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Role of Wnt Signaling in Central Nervous System Injury

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Abstract

The central nervous system (CNS) is highly sensitive to external mechanical damage, presenting a limited capacity for regeneration explained in part by its inability to restore either damaged neurons or the synaptic network. The CNS may suffer different types of external injuries affecting its function and/or structure, including stroke, spinal cord injury, and traumatic brain injury. These pathologies critically affect the quality of life of a large number of patients worldwide and are often fatal because available therapeutics are ineffective and produce limited results. Common effects of the mentioned pathologies involves the triggering of several cellular and metabolic responses against injury, including infiltration of blood cells, inflammation, glial activation, and neuronal death. Although some of the underlying molecular mechanisms of those responses have been elucidated, the mechanisms driving these processes are poorly understood in the context of CNS injury. In the last few years, it has been suggested that the activation of the Wnt signaling pathway could be important in the regenerative response after CNS injury, activating diverse protective mechanisms including the stimulation of neurogenesis, blood brain structure consolidation and the recovery of cognitive brain functions. Because Wnt signaling is involved in several physiological processes, the putative positive role of its activation after injury could be the basis for novel therapeutic approaches to CNS injury.

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References

  1. Marchetti B, Pluchino S (2013) Wnt your brain be inflamed? Yes, it Wnt! Trends Mol Med 19(3):144–156. doi:10.1016/j.molmed.2012.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. David MD, Canti C, Herreros J (2010) Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signaling. J Neurosci Res 88(14):3011–3023. doi:10.1002/jnr.22464

    Article  CAS  PubMed  Google Scholar 

  3. Varela-Nallar L, Alfaro IE, Serrano FG, Parodi J, Inestrosa NC (2010) Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses. Proc Natl Acad Sci U S A 107(49):21164–21169. doi:10.1073/pnas.1010011107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nusse R, Varmus H (2012) Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J 31(12):2670–2684. doi:10.1038/emboj.2012.146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nusse R (2012) Wnt signaling. Cold Spring Harb Perspect Biol 4(5). doi:10.1101/cshperspect.a011163

  6. Cisternas P, Henriquez JP, Brandan E, Inestrosa NC (2014) Wnt signaling in skeletal muscle dynamics: myogenesis, neuromuscular synapse and fibrosis. Mol Neurobiol 49(1):574–589. doi:10.1007/s12035-013-8540-5

    Article  CAS  PubMed  Google Scholar 

  7. Varela-Nallar L, Inestrosa NC (2013) Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci 7:100. doi:10.3389/fncel.2013.00100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rios JA, Cisternas P, Arrese M, Barja S, Inestrosa NC (2014) Is Alzheimer's disease related to metabolic syndrome? A Wnt signaling conundrum. Prog Neurobiol 121:125–146. doi:10.1016/j.pneurobio.2014.07.004

    Article  CAS  PubMed  Google Scholar 

  9. Rosso SB, Inestrosa NC (2013) WNT signaling in neuronal maturation and synaptogenesis. Front Cell Neurosci 7:103. doi:10.3389/fncel.2013.00103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Silva-Alvarez C, Arrazola MS, Godoy JA, Ordenes D, Inestrosa NC (2013) Canonical Wnt signaling protects hippocampal neurons from Abeta oligomers: role of non-canonical Wnt-5a/Ca(2+) in mitochondrial dynamics. Front Cell Neurosci 7:97. doi:10.3389/fncel.2013.00097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Inestrosa NC, Arenas E (2010) Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11(2):77–86. doi:10.1038/nrn2755

    Article  CAS  PubMed  Google Scholar 

  12. Cao HQ, Dong ED (2013) An update on spinal cord injury research. Neurosci Bull 29(1):94–102. doi:10.1007/s12264-012-1277-8

    Article  PubMed  Google Scholar 

  13. O'Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S et al (2010) Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 376(9735):112–123. doi:10.1016/S0140-6736(10)60834-3

    Article  PubMed  Google Scholar 

  14. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K et al (2009) Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119(3):e21–e181. doi:10.1161/CIRCULATIONAHA.108.191261

