The role of mTOR signaling pathway in spinal cord injury

Cell Cycle

Volumn 11, Issue 17, 2012, Pages 3175-3179

  Kanno, Haruo ^a   Ozawa, Hiroshi ^a   Sekiguchi, Akira ^a   Yamaya, Seiji ^a   Tateda, Satoshi ^a   Yahata, Kenichiro ^a   Itoi, Eiji ^a  

^a TOHOKU UNIVERSITY SCHOOL OF MEDICINE   (Japan)

Author keywords

Apoptosis; Autophagy; mTOR; Rapamycin; Spinal cord injury

Indexed keywords

EVEROLIMUS; MAMMALIAN TARGET OF RAPAMYCIN; RAPAMYCIN; RIDAFOROLIMUS; TEMSIROLIMUS; ZOTAROLIMUS;

CELL ACTIVATION; CELL AGING; CELL DEATH; DEMYELINATION; HUMAN; INFLAMMATION; LOCOMOTION; MACROPHAGE; MICROGLIA; NERVE FIBER DEGENERATION; NERVE REGENERATION; NEUROPROTECTION; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION; SPINAL CORD INJURY; TISSUE INJURY;

MAMMALIA; MUS;

EID: 84866282616     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.21262     Document Type: Review

References (77)

1. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124:471-84; PMID:16469695; http://dx.doi.org/10.1016/j. cell.2006.01.016.
2. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004; 36:585-95; PMID:15146184; http://dx.doi.org/10.1038/ng1362.
3. Santini E, Heiman M, Greengard P, Valjent E, Fisone G. Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced dyskinesia. Sci Signal 2009; 2:ra36; PMID:19622833; http://dx.doi.org/10.1126/scisignal.2000308.
4. Ma T, Hoeffer CA, Capetillo-Zarate E, Yu F, Wong H, Lin MT, et al. Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. PLoS ONE 2010; 5:5; PMID:20862226; http://dx.doi.org/10.1371/journal.pone.0012845.
5. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS ONE 2010; 5:e9979; PMID:20376313; http://dx.doi.org/10.1371/journal.pone.0009979.
6. Erlich S, Alexandrovich A, Shohami E, Pinkas-Kramarski R. Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol Dis 2007; 26:86-93; PMID:17270455; http://dx.doi.org/10.1016/j.nbd.2006.12.003.
7. Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis 2008; 32:329-39; PMID:18760364; http://dx.doi.org/10.1016/j.nbd.2008.07.022.
8. Sekiguchi A, Kanno H, Ozawa H, Yamaya S, Itoi E. Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. J Neurotrauma 2012; 29:946-56; PMID:21806471; http://dx.doi.org/10.1089/neu.2011.1919.
9. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 2008; 322:963-6; PMID:18988856; http://dx.doi.org/10.1126/science.1161566.
10. Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 2010; 13:1075-81; PMID:20694004; http://dx.doi.org/10.1038/nn.2603.
11. Codeluppi S, Svensson CI, Hefferan MP, Valencia F, Silldorff MD, Oshiro M, et al. The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord. J Neurosci 2009; 29:1093-104; PMID:19176818; http://dx.doi.org/10.1523/JNEUROSCI.4103-08.2009.
12. Schwab ME, Bartholdi D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 1996; 76:319-70; PMID:8618960.
13. Ozawa H, Keane RW, Marcillo AE, Diaz PH, Dietrich WD. Therapeutic strategies targeting caspase inhibition following spinal cord injury in rats. Exp Neurol 2002; 177:306-13; PMID:12429232; http://dx.doi.org/10.1006/exnr.2002. 7998.
14. Beattie MS, Farooqui AA, Bresnahan JC. Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma 2000; 17:915-25; PMID:11063057; http://dx.doi.org/10.1089/neu.2000.17.915.
15. Yong C, Arnold PM, Zoubine MN, Citron BA, Watanabe I, Berman NE, et al. Apoptosis in cellular compartments of rat spinal cord after severe contusion injury. J Neurotrauma 1998; 15:459-72; PMID:9674550; http://dx.doi.org/10.1089/ neu.1998.15.459.
16. Dusart I, Schwab ME. Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur J Neurosci 1994; 6:712-24; PMID:8075816; http://dx.doi.org/10.1111/j.1460-9568.1994.tb00983.x.
17. Citron BA, Arnold PM, Sebastian C, Qin F, Malladi S, Ameenuddin S, et al. Rapid upregulation of caspase-3 in rat spinal cord after injury: mRNA, protein, and cellular localization correlates with apoptotic cell death. Exp Neurol 2000; 166:213-26; PMID:11085887; http://dx.doi.org/10.1006/exnr.2000.7523.
