Spinal cord injury (WP2431)

Homo sapiens

Open in new tab Open in NDEx Open in Newt (SBGN)
Download PNG Download SVG Download JSON Download GPML Learn more about Downloads
This pathway provides an overview of cell types, therapeutic targets, drugs, new proposed targets and pathways implicated in spinal cord injury. Spinal cord injury is a complex multistep process that involves the regulation of gene expression and signaling in motor neurons, oligodentrocytes, microglia, and astrocytes that trigger immediate immune responses lasting several weeks. Within 24 hours, chemoattractants and cytokines released from the site of injury activate neutrophils which further recruit B and T cells or recruit monocytes that ultimately result in infiltration and activation by microglia and macrophages. These immune responses result in inflammation, excitotoxicity, cell death, formation of glial scar, and suppression of axonal regeneration. An increase in the expression of cell cycle genes further results in proliferation of astrocytes and microglia that leads to apoptosis and necrosis of oligodentrocytes and neurons. An example therapy is the administration of the immunosuppressant FK506, also used in transplantation to offer neuroprotection. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2431 CPTAC Assay Portal].

Authors

Deborah Micael , Nathan Salomonis , Egon Willighagen , Anders Riutta , Martina Summer-Kutmon , Chris Evelo , Zahra Roudbari , Kristina Hanspers , Linda Rieswijk , Denise Slenter , Eric Weitz , and Susan Coort

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

Diseases ExRNA

Annotations

Cell Type Ontology

motor neuron T cell monocyte macrophage oligodendrocyte neutrophil spinal cord motor neuron microglial cell astrocyte of the spinal cord B cell