    Article  PubMed  Google Scholar 

  15. Warlow C (2003) Stroke: killer clots and killer drugs. J Thromb Haemost 1(7):1422–1428

    Article  CAS  PubMed  Google Scholar 

  16. Warlow C, Sudlow C, Dennis M, Wardlaw J, Sandercock P (2003) Stroke. Lancet 362(9391):1211–1224. doi:10.1016/S0140-6736(03)14544-8

    Article  PubMed  Google Scholar 

  17. Devivo MJ (2012) Epidemiology of traumatic spinal cord injury: trends and future implications. Spinal Cord 50(5):365–372. doi:10.1038/sc.2011.178

    Article  CAS  PubMed  Google Scholar 

  18. Oyinbo CA (2011) Secondary injury mechanisms in traumatic spinal cord injury: a nugget of this multiply cascade. Acta Neurobiol Exp 71(2):281–299

    Google Scholar 

  19. Bullock MR, Lyeth BG, Muizelaar JP (1999) Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. Neurosurgery 45(2):207–217, discussion 217-220

    Article  CAS  PubMed  Google Scholar 

  20. Whiting MD, Baranova AI, Hamm RJ (2006) Cognitive impairment following traumatic brain injury

  21. Kang WH, Cao W, Graudejus O, Patel T, Wagner S, Meaney D, Morrison Iii B 3rd (2014) Alterations in hippocampal network activity after in vitro traumatic brain injury. J Neurotrauma. doi:10.1089/neu.2014.3667

    PubMed  PubMed Central  Google Scholar 

  22. Edvinsson LI, Povlsen GK (2011) Vascular plasticity in cerebrovascular disorders. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 31(7):1554–1571. doi:10.1038/jcbfm.2011.70

    Article  CAS  Google Scholar 

  23. Profyris C, Cheema SS, Zang D, Azari MF, Boyle K, Petratos S (2004) Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Dis 15(3):415–436. doi:10.1016/j.nbd.2003.11.015

    Article  PubMed  Google Scholar 

  24. Xiong Y, Mahmood A, Chopp M (2013) Animal models of traumatic brain injury. Nat Rev Neurosci 14(2):128–142. doi:10.1038/nrn3407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang J, Mao X, Zhou T, Cheng X, Lin Y (2014) IL-17A contributes to brain ischemia reperfusion injury through calpain-TRPC6 pathway in mice. Neuroscience 274:419–428. doi:10.1016/j.neuroscience.2014.06.001

    Article  CAS  PubMed  Google Scholar 

  26. Xie R, Wang P, Cheng M, Sapolsky R, Ji X, Zhao H (2014) Mammalian target of rapamycin cell signaling pathway contributes to the protective effects of ischemic postconditioning against stroke. Stroke J Cereb Circ. doi:10.1161/strokeaha.114.005406

    Google Scholar 

  27. Mufti RE, Sarker K, Jin Y, Fu S, Rosales JL, Lee KY (2014) Thrombin enhances NGF-mediated neurite extension via increased and sustained activation of p44/42 MAPK and p38 MAPK. PLoS One 9(7):e103530. doi:10.1371/journal.pone.0103530

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Feigenson K, Reid M, See J, Crenshaw IE, Grinspan JB (2011) Canonical Wnt signalling requires the BMP pathway to inhibit oligodendrocyte maturation. ASN Neuro 3(3):e00061. doi:10.1042/AN20110004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Piccin D, Morshead CM (2011) Wnt signaling regulates symmetry of division of neural stem cells in the adult brain and in response to injury. Stem Cells 29(3):528–538. doi:10.1002/stem.589

    Article  CAS  PubMed  Google Scholar 

  30. Habib SJ, Chen BC, Tsai FC, Anastassiadis K, Meyer T, Betzig E, Nusse R (2013) A localized Wnt signal orients asymmetric stem cell division in vitro. Science 339(6126):1445–1448. doi:10.1126/science.1231077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Inestrosa NC, Montecinos-Oliva C, Fuenzalida M (2012) Wnt signaling: role in Alzheimer disease and schizophrenia. J Neuroimmune Pharmacol 7(4):788–807. doi:10.1007/s11481-012-9417-5

    Article  PubMed  Google Scholar 

  32. Zimmerman ZF, Moon RT, Chien AJ (2012) Targeting Wnt pathways in disease. Cold Spring Harb Perspect Biol 4(11). doi:10.1101/cshperspect.a008086

  33. Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149(6):1192–1205. doi:10.1016/j.cell.2012.05.012

    Article  CAS  PubMed  Google Scholar 

  34. Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13(12):767–779. doi:10.1038/nrm3470

    Article  CAS  PubMed  Google Scholar 

  35. Wang HY, Liu T, Malbon CC (2006) Structure-function analysis of Frizzleds. Cell Signal 18(7):934–941. doi:10.1016/j.cellsig.2005.12.008

    Article  CAS  PubMed  Google Scholar 

  36. Arrazola MS, Varela-Nallar L, Colombres M, Toledo EM, Cruzat F, Pavez L, Assar R, Aravena A et al (2009) Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/beta-catenin signaling pathway. J Cell Physiol 221(3):658–667. doi:10.1002/jcp.21902

    Article  CAS  PubMed  Google Scholar 

  37. Hodar C, Assar R, Colombres M, Aravena A, Pavez L, Gonzalez M, Martinez S, Inestrosa NC et al (2010) Genome-wide identification of new Wnt/beta-catenin target genes in the human genome using CART method. BMC Genomics 11:348. doi:10.1186/1471-2164-11-348

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC (2005) Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat Neurosci 8(1):34–42. doi:10.1038/nn1374

    Article  CAS  PubMed  Google Scholar 

  39. Toledo EM, Inestrosa NC (2010) Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease. Mol Psychiatry 15(3):272–285. doi:10.1038/mp.2009.72, 228

    Article  CAS  PubMed  Google Scholar 

  40. Clark CE, Liu Y, Cooper HM (2014) The Yin and Yang of Wnt/Ryk axon guidance in development and regeneration. Sci China Life Sci 57(4):366–371. doi:10.1007/s11427-014-4640-3

    Article  PubMed  Google Scholar 

  41. Salinas PC, Zou Y (2008) Wnt signaling in neural circuit assembly. Annu Rev Neurosci 31:339–358. doi:10.1146/annurev.neuro.31.060407.125649

    Article  CAS  PubMed  Google Scholar 

  42. Hall AC, Lucas FR, Salinas PC (2000) Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100(5):525–535

    Article  CAS  PubMed  Google Scholar 

  43. Farias GG, Valles AS, Colombres M, Godoy JA, Toledo EM, Lukas RJ, Barrantes FJ, Inestrosa NC (2007) Wnt-7a induces presynaptic colocalization of alpha 7-nicotinic acetylcholine receptors and adenomatous polyposis coli in hippocampal neurons. J Neurosci Off J Soc Neurosci 27(20):5313–5325. doi:10.1523/JNEUROSCI. 3934-06.2007

    Article  CAS  Google Scholar 

  44. Cerpa W, Godoy JA, Alfaro I, Farias GG, Metcalfe MJ, Fuentealba R, Bonansco C, Inestrosa NC (2008) Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons. J Biol Chem 283(9):5918–5927. doi:10.1074/jbc.M705943200

    Article  CAS  PubMed  Google Scholar 

  45. Farias GG, Alfaro IE, Cerpa W, Grabowski CP, Godoy JA, Bonansco C, Inestrosa NC (2009) Wnt-5a/JNK signaling promotes the clustering of PSD-95 in hippocampal neurons. J Biol Chem 284(23):15857–15866. doi:10.1074/jbc.M808986200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A 93(16):8455–8459

  47. De Ferrari GV, Chacon MA, Barria MI, Garrido JL, Godoy JA, Olivares G, Reyes AE, Alvarez A, Bronfman M, Inestrosa NC (2003) Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol Psychiatry 8(2):195–208. doi:10.1038/sj.mp.4001208

    Article  PubMed  CAS  Google Scholar 

  48. Tapia-Rojas C, Schuller A, Lindsay CB, Ureta RC, Mejias-Reyes C, Hancke J, Melo F, Inestrosa NC (2014) Andrographolide activates the canonical Wnt signalling pathway by a mechanism that implicates the non-ATP competitive inhibition of GSK-3beta: Auto regulation of GSK-3beta in vivo. Biochem J. doi:10.1042/BJ20140207

    Google Scholar 

  49. Serrano FG, Tapia-Rojas C, Carvajal FJ, Hancke J, Cerpa W, Inestrosa NC (2014) Andrographolide reduces cognitive impairment in young and mature AbetaPPswe/PS-1 mice. Mol Neurodegener 9(1):61. doi:10.1186/1750-1326-9-61

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Kahn M (2014) Can we safely target the WNT pathway? Nat Rev Drug Discov 13(7):513–532. doi:10.1038/nrd4233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang Z, Hartmann H, Minh Do V, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Sommer B, van de Wetering M, Clevers H, Saftig P, De Strooper B, He X, Yankner BA (1998) Destabilization of [beta]-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 395(6703):698–702

    Article  CAS  PubMed  Google Scholar 

  52. Alvarez AR, Godoy JA, Mullendorff K, Olivares GH, Bronfman M, Inestrosa NC (2004) Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons. Exp Cell Res 297(1):186–196. doi:10.1016/j.yexcr.2004.02.028

    Article  CAS  PubMed  Google Scholar 

  53. Pinto C, Cardenas P, Osses N, Henriquez JP (2013) Characterization of Wnt/beta-catenin and BMP/Smad signaling pathways in an in vitro model of amyotrophic lateral sclerosis. Front Cell Neurosci 7:239. doi:10.3389/fncel.2013.00239

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Chen Y, Guan Y, Zhang Z, Liu H, Wang S, Yu L, Wu X, Wang X (2012) Wnt signaling pathway is involved in the pathogenesis of amyotrophic lateral sclerosis in adult transgenic mice. Neurol Res 34(4):390–399. doi:10.1179/1743132812y.0000000027

    Article  CAS  PubMed  Google Scholar 

  55. Li X, Guan Y, Chen Y, Zhang C, Shi C, Zhou F, Yu L, Juan J, Wang X (2013) Expression of Wnt5a and its receptor Fzd2 is changed in the spinal cord of adult amyotrophic lateral sclerosis transgenic mice. Int J Clin Exp Pathol 6(7):1245–1260

    PubMed  PubMed Central  Google Scholar 

  56. Wang S, Guan Y, Chen Y, Li X, Zhang C, Yu L, Zhou F, Wang X (2013) Role of Wnt1 and Fzd1 in the spinal cord pathogenesis of amyotrophic lateral sclerosis-transgenic mice. Biotechnol Lett 35(8):1199–1207. doi:10.1007/s10529-013-1199-1

    Article  CAS  PubMed  Google Scholar 

  57. Tourette C, Farina F, Vazquez-Manrique RP, Orfila AM, Voisin J, Hernandez S, Offner N, Parker JA, Menet S, Kim J, Lyu J, Choi SH, Cormier K, Edgerly CK, Bordiuk OL, Smith K, Louise A, Halford M, Stacker S, Vert JP, Ferrante RJ, Lu W, Neri C (2014) The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity. PLoS Biol 12(6):e1001895. doi:10.1371/journal.pbio.1001895

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Dupont P, Besson MT, Devaux J, Lievens JC (2012) Reducing canonical Wingless/Wnt signaling pathway confers protection against mutant Huntingtin toxicity in Drosophila. Neurobiol Dis 47(2):237–247. doi:10.1016/j.nbd.2012.04.007

    Article  CAS  PubMed  Google Scholar 

  59. Lees AJ, Hardy J, Revesz T (2009) Parkinson's disease. Lancet 373(9680):2055–2066. doi:10.1016/s0140-6736(09)60492-x

    Article  CAS  PubMed  Google Scholar 

  60. Jansen O, Rohr A (2013) Neurothrombectomy in the treatment of acute ischaemic stroke. Nat Rev Neurol 9(11):645–652. doi:10.1038/nrneurol.2013.204

    Article  PubMed  Google Scholar 

  61. Liu FJ, Lim KY, Kaur P, Sepramaniam S, Armugam A, Wong PT, Jeyaseelan K (2013) microRNAs involved in regulating spontaneous recovery in embolic stroke model. PLoS One 8(6):e66393. doi:10.1371/journal.pone.0066393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Stenman JM, Rajagopal J, Carroll TJ, Ishibashi M, McMahon J, McMahon AP (2008) Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322(5905):1247–1250. doi:10.1126/science.1164594

    Article  CAS  PubMed  Google Scholar 

  63. Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, Reis M, Felici A et al (2008) Wnt/beta-catenin signaling controls development of the blood-brain barrier. J Cell Biol 183(3):409–417. doi:10.1083/jcb.200806024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Scott EL, Brann DW (2013) Estrogen regulation of Dkk1 and Wnt/beta-Catenin signaling in neurodegenerative disease. Brain Res 1514:63–74. doi:10.1016/j.brainres.2012.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhang QG, Wang R, Khan M, Mahesh V, Brann DW (2008) Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. J Neurosci Off J Soc Neurosci 28(34):8430–8441. doi:10.1523/JNEUROSCI. 2752-08.2008

    Article  CAS  Google Scholar 

  66. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L (2008) Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 7(10):915–926. doi:10.1016/s1474-4422(08)70193-5

    Article  PubMed  PubMed Central  Google Scholar 

  67. Tian Y, Stamova B, Jickling GC, Liu D, Ander BP, Bushnell C, Zhan X, Davis RR et al (2012) Effects of gender on gene expression in the blood of ischemic stroke patients. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 32(5):780–791. doi:10.1038/jcbfm.2011.179

    Article  CAS  Google Scholar 

  68. Mastroiacovo F, Busceti CL, Biagioni F, Moyanova SG, Meisler MH, Battaglia G, Caricasole A, Bruno V et al (2009) Induction of the Wnt antagonist, Dickkopf-1, contributes to the development of neuronal death in models of brain focal ischemia. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 29(2):264–276. doi:10.1038/jcbfm.2008.111

    Article  CAS  Google Scholar 

  69. Seifert-Held T, Pekar T, Gattringer T, Simmet NE, Scharnagl H, Stojakovic T, Fazekas F, Storch MK (2011) Circulating Dickkopf-1 in acute ischemic stroke and clinically stable cerebrovascular disease. Atherosclerosis 218(1):233–237. doi:10.1016/j.atherosclerosis.2011.05.015

    Article  CAS  PubMed  Google Scholar 

  70. Guo S, Zhou Y, Xing C, Lok J, Som AT, Ning M, Ji X, Lo EH (2012) The vasculome of the mouse brain. PLoS One 7(12):e52665. doi:10.1371/journal.pone.0052665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fancy SP, Harrington EP, Yuen TJ, Silbereis JC, Zhao C, Baranzini SE, Bruce CC, Otero JJ et al (2011) Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat Neurosci 14(8):1009–1016. doi:10.1038/nn.2855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pi X, Wu Y, Ferguson JE 3rd, Portbury AL, Patterson C (2009) SDF-1alpha stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration. Proc Natl Acad Sci U S A 106(14):5675–5680. doi:10.1073/pnas.0809568106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Planutiene M, Planutis K, Holcombe RF (2011) Lymphoid enhancer-binding factor 1, a representative of vertebrate-specific Lef1/Tcf1 sub-family, is a Wnt-beta-catenin pathway target gene in human endothelial cells which regulates matrix metalloproteinase-2 expression and promotes endothelial cell invasion. Vasc Cell 3:28. doi:10.1186/2045-824X-3-28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kalani MY, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, Weissman IL, Palmer TD, Nusse R (2008) Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci U S A 105(44):16970–16975. doi:10.1073/pnas.0808616105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Weinsheimer SM, Xu H, Achrol AS, Stamova B, McCulloch CE, Pawlikowska L, Tian Y, Ko NU et al (2011) Gene expression profiling of blood in brain arteriovenous malformation patients. Trans Stroke Res 2(4):575–587. doi:10.1007/s12975-011-0103-3

    Article  CAS  Google Scholar 

  76. Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, Ho KL, Morshead C et al (2004) Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 24(4):441–448. doi:10.1097/00004647-200404000-00009

    Article  Google Scholar 

  77. Tyor WR, Avgeropoulos N, Ohlandt G, Hogan EL (2002) Treatment of spinal cord impact injury in the rat with transforming growth factor-beta. J Neurol Sci 200(1–2):33–41

    Article  CAS  PubMed  Google Scholar 

  78. Fernandez-Martos CM, Gonzalez-Fernandez C, Gonzalez P, Maqueda A, Arenas E, Rodriguez FJ (2011) Differential expression of Wnts after spinal cord contusion injury in adult rats. PLoS One 6(11):e27000. doi:10.1371/journal.pone.0027000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gonzalez-Fernandez C, Fernandez-Martos CM, Shields SD, Arenas E, Javier Rodriguez F (2014) Wnts are expressed in the spinal cord of adult mice and are differentially induced after injury. J Neurotrauma 31(6):565–581. doi:10.1089/neu.2013.3067

    Article  PubMed  PubMed Central  Google Scholar 

  80. Gonzalez P, Fernandez-Martos CM, Gonzalez-Fernandez C, Arenas E, Rodriguez FJ (2012) Spatio-temporal expression pattern of frizzled receptors after contusive spinal cord injury in adult rats. PLoS One 7(12):e50793. doi:10.1371/journal.pone.0050793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Liu Y, Wang X, Lu CC, Kerman R, Steward O, Xu XM, Zou Y (2008) Repulsive Wnt signaling inhibits axon regeneration after CNS injury. J Neurosc Off J Soc Neurosci 28(33):8376–8382. doi:10.1523/JNEUROSCI. 1939-08.2008

    Article  CAS  Google Scholar 

  82. Miyashita T, Koda M, Kitajo K, Yamazaki M, Takahashi K, Kikuchi A, Yamashita T (2009) Wnt-Ryk signaling mediates axon growth inhibition and limits functional recovery after spinal cord injury. J Neurotrauma 26(7):955–964. doi:10.1089/neu.2008.0776

    Article  PubMed  Google Scholar 

  83. Zhang YK, Huang ZJ, Liu S, Liu YP, Song AA, Song XJ (2013) WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest 123(5):2268–2286. doi:10.1172/JCI65364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Maas AI, Stocchetti N, Bullock R (2008) Moderate and severe traumatic brain injury in adults. Lancet Neurol 7(8):728–741. doi:10.1016/S1474-4422(08)70164-9

    Article  PubMed  Google Scholar 

  85. Dobkin BH (1997) Experimental brain injury and repair. Curr Opin Neurol 10(6):493–497

    Article  CAS  PubMed  Google Scholar 

  86. Hall EC, Lund E, Brown D, Murdock KR, Gettings L, Scalea TM, Stein DM (2014) How are you really feeling? A prospective evaluation of cognitive function following trauma. J Trauma Acute Care Surg 76(3):859–864. doi:10.1097/ta.0000000000000148, discussion 864–855

  87. Xiong Y, Shie FS, Zhang J, Lee CP, Ho YS (2004) The protective role of cellular glutathione peroxidase against trauma-induced mitochondrial dysfunction in the mouse brain. J Stroke Cerebrovasc Dis 13(3):129–137. doi:10.1016/j.jstrokecerebrovasdis.2004.05.001

    Article  PubMed  Google Scholar 

  88. Mussack T, Biberthaler P, Gippner-Steppert C, Kanz KG, Wiedemann E, Mutschler W, Jochum M (2001) Early cellular brain damage and systemic inflammatory response after cardiopulmonary resuscitation or isolated severe head trauma: a comparative pilot study on common pathomechanisms. Resuscitation 49(2):193–199

    Article  CAS  PubMed  Google Scholar 

  89. Borgens RB, Liu-Snyder P (2012) Understanding secondary injury. Q Rev Biol 87(2):89–127

    Article  PubMed  Google Scholar 

  90. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Giunta B, Obregon D, Velisetty R, Sanberg PR, Borlongan CV, Tan J (2012) The immunology of traumatic brain injury: a prime target for Alzheimer's disease prevention. J Neuroinflammation 9:185. doi:10.1186/1742-2094-9-185

    Article  PubMed  PubMed Central  Google Scholar 

  92. Muir KW (2006) Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Curr Opin Pharmacol 6(1):53–60. doi:10.1016/j.coph.2005.12.002

    Article  CAS  PubMed  Google Scholar 

  93. Lee LL, Galo E, Lyeth BG, Muizelaar JP, Berman RF (2004) Neuroprotection in the rat lateral fluid percussion model of traumatic brain injury by SNX-185, an N-type voltage-gated calcium channel blocker. Exp Neurol 190(1):70–78. doi:10.1016/j.expneurol.2004.07.003

    Article  CAS  PubMed  Google Scholar 

  94. Hamby ME, Sofroniew MV (2010) Reactive astrocytes as therapeutic targets for CNS disorders. Neurotherapeut J Am Soc Exp Neuro Ther 7(4):494–506. doi:10.1016/j.nurt.2010.07.003

    Article  CAS  Google Scholar 

  95. Cornelius C, Crupi R, Calabrese V, Graziano A, Milone P, Pennisi G, Radak Z, Calabrese EJ, Cuzzocrea S (2013) Traumatic brain injury: oxidative stress and neuroprotection. Antioxid Redox Signaling 19(8):836–853. doi:10.1089/ars.2012.4981

    Article  CAS  Google Scholar 

  96. Andriessen TM, Jacobs B, Vos PE (2010) Clinical characteristics and pathophysiological mechanisms of focal and diffuse traumatic brain injury. J Cell Mol Med 14(10):2381–2392. doi:10.1111/j.1582-4934.2010.01164.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Langlois JA, Rutland-Brown W, Wald MM (2006) The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil 21(5):375–378

    Article  PubMed  Google Scholar 

  98. Zhang L, Yan R, Zhang Q, Wang H, Kang X, Li J, Yang S, Zhang J et al (2013) Survivin, a key component of the Wnt/betacatenin signaling pathway, contributes to traumatic brain injury-induced adult neurogenesis in the mouse dentate gyrus. Int J Mol Med 32(4):867–875. doi:10.3892/ijmm.2013.1456

    PubMed  Google Scholar 

  99. Zou F, Xu J, Fu H, Cao J, Mao H, Gong M, Cui G, Zhang Y et al (2013) Different functions of HIPK2 and CtBP2 in traumatic brain injury. J Mol Neurosci 49(2):395–408. doi:10.1007/s12031-012-9906-2

    Article  CAS  PubMed  Google Scholar 

  100. Colicos MA, Dixon CE, Dash PK (1996) Delayed, selective neuronal death following experimental cortical impact injury in rats: possible role in memory deficits. Brain Res 739(1–2):111–119

    Article  CAS  PubMed  Google Scholar 

  101. Benbrook DM, Masamha CP (2011) The pro-survival function of Akt kinase can be overridden or altered to contribute to induction of apoptosis. Curr Cancer Drug Targets 11(5):586–599

    Article  CAS  PubMed  Google Scholar 

  102. Young W (2009) Review of lithium effects on brain and blood. Cell Transplant 18(9):951–975. doi:10.3727/096368909X471251

    Article  PubMed  Google Scholar 

  103. Zhao S, Fu J, Liu X, Wang T, Zhang J, Zhao Y (2012) Activation of Akt/GSK-3beta/beta-catenin signaling pathway is involved in survival of neurons after traumatic brain injury in rats. Neurol Res 34(4):400–407. doi:10.1179/1743132812Y.0000000025

    Article  CAS  PubMed  Google Scholar 

  104. Leeds PR, Yu F, Wang Z, Chiu CT, Zhang Y, Leng Y, Linares GR, Chuang DM (2014) A New Avenue for Lithium: Intervention in Traumatic Brain Injury. ACS Chem Neurosci. doi:10.1021/cn500040g

    PubMed  PubMed Central  Google Scholar 

  105. Yu F, Wang Z, Tanaka M, Chiu CT, Leeds P, Zhang Y, Chuang DM (2013) Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood-brain barrier disruption, and improvement in motor coordination in mice with traumatic brain injury. J Neurosurg 119(3):766–773. doi:10.3171/2013.6.JNS13135

    Article  CAS  PubMed  Google Scholar 

  106. Liu B, Hunter DJ, Rooker S, Chan A, Paulus YM, Leucht P, Nusse Y, Nomoto H et al (2013) Wnt signaling promotes Muller cell proliferation and survival after injury. Invest Ophthalmol Vis Sci 54(1):444–453. doi:10.1167/iovs. 12-10774

    Article  CAS  PubMed  Google Scholar 

  107. Yang XT, Bi YY, Chen ET, Feng DF (2014) Overexpression of Wnt3a facilitates the proliferation and neural differentiation of neural stem cells in vitro and after transplantation into an injured rat retina. J Neurosci Res 92(2):148–161. doi:10.1002/jnr.23314

    Article  CAS  PubMed  Google Scholar 

  108. White BD, Nathe RJ, Maris DO, Nguyen NK, Goodson JM, Moon RT, Horner PJ (2010) Beta-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain. Stem Cells 28(2):297–307. doi:10.1002/stem.268

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Yin Y, Zhang X, Li Z, Deng L, Jiao G, Zhang B, Xie P, Mu H et al (2013) Glucocorticoid receptor beta regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of beta-catenin/TCF transcriptional activity. Neurobiol Dis 59:165–176. doi:10.1016/j.nbd.2013.07.013,S0969-9961(13)00207-6

    Article  CAS  PubMed  Google Scholar 

  110. Niu LJ, Xu RX, Zhang P, Du MX, Jiang XD (2012) Suppression of Frizzled-2-mediated Wnt/Ca(2)(+) signaling significantly attenuates intracellular calcium accumulation in vitro and in a rat model of traumatic brain injury. Neuroscience 213:19–28. doi:10.1016/j.neuroscience.2012.03.057

    Article  CAS  PubMed  Google Scholar 

  111. Yu F, Wang Z, Tchantchou F, Chiu CT, Zhang Y, Chuang DM (2012) Lithium ameliorates neurodegeneration, suppresses neuroinflammation, and improves behavioral performance in a mouse model of traumatic brain injury. J Neurotrauma 29(2):362–374. doi:10.1089/neu.2011.1942

    Article  PubMed  PubMed Central  Google Scholar 

  112. Wu X, Mao H, Liu J, Xu J, Cao J, Gu X, Cui G (2013) Dynamic change of SGK expression and its role in neuron apoptosis after traumatic brain injury. Int J Clin Exp Pathol 6(7):1282–1293

    PubMed  PubMed Central  Google Scholar 

  113. BelAiba RS, Djordjevic T, Bonello S, Artunc F, Lang F, Hess J, Gorlach A (2006) The serum- and glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary vascular remodeling: role in redox-sensitive regulation of tissue factor by thrombin. Circ Res 98(6):828–836. doi:10.1161/01.RES.0000210539.54861.27

    Article  CAS  PubMed  Google Scholar 

  114. Dash PK, Johnson D, Clark J, Orsi SA, Zhang M, Zhao J, Grill RJ, Moore AN et al (2011) Involvement of the glycogen synthase kinase-3 signaling pathway in TBI pathology and neurocognitive outcome. PLoS One 6(9):e24648. doi:10.1371/journal.pone.0024648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Umschweif G, Alexandrovich AG, Trembovler V, Horowitz M, Shohami E (2013) The Role and Dynamics of b-Catenin in Precondition Induced Neuroprotection after Traumatic Brain Injury. PLoS One 8(10):e76129. doi:10.1371/journal.pone.0076129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from the Basal Center for Excellence in Science and Technology (Conicyt-PFB 12/2007) and from Fondecyt: to NCI (N° 1120156) to CL (postdoctoral fellowships N°3150291) and PC (postdoctoral fellowships N°3150475). We also thank the Sociedad Química y Minera de Chile (SQM) for special grants to study “The role of potassium in hypertension and cognition” and “The role of lithium in human health". We also thank Felipe G. Serrano for artwork (www.illustrative-science.com).

Conflict of Interests

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, P.O. Box 114-D, Santiago, Chile

    Catherine Lambert, Pedro Cisternas & Nibaldo C. Inestrosa

  2. Center for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Nibaldo C. Inestrosa

  3. Centro UC, Síndrome de Down, Pontificia Universidad Católica de Chile, Santiago, Chile

    Nibaldo C. Inestrosa

  4. Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile

    Nibaldo C. Inestrosa

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  1. Catherine Lambert
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  2. Pedro Cisternas
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  3. Nibaldo C. Inestrosa
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Correspondence to Nibaldo C. Inestrosa.

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Lambert, C., Cisternas, P. & Inestrosa, N.C. Role of Wnt Signaling in Central Nervous System Injury. Mol Neurobiol 53, 2297–2311 (2016). https://doi.org/10.1007/s12035-015-9138-x

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