18. Hill CE, Beattie MS, Bresnahan JC. Degeneration and sprouting of identified descending supraspinal axons after contusive spinal cord injury in the rat. Exp Neurol 2001; 171:153-69; PMID:11520130; http://dx.doi.org/10.1006/ exnr.2001.7734.
19. Totoiu MO, Keirstead HS. Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol 2005; 486:373-83; PMID:15846782; http://dx.doi.org/10.1002/cne.20517.
20. Barrett CP, Guth L, Donati EJ, Krikorian JG. Astroglial reaction in the gray matter lumbar segments after midthoracic transection of the adult rat spinal cord. Exp Neurol 1981; 73:365-77; PMID:6167460; http://dx.doi.org/10. 1016/0014-4886(81)90272-7.
21. Tokunaga S, Ozawa H, Kokubun S. Astrocytic response to spinal cord injury. J East Jpn Orthop Traumatol 2005; 17:550-8.
22. Dello Russo C, Lisi L, Tringali G, Navarra P. Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol 2009; 78:1242-51; PMID:19576187; http://dx.doi.org/10.1016/j.bcp.2009. 06.097.
23. Lu DY, Liou HC, Tang CH, Fu WM. Hypoxia-induced iNOS expression in microglia is regulated by the PI3-kinase/Akt/mTOR signaling pathway and activation of hypoxia inducible factor-1alpha. Biochem Pharmacol 2006; 72:992-1000; PMID:16919605; http://dx.doi.org/10.1016/j.bcp.2006.06.038.
24. Hu LY, Sun ZG, Wen YM, Cheng GZ, Wang SL, Zhao HB, et al. ATP-mediated protein kinase B Akt/mammalian target of rapamycin mTOR/p70 ribosomal S6 protein p70S6 kinase signaling pathway activation promotes improvement of locomotor function after spinal cord injury in rats. Neuroscience 2010; 169:1046-62; PMID:20678995; http://dx.doi.org/10.1016/j.neuroscience.2010.05.046.
25. Narayanan SP, Flores AI, Wang F, Macklin WB. Akt signals through the mammalian target of rapamycin pathway to regulate CNS myelination. J Neurosci 2009; 29:6860-70; PMID:19474313; http://dx.doi.org/10.1523/JNEUROSCI.0232-09. 2009.
26. Tyler WA, Gangoli N, Gokina P, Kim HA, Covey M, Levison SW, et al. Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. J Neurosci 2009; 29:6367-78; PMID:19439614; http://dx.doi.org/10.1523/JNEUROSCI.0234-09.2009.
27. Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J Neurosci 2010; 30:1166-75; PMID:20089925; http://dx.doi.org/10.1523/JNEUROSCI.3944-09.2010.
28. Khan S, Salloum F, Das A, Xi L, Vetrovec GW, Kukreja RC. Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. J Mol Cell Cardiol 2006; 41:256-64; PMID:16769083; http://dx.doi.org/10.1016/j.yjmcc.2006.04.014.
29. Pan T, Kondo S, Zhu W, Xie W, Jankovic J, Le W. Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol Dis 2008; 32:16-25; PMID:18640276; http://dx.doi.org/10.1016/j.nbd. 2008.06.003.
30. Ravikumar B, Berger Z, Vacher C, O'Kane CJ, Rubinsztein DC. Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 2006; 15:1209-16; PMID:16497721; http://dx.doi.org/10.1093/hmg/ddl036.
31. David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011; 12:388-99; PMID:21673720; http://dx.doi.org/10.1038/nrn3053.
32. Pineau I, Lacroix S. Proinflammatory cytokine synthesis in the injured mouse spinal cord: multiphasic expression pattern and identification of the cell types involved. J Comp Neurol 2007; 500:267-85; PMID:17111361; http://dx.doi.org/10.1002/cne.21149.
33. Yang L, Blumbergs PC, Jones NR, Manavis J, Sarvestani GT, Ghabriel MN. Early expression and cellular localization of proinf lammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in human traumatic spinal cord injury. Spine (Phila Pa 1976) 2004; 29:966-71; PMID:15105666; http://dx.doi.org/10.1097/00007632-200405010-00004.
34. Popovich PG, Guan Z, Wei P, Huitinga I, van Rooijen N, Stokes BT. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 1999; 158:351-65; PMID:10415142; http://dx.doi.org/10.1006/exnr.1999.7118.