Disease Ontology

post-traumatic stress disorder spinal cord disease

Pathway Ontology

neurological disorder pathway disease pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
LTB4 Metabolite pubchem.compound:169
NO Metabolite pubchem.compound:145068
melittin Metabolite pubchem.compound:16133648
FK506 Metabolite cas:104987-11-3
Arachidonic acid Metabolite hmdb:HMDB0001043
PGH2 Metabolite hmdb:HMDB0001381
Olomoucine Metabolite hmdb:HMDB0035233
2-Methoxyestradiol Metabolite pubchem.compound:66414
PD 168393 Metabolite pubchem.compound:4708
NGFR GeneProduct ensembl:ENSG00000064300
APEX1 GeneProduct ensembl:ENSG00000100823
MIF GeneProduct ensembl:ENSG00000240972
LEP GeneProduct ensembl:ENSG00000174697
LGALS3 GeneProduct ensembl:ENSG00000131981
TNFSF13 GeneProduct ensembl:ENSG00000161955
LTB4R GeneProduct ensembl:ENSG00000213903
AQP1 GeneProduct ensembl:ENSG00000240583
TNFSF13B GeneProduct ensembl:ENSG00000102524
AIF1 GeneProduct ncbigene:199
PTPRZ1 GeneProduct ensembl:ENSG00000106278
PDYN GeneProduct ensembl:ENSG00000101327
LTB GeneProduct ensembl:ENSG00000227507
PLXNA2 GeneProduct ensembl:ENSG00000076356
FECHP1 GeneProduct ensembl:ENSG00000235534
CSPG4 GeneProduct ensembl:ENSG00000173546
CD47 GeneProduct ensembl:ENSG00000196776
C1QB GeneProduct ensembl:ENSG00000173369
CDC42 GeneProduct ensembl:ENSG00000070831
ZFP36 GeneProduct ensembl:ENSG00000128016
FCGR2A GeneProduct ensembl:ENSG00000143226
PRB1 GeneProduct ensembl:ENSG00000251655
PTPRA GeneProduct ensembl:ENSG00000132670
IL1B GeneProduct ensembl:ENSG00000125538
NOS2 GeneProduct ensembl:ENSG00000007171
TNF GeneProduct ensembl:ENSG00000232810
NR4A1 GeneProduct ensembl:ENSG00000123358
IL4 GeneProduct ensembl:ENSG00000113520
BTG2 GeneProduct ensembl:ENSG00000159388
CDK2 GeneProduct ensembl:ENSG00000123374
NOS1 GeneProduct ensembl:ENSG00000089250
IL2 GeneProduct ensembl:ENSG00000109471
IL6 GeneProduct ensembl:ENSG00000136244
TLR4 GeneProduct ensembl:ENSG00000136869
FOS GeneProduct ensembl:ENSG00000170345
TGFB1 GeneProduct ensembl:ENSG00000105329
EGR1 GeneProduct ensembl:ENSG00000120738
MMP12 GeneProduct ensembl:ENSG00000262406
IFNG GeneProduct ensembl:ENSG00000111537
MBP GeneProduct ensembl:ENSG00000197971
RTN4 GeneProduct ensembl:ENSG00000115310
C5 GeneProduct ensembl:ENSG00000106804
CXCL1 GeneProduct ensembl:ENSG00000163739
CXCL8 GeneProduct ensembl:ENSG00000169429
AQP4 GeneProduct ensembl:ENSG00000171885
ARG1 GeneProduct ensembl:ENSG00000118520
EPHA4 GeneProduct ensembl:ENSG00000116106
EPHNB2 GeneProduct ensembl:ENSG00000125266
CXCL10 GeneProduct ensembl:ENSG00000169245
CCNG1 GeneProduct ensembl:ENSG00000113328
MMP9 GeneProduct ensembl:ENSG00000100985
NCAN GeneProduct ensembl:ENSG00000130287
SLIT1 GeneProduct ensembl:ENSG00000187122
SLIT2 GeneProduct ensembl:ENSG00000145147
SLIT3 GeneProduct ensembl:ENSG00000184347
NTN1 GeneProduct ensembl:ENSG00000065320
RGMA GeneProduct ensembl:ENSG00000182175
CCR2 GeneProduct ensembl:ENSG00000121807
IL1R1 GeneProduct ensembl:ENSG00000115594
IL1A GeneProduct ncbigene:3552
CXCL2 GeneProduct ensembl:ENSG00000081041
CCL2 GeneProduct ensembl:ENSG00000108691
PLA2G6 GeneProduct ensembl:ENSG00000184381
PLA2G5 GeneProduct ensembl:ENSG00000127472
PLA2G2A GeneProduct ensembl:ENSG00000188257
ANXA1 GeneProduct ensembl:ENSG00000135046
ICAM1 GeneProduct ensembl:ENSG00000090339
SELP GeneProduct ensembl:ENSG00000174175
KLK8 GeneProduct ensembl:ENSG00000129455
GFAP GeneProduct ensembl:ENSG00000131095
CDK4 GeneProduct ensembl:ENSG00000135446
TACR1 GeneProduct ensembl:ENSG00000115353
E2F5 GeneProduct ensembl:ENSG00000133740
RB1 GeneProduct ensembl:ENSG00000139687
PRKCA GeneProduct ensembl:ENSG00000154229
E2F1 GeneProduct ensembl:ENSG00000101412
MAPK1 GeneProduct ensembl:ENSG00000100030
CCND1 GeneProduct ensembl:ENSG00000110092
MYC GeneProduct ensembl:ENSG00000136997
GADD45A GeneProduct ensembl:ENSG00000116717
MAPK3 GeneProduct ensembl:ENSG00000102882
TP53 GeneProduct ensembl:ENSG00000141510
CHST11 GeneProduct ensembl:ENSG00000171310
VCAN GeneProduct ensembl:ENSG00000038427
COL4A1 GeneProduct ensembl:ENSG00000187498
XYLT1 GeneProduct ensembl:ENSG00000103489
COL2A1 GeneProduct ensembl:ENSG00000139219
ACAN GeneProduct ensembl:ENSG00000157766
BCAN GeneProduct ensembl:ENSG00000132692
SOX9 GeneProduct ensembl:ENSG00000125398
GRIN1 GeneProduct ensembl:ENSG00000176884
VIM GeneProduct ensembl:ENSG00000026025
PPP3CA GeneProduct ensembl:ENSG00000138814
GAP43 GeneProduct ensembl:ENSG00000172020
FKBP1A GeneProduct ensembl:ENSG00000088832
MAG GeneProduct ensembl:ENSG00000105695
RHOA GeneProduct ensembl:ENSG00000067560
RHOC GeneProduct ensembl:ENSG00000155366
RHOB GeneProduct ensembl:ENSG00000143878
ROCK2 GeneProduct ensembl:ENSG00000134318
OMG GeneProduct ensembl:ENSG00000126861
RTN4R GeneProduct ensembl:ENSG00000040608
LILRB3 GeneProduct ensembl:ENSG00000204577
PTGS2 GeneProduct ncbigene:5743
ROS GeneProduct ncbigene:6098
NOX4 GeneProduct ensembl:ENSG00000086991
CDK1 GeneProduct ensembl:ENSG00000170312
GDNF GeneProduct ensembl:ENSG00000168621
SEMA6A GeneProduct ensembl:ENSG00000092421
GJA1 GeneProduct ensembl:ENSG00000152661
BDNF GeneProduct ensembl:ENSG00000176697
RAC1 GeneProduct ensembl:ENSG00000136238
FOXO3 GeneProduct ensembl:ENSG00000118689
CDKN1B GeneProduct ensembl:ENSG00000111276
EGFR GeneProduct ensembl:ENSG00000146648
CASP3 GeneProduct ensembl:ENSG00000164305

References

  1. Role of cyclooxygenase 2 in acute spinal cord injury. Resnick DK, Graham SH, Dixon CE, Marion DW. J Neurotrauma. 1998 Dec;15(12):1005–13. PubMed Europe PMC Scholia
  2. Improved recovery after spinal cord trauma in ICAM-1 and P-selectin knockout mice. Farooque M, Isaksson J, Olsson Y. Neuroreport. 1999 Jan 18;10(1):131–4. PubMed Europe PMC Scholia
  3. Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Eng LF, Ghirnikar RS, Lee YL. Neurochem Res. 2000 Oct;25(9–10):1439–51. PubMed Europe PMC Scholia
  4. A neutrophil elastase inhibitor (ONO-5046) reduces neurologic damage after spinal cord injury in rats. Tonai T, Shiba K, Taketani Y, Ohmoto Y, Murata K, Muraguchi M, et al. J Neurochem. 2001 Sep;78(5):1064–72. PubMed Europe PMC Scholia
  5. AIF-1 expression defines a proliferating and alert microglial/macrophage phenotype following spinal cord injury in rats. Schwab JM, Frei E, Klusman I, Schnell L, Schwab ME, Schluesener HJ. J Neuroimmunol. 2001 Oct 1;119(2):214–22. PubMed Europe PMC Scholia
  6. Gene profiling in spinal cord injury shows role of cell cycle in neuronal death. Di Giovanni S, Knoblach SM, Brandoli C, Aden SA, Hoffman EP, Faden AI. Ann Neurol. 2003 Apr;53(4):454–68. PubMed Europe PMC Scholia
  7. Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Menet V, Prieto M, Privat A, Giménez y Ribotta M. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8999–9004. PubMed Europe PMC Scholia
  8. Stimulation of production of glial cell line-derived neurotrophic factor and nitric oxide by lipopolysaccharide with different dose-responsiveness in cultured rat macrophages. Hashimoto M, Ito T, Fukumitsu H, Nomoto H, Furukawa Y, Furukawa S. Biomed Res. 2005 Oct;26(5):223–9. PubMed Europe PMC Scholia
  9. Macrophage migration inhibitory factor induces cell death and decreases neuronal nitric oxide expression in spinal cord neurons. Chalimoniuk M, King-Pospisil K, Metz CN, Toborek M. Neuroscience. 2006;139(3):1117–28. PubMed Europe PMC Scholia
  10. Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity. Woods AS, Kaminski R, Oz M, Wang Y, Hauser K, Goody R, et al. J Proteome Res. 2006 Apr;5(4):1017–23. PubMed Europe PMC Scholia
  11. Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion. Fabes J, Anderson P, Yáñez-Muñoz RJ, Thrasher A, Brennan C, Bolsover S. Eur J Neurosci. 2006 Apr;23(7):1721–30. PubMed Europe PMC Scholia
  12. Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model. Tian D shi, Dong Q, Pan D ji, He Y, Yu Z yuan, Xie M jie, et al. Brain Res. 2007 Jun 18;1154:206–14. PubMed Europe PMC Scholia
  13. Inhibiting epidermal growth factor receptor improves structural, locomotor, sensory, and bladder recovery from experimental spinal cord injury. Erschbamer M, Pernold K, Olson L. J Neurosci. 2007 Jun 13;27(24):6428–35. PubMed Europe PMC Scholia
  14. TNF-alpha blockage in a mouse model of SCI: evidence for improved outcome. Genovese T, Mazzon E, Crisafulli C, Di Paola R, Muià C, Esposito E, et al. Shock. 2008 Jan;29(1):32–41. PubMed Europe PMC Scholia
  15. Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury. Terayama R, Bando Y, Murakami K, Kato K, Kishibe M, Yoshida S. Neuroscience. 2007 Aug 10;148(1):175–87. PubMed Europe PMC Scholia
  16. Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons. Adjan VV, Hauser KF, Bakalkin G, Yakovleva T, Gharibyan A, Scheff SW, et al. Neuroscience. 2007 Sep 7;148(3):724–36. PubMed Europe PMC Scholia
  17. The p75 neurotrophin receptor is essential for neuronal cell survival and improvement of functional recovery after spinal cord injury. Chu GKT, Yu W, Fehlings MG. Neuroscience. 2007 Sep 7;148(3):668–82. PubMed Europe PMC Scholia
  18. Annexin A1 reduces inflammatory reaction and tissue damage through inhibition of phospholipase A2 activation in adult rats following spinal cord injury. Liu NK, Zhang YP, Han S, Pei J, Xu LY, Lu PH, et al. J Neuropathol Exp Neurol. 2007 Oct;66(10):932–43. PubMed Europe PMC Scholia
  19. Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Saadoun S, Bell BA, Verkman AS, Papadopoulos MC. Brain. 2008 Apr;131(Pt 4):1087–98. PubMed Europe PMC Scholia
  20. Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/ref-1) and DNA damage in the caudal region of acute and chronic spinal cord injured rats treated by embryonic neural stem cells. Dagci T, Armagan G, Konyalioglu S, Yalcin A. Physiol Res. 2009;58(3):427–34. PubMed Europe PMC Scholia
  21. Effects of long-term FK506 administration on functional and histopathological outcome after spinal cord injury in adult rat. Saganová K, Orendácová J, Sulla I Jr, Filipcík P, Cízková D, Vanický I. Cell Mol Neurobiol. 2009 Sep;29(6–7):1045–51. PubMed Europe PMC Scholia
  22. Pathogenic antibodies are active participants in spinal cord injury. Dekaban GA, Thawer S. J Clin Invest. 2009 Oct;119(10):2881–4. PubMed Europe PMC Scholia
  23. Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion. Pineau I, Sun L, Bastien D, Lacroix S. Brain Behav Immun. 2010 May;24(4):540–53. PubMed Europe PMC Scholia
  24. Eph receptor tyrosine kinases regulate astrocyte cytoskeletal rearrangement and focal adhesion formation. Puschmann TB, Turnley AM. J Neurochem. 2010 May;113(4):881–94. PubMed Europe PMC Scholia
  25. The LTB4-BLT1 axis mediates neutrophil infiltration and secondary injury in experimental spinal cord injury. Saiