  52. 52.

    Alano CC, Ying W, Swanson RA. Poly(ADP-ribose) polymerase-1-mediated cell death in astrocytes requires NAD+ depletion and mitochondrial permeability transition. J Biol Chem 2004;279:18895–18902.

  53. 53.

    Moubarak RS, Yuste VJ, Artus C, et al. Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol 2007;27:4844–4862.

  54. 54.

    Lee BI, Lee DJ, Cho KJ, Kim GW. Early nuclear translocation of endonuclease G and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Neurosci Lett 2005;386:23–27.

  55. 55.

    Noshita N, Lewén A, Sugawara T, Chan PH. Akt phosphorylation and neuronal survival after traumatic brain injury in mice. Neurobiol Dis 2002;9:294–304.

  56. 56.

    Wang SJ, Omori N, Li F, et al. Potentiation of Akt and suppression of caspase-9 activations by electroacupuncture after transient middle cerebral artery occlusion in rats Neurosci Lett 2002;331:115–118.

  57. 57.

    Mori T, Wang X, Jung JC, et al. Mitogen-activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects. J Cereb Blood Flow Metab 2002;22:444–452.

  58. 58.

    Salvesen GS, Dixit VM. Caspase activation: the induced-proximity model. Proc Natl Acad Sci USA 1999;96:10964–10967.

  59. 59.

    Bermpohl D, You Z, Lo EH, Kim HH, Whalen MJ. TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice. J Cereb Blood Flow Metab 2007;27:1806–1818.

  60. 60.

    Rosenbaum DM, Gupta G, D'Amore J, et al. Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia. J Neurosci Res 2000;61:686–692.

  61. 61.

    Jin K, Graham SH, Mao X, Nagayama T, Simon RP, Greenberg DA. Fas (CD95) may mediate delayed cell death in hippocampal CA1 sector after global cerebral ischemia. J Cereb Blood Flow Metab 2001;21:1411–1421.

  62. 62.

    Plesnila N, Zinkel S, Le DA, et al. BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia. Proc Natl Acad Sci USA 2001;98:15318–15323.

  63. 63.

    Bell JD. Molecular cross talk in traumatic brain injury. J Neurosci 2007;27:2153–2154.

  64. 64.

    Sugawara T, Lewén A, Gasche Y, Yu F, Chan PH. Overexpression of SOD1 protects vulnerable motor neurons after spinal cord injury by attenuating mitochondrial cytochrome c release. FASEB J 2002;16:1997–1999.

  65. 65.

    Lawson LJ, Perry VH, Gordon S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 1992;48:405–415.

  66. 66.

    Tremblay MÈ, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A. The role of microglia in the healthy brain. J Neurosci 2011;31:16064–16069.

  67. 67.

    Marín-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M. Microglia promote the death of developing Purkinje cells. Neuron 2004;41:535–547.

  68. 68.

    Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med 2017;23:1018–1027.

  69. 69.

    Frade JM, Barde YA. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 1998;20:35–41.

  70. 70.

    Sedel F, Béchade C, Vyas S, Triller A. Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death. J Neurosci 2004;24:2236–2246.

  71. 71.

    Wang CF, Zhao CC, Liu WL, et al. Depletion of Microglia Attenuates Dendritic Spine Loss and Neuronal Apoptosis in the Acute Stage of Moderate Traumatic Brain Injury in Mice. J Neurotrauma 2020;37:43–54.

  72. 72.

    Bennett RE, Brody DL. Acute reduction of microglia does not alter axonal injury in a mouse model of repetitive concussive traumatic brain injury. J Neurotrauma 2014;31:1647–1663.

  73. 73.

    Hanlon LA, Raghupathi R, Huh JW. Depletion of microglia immediately following traumatic brain injury in the pediatric rat: Implications for cellular and behavioral pathology. Exp Neurol 2019;316:39–51.

  74. 74.

    Lin JH, Weigel H, Cotrina ML, et al. Gap-junction-mediated propagation and amplification of cell injury. Nat Neurosci 1998;1:494–500.

  75. 75.

    Ohsumi A, Nawashiro H, Otani N, Ooigawa H, Toyooka T, Shima K. Temporal and spatial profile of phosphorylated connexin43 after traumatic brain injury in rats. J Neurotrauma 2010;27:1255–1263.

  76. 76.

    Rovegno M, Soto PA, Sáez PJ, Naus CC, Sáez JC, von Bernhardi R. Connexin43 hemichannels mediate secondary cellular damage spread from the trauma zone to distal zones in astrocyte monolayers. Glia 2015;63:1185–1199.

  77. 77.

    Frantseva MV, Kokarovtseva L, Naus CG, Carlen PL, MacFabe D, Perez Velazquez JL. Specific gap junctions enhance the neuronal vulnerability to brain traumatic injury. J Neurosci 2002;22:644–653.

  78. 78.

    Siushansian R, Bechberger JF, Cechetto DF, Hachinski VC, Naus CC. Connexin43 null mutation increases infarct si ze after stroke. J Comp Neurol 2001;440:387–394.

  79. 79.

    Holroyd KA, Penzien DB. Meta-analysis minus the analysis: a prescription for confusio n. Pain 1989;39:359–363.

  80. 80.

    Carvey PM, Hendey B, Monahan AJ. The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. J Neurochem 2009;111:291–314.

  81. 81.

    Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000;1:120–129.

  82. 82.

    Bailes JE, Petraglia AL, Omalu BI, Nauman E, Talavage T. Role of subconcussion in repetitive mild traumatic brain injury. J Neurosurg 2013;119:1235–1245.

  83. 83.

    Daneshvar DH, Goldstein LE, Kiernan PT, Stein TD, McKee AC. Post-traumatic neurodegeneration and chronic traumatic encephalopathy. Mol Cell Neurosci 2015;66:81–90.

  84. 84.

    Smith DH, Chen XH, Pierce JE, et al. Progressive atrophy and neuron death for one year following brain trauma in the rat. J Neurotrauma 1997;14:715–727.

  85. 85.

    Bramlett HM, Dietrich WD. Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathol 2002;103:607–614.

  86. 86.

    Glushakova OY, Glushakov AO, Borlongan CV, Valadka AB, Hayes RL, Glushakov AV. Role of Caspase-3-Mediated Apoptosis in Chronic Caspase-3-Cleaved Tau Accumulation and Blood-Brain Barrier Damage in the Corpus Callosum after Traumatic Brain Injury in Rats. J Neurotrauma 2018;35:157–173.

  87. 87.

    Gaetz M, Goodman D, Weinberg H. Electrophysiological evidence for the cumulative effects of concussion. Brain Inj 2000;14:1077–1088.

  88. 88.

    Nakajima Y, Horiuchi Y, Kamata H, Yukawa M, Kuwabara M, Tsubokawa T. Distinct time courses of secondary brain damage in the hippocampus following brain concussion and contusion in rats. Tohoku J Exp Med 2010;221:229–235.

  89. 89.

    Luo Y, Zou H, Wu Y, Cai F, Zhang S, Song W. Mild traumatic brain injury induces memory deficits with alteration of gene expression

  90. 90.

    Luo Y, Zou H, Wu Y, Cai F, Zhang S, Song W. Mild traumatic brain injury induces memory deficits with alteration of gene expression profile. Sci Rep 2017;7:10846.

  91. 91.

    Dikranian K, Cohen R, Mac Donald C, et al. Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons. Exp Neurol 2008;211:551–560.

  92. 92.

    Matser JT, Kessels AG, Jordan BD, Lezak MD, Troost J. Chronic traumatic brain injury in professional soccer players. Neurology 1998;51:791–796.

  93. 93.

    Aungst SL, Kabadi SV, Thompson SM, Stoica BA, Faden AI. Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits. J Cereb Blood Flow Metab 2014;34:1223–1232.

  94. 94.

    Uzan M, Erman H, Tanriverdi T, Sanus GZ, Kafadar A, Uzun H. Evaluation of apoptosis in cerebrospinal fluid of patients with severe head injury. Acta Neurochir (Wien) 2006;148:1157–64; discussion.

  95. 95.

    Härter L, Keel M, Hentze H, Leist M, Ertel W. Caspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury. J Neuroimmunol 2001;121:76–78.

  96. 96.

    Lorente L, Martín MM, Argueso M, et al. Serum caspase-3 levels and mortality are associated in patients with severe traumatic brain injury. BMC Neurol 2015;15:228.

  97. 97.

    Darwish RS, Amiridze NS. Detectable levels of cytochrome C and activated caspase-9 in cerebrospinal fluid after human traumatic brain injury. Neurocrit Care 2010;12:337–341.

  98. 98.

    Lorente L, Martín MM, González-Rivero AF, et al. Serum levels of caspase-cleaved cytokeratin-18 in patients with severe traumatic brain injury are associated with mortality: a pilot study. PLoS ONE 2015;10:e0121739.

  99. 99.

    Pineda JA, Lewis SB, Valadka AB, et al. Clinical significance of alphaII-spectrin breakdown products in cerebrospinal fluid after severe traumatic brain injury. J Neurotrauma 2007;24:354–366.

  100. 100.

    Mondello S, Robicsek SA, Gabrielli A, et al. αII-spectrin breakdown products (SBDPs): diagnosis and outcome in severe traumatic brain injury patients. J Neurotrauma 2010;27:1203–1213.

  101. 101.

    Shahim P, Linemann T, Inekci D, et al. Serum Tau Fragments Predict Return to Play in Concussed Professional Ice Hockey Players. J Neurotrauma 2016;33:1995–1999.

  102. 102.

    Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci 1991;14:453–501.

  103. 103.

    Yakovlev AG, Knoblach SM, Fan L, Fox GB, Goodnight R, Faden AI. Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 1997;17:7415–7424.

  104. 104.

    Clark RS, Kochanek PM, Watkins SC, et al. Caspase-3 mediated neuronal death after traumatic brain injury in rats. J Neurochem 2000;74:740–753.

  105. 105.

    Knoblach SM, Nikolaeva M, Huang X, et al. Multiple caspases are activated after traumatic brain injury: evidence for involvement in functional outcome. J Neurotrauma 2002;19:1155–1170

  106. 106.

    Clark RS, Nathaniel PD, Zhang X, et al. boc-Aspartyl(OMe)-fluoromethylketone attenuates mitochondrial release of cytochrome c and delays brain tissue loss after traumatic brain injury in rats. J Cereb Blood Flow Metab 2007;27:316–326.

  107. 107.

    Clark RS, Vagni VA, Nathaniel PD, Jenkins LW, Dixon CE, Szabó C. Local administration of the poly(ADP-ribose) polymerase inhibitor INO-1001 prevents NAD+ depletion and improves water maze performance after traumatic brain injury in mice. J Neurotrauma 2007;24:1399–1405.

  108. 108.

    LaPlaca MC, Zhang J, Raghupathi R, et al. Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats. J Neurotrauma 2001;18:369–376.

  109. 109.

    Yu SW, Wang H, Poitras MF, et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 2002;297:259–263.

  110. 110.

    Vink R, Nimmo AJ. Multifunctional drugs for head injury. Neurotherapeutics 2009;6:28–42.

  111. 111.

    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.

  112. 112.

    Chen G, Zhang S, Shi J, Ai J, Qi M, Hang C. Simvastatin reduces secondary brain injury caused by cortical contusion in rats: possible involvement of TLR4/NF-kappaB pathway. Exp Neurol 2009;216:398–406.

  113. 113.

    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.

  114. 114.

    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.

  115. 115.

    Tapia-Perez J, 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.

  116. 116.

    Sánchez-Aguilar M, Tapia-Pérez JH, Sánchez-Rodríguez JJ, et al. Effect of rosuvastatin on cytokines after traumatic head injury. J Neurosurg 2013;118:669–675.

  117. 117.

    Whyte J, Ketchum JM, Bogner J, et al. Effects of Statin Treatment on Outcomes after Traumatic Brain Injury. J Neurotrauma [published online: August 28, 2018]. https://doi.org/10.1089/neu.2017.5545

  118. 118.

    Smith SS. Progesterone administration attenuates excitatory amino acid responses of cerebellar Purkinje cells. Neuroscience 1991;42:309–320.

  119. 119.

    Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol 1997;31:1–11.

  120. 120.

    Pan DS, Liu WG, Yang XF, Cao F. Inhibitory effect of progesterone on inflammatory factors after experimental traumatic brain injury. Biomed Environ Sci 2007;20:432–438.

  121. 121.

    Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res 2005;1049:112–119.

  122. 122.

    He J, Hoffman SW, Stein DG. Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury. Restor Neurol Neurosci 2004;22:19–31.

  123. 123.

    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, 402.e1–2.

  124. 124.

    Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 2008;12:R61.

  125. 125.

    Skolnick BE, Maas AI, Narayan RK, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med 2014;371:2467–2476.

  126. 126.

    Mazzeo AT, Beat A, Singh A, Bullock MR. The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI. Exp Neurol 2009;218:363–370.

  127. 127.

    Mbye LH, Singh IN, Carrico KM, Saatman KE, Hall ED. Comparative neuroprotective effects of cyclosporin A and NIM811, a nonimmunosuppressive cyclosporin A analog, following traumatic brain injury. J Cereb Blood Flow Metab 2009;29:87–97.

  128. 128.

    Mazzeo AT, Alves OL, Gilman CB, et al. Brain metabolic and hemodynamic effects of cyclosporin A after human severe traumatic brain injury: a microdialysis study. Acta Neurochir (Wien) 2008;150:1019–31; discussion 1031.

  129. 129.

    Margulies S, Hicks R, Ansel B, et al. Combination therapies for traumatic brain injury: prospective considerations. J Neurotrauma 2009;26:925–939.

  130. 130.

    Karlsson M, Pukenas B, Chawla S, et al. Neuroprotective Effects of Cyclosporine in a Porcine Pre-Clinical Trial of Focal Traumatic Brain Injury. J Neurotrauma [published online: July 24, 2018]. https://doi.org/10.1089/neu.2018.5706

Download references

Acknowledgments

Dr. Hanafy receives support from the National Institute of Neurological Disorders and Stroke (R21NS099606 and R01NS109174) and the American Heart Association Grant in Aid (17GRNT33670058).

Required Author Forms Disclosure Forms provided by the authors are available with the online version of this article.

Author information

YA and KAH were involved in drafting and editing the manuscript and figures. Both authors consent to this publication.

Correspondence to Khalid A. Hanafy.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Akamatsu, Y., Hanafy, K.A. Cell Death and Recovery in Traumatic Brain Injury. Neurotherapeutics (2020). https://doi.org/10.1007/s13311-020-00840-7

Download citation

Keywords

  • Cell death
  • Recovery
  • Traumatic brain injury