35. Ferguson AR, Christensen RN, Gensel JC, Miller BA, Sun F, Beattie EC, et al. Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane. J Neurosci 2008; 28:11391-400; PMID:18971481; http://dx.doi.org/10.1523/JNEUROSCI. 3708-08.2008.
36. Probert L, Eugster HP, Akassoglou K, Bauer J, Frei K, Lassmann H, et al. TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease. Brain 2000; 123:2005-19; PMID:11004118; http://dx.doi.org/10.1093/brain/123.10.2005.
37. Karar J, Maity A. PI3K/AKT/mTOR Pathway in Angiogenesis. Front Mol Neurosci 2011; 4:51; PMID:22144946; http://dx.doi.org/10.3389/fnmol.2011.00051.
38. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000; 60:1541-5; PMID:10749120.
39. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8:128-35; PMID:11821896; http://dx.doi.org/10.1038/nm0202-128.
40. Mautes AE, Weinzierl MR, Donovan F, Noble LJ. Vascular events after spinal cord injury: contribution to secondary pathogenesis. Phys Ther 2000; 80:673-87; PMID:10869130.
41. Facchiano F, Fernandez E, Mancarella S, Maira G, Miscusi M, D'Arcangelo D, et al. Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor. J Neurosurg 2002; 97:161-8; PMID:12134907; http://dx.doi.org/10.3171/jns.2002.97.1.0161.
42. Widenfalk J, Lipson A, Jubran M, Hofstetter C, Ebendal T, Cao Y, et al. Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury. Neuroscience 2003; 120:951-60; PMID:12927201; http://dx.doi.org/10.1016/S0306- 4522(03)00399-3.
43. Jaerve A, Schiwy N, Schmitz C, Mueller HW. Differential effect of aging on axon sprouting and regenerative growth in spinal cord injury. Exp Neurol 2011; 231:284-94; PMID:21806987; http://dx.doi.org/10.1016/j.expneurol.2011.07. 002.
44. Siegenthaler MM, Ammon DL, Keirstead HS. Myelin pathogenesis and functional deficits following SCI are age-associated. Exp Neurol 2008; 213:363-71; PMID:18644369; http://dx.doi.org/10.1016/j.expneurol.2008.06.015.
45. Genovese T, Mazzon E, Di Paola R, Crisafulli C, Muià C, Bramanti P, et al. Increased oxidative-related mechanisms in the spinal cord injury in old rats. Neurosci Lett 2006; 393:141-6; PMID:16236449; http://dx.doi.org/10. 1016/j.neulet.2005.09.060.
46. Gwak YS, Hains BC, Johnson KM, Hulsebosch CE. Locomotor recovery and mechanical hyperalgesia following spinal cord injury depend on age at time of injury in rat. Neurosci Lett 2004; 362:232-5; PMID:15158021; http://dx.doi.org/10.1016/j.neulet.2004.03.019.
47. Xie YY, Yao ZB, Wu WT. Survival of motor neurons and expression of beta-amyloid protein in the aged rat spinal cord. Neuroreport 2000; 11:697-700; PMID:10757503; http://dx.doi.org/10.1097/00001756-200003200-00009.
48. Ahlgren S, Li GL, Olsson Y. Accumulation of beta-amyloid precursor protein and ubiquitin in axons after spinal cord trauma in humans: immunohistochemical observations on autopsy material. Acta Neuropathol 1996; 92:49-55; PMID:8811125; http://dx.doi.org/10.1007/s004010050488.
49. Menendez JA, Vellon L, Oliveras-Ferraros C, Cufí S, Vazquez-Martin A. mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: a roadmap from energy metabolism to stem cell renewal and aging. Cell Cycle 2011; 10:3658-77; PMID:22052357; http://dx.doi.org/10.4161/ cc.10.21.18128.
50. Conti A, Miscusi M, Cardali S, Germanò A, Suzuki H, Cuzzocrea S, et al. Nitric oxide in the injured spinal cord: synthases cross-talk, oxidative stress and inflammation. Brain Res Rev 2007; 54:205-18; PMID:17500094; http://dx.doi.org/10.1016/j.brainresrev.2007.01.013.
51. Vaziri ND, Lee YS, Lin CY, Lin VW, Sindhu RK. NAD(P)H oxidase, superoxide dismutase, catalase, glutathione peroxidase and nitric oxide synthase expression in subacute spinal cord injury. Brain Res 2004; 995:76-83; PMID:14644473; http://dx.doi.org/10.1016/j.brainres.2003.09.056.
52. Yang JY, Kim HS, Lee JK. Changes in nitric oxide synthase expression in young and adult rats after spinal cord injury. Spinal Cord 2007; 45:731-8; PMID:17353913; http://dx.doi.org/10.1038/sj.sc.3102036.
53. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 2011; 10:4230-6; PMID:22107964; http://dx.doi.org/10.4161/cc.10.24.18486.
54. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009; 460:392-5; PMID:19587680.
55. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle 2009; 8:1888-95; PMID:19471117; http://dx.doi.org/10.4161/cc.8.12.8606.
56. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY) 2009; 1:281-8; PMID:20157517.
57. Bové J, Martínez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci 2011; 12:437-52; PMID:21772323; http://dx.doi.org/10.1038/nrn3068.
58. Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol 2011; 23:744-55; PMID:21963299; http://dx.doi.org/10.1016/j.ceb.2011.09.003.
59. Zhao C, Vollrath D. mTOR pathway activation in age-related retinal disease. Aging (Albany NY) 2011; 3:346-7; PMID:21483039.
60. Garelick MG, Kennedy BK. TOR on the brain. Exp Gerontol 2011; 46:155-63; PMID:20849946; http://dx.doi.org/10.1016/j.exger.2010.08.030.
61. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 2010; 285:13107-20; PMID:20178983; http://dx.doi.org/10.1074/jbc.M110.100420.
62. Pani G. P66SHC and ageing: ROS and TOR? Aging (Albany NY) 2010; 2:514-8; PMID:20689155.
63. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, et al. Mechanisms of lifespan extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 2010; 11:35-46; PMID:20074526; http://dx.doi.org/10. 1016/j.cmet.2009.11.010.
64. Araki K, Ellebedy AH, Ahmed R. TOR in the immune system. Curr Opin Cell Biol 2011; 23:707-15; PMID:21925855; http://dx.doi.org/10.1016/j.ceb.2011.08. 006.
65. Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 2010; 7:209-19; PMID:20234352; http://dx.doi.org/10.1038/nrclinonc.2010. 21.
66. Delgoffe GM, Powell JD. mTOR: taking cues from the immune microenvironment. Immunology 2009; 127:459-65; PMID:19604300; http://dx.doi.org/10.1111/j.1365-2567.2009.03125.x.
67. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 2009; 9:324-37; PMID:19390566; http://dx.doi.org/10. 1038/nri2546.
68. Pópulo H, Lopes JM, Soares P. The mTOR Signalling Pathway in Human Cancer. Int J Mol Sci 2012; 13:1886-918; PMID:22408430; http://dx.doi.org/10. 3390/ijms13021886.
69. Khokhar NZ, Altman JK, Platanias LC. Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies. Curr Opin Oncol 2011; 23:578-86; PMID:21892085; http://dx.doi.org/10.1097/CCO.0b013e32834b892d.
70. De Simone P, Metselaar HJ, Fischer L, Dumortier J, Boudjema K, Hardwigsen J, et al. Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial. Liver Transpl 2009; 15:1262-9; PMID:19790150; http://dx.doi.org/10.1002/ lt.21827.
71. Fishbein TM, Florman S, Gondolesi G, Schiano T, LeLeiko N, Tschernia A, et al. Intestinal transplantation before and after the introduction of sirolimus. Transplantation 2002; 73:1538-42; PMID:12042637; http://dx.doi.org/ 10.1097/00007890-200205270-00004.
72. Raichlin E, Khalpey Z, Kremers W, Frantz RP, Rodeheffer RJ, Clavell AL, et al. Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients. Transplantation 2007; 84:467-74; PMID:17713429; http://dx.doi.org/10.1097/01.tp.0000276959.56959.69.
73. Fleming GF, Ma CX, Huo D, Sattar H, Tretiakova M, Lin L, et al. Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 2012; PMID:22245973; http://dx.doi.org/10.1007/s10549-011-1910-7.
74. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al.; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378:2005-12; PMID:22119496; http://dx.doi.org/10.1016/S0140-6736(11)61742- X.
75. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al.; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372:449-56; PMID:18653228; http://dx.doi.org/10.1016/S0140-6736(08)61039-9.
76. Zhou H, Luo Y, Huang S. Updates of mTOR inhibitors. Anticancer Agents Med Chem 2010; 10:571-81; PMID:20812900.
77. Fasolo A, Sessa C. Targeting mTOR pathways in human malignancies. Curr Pharm Des 2012; 18:2766-77; PMID:22475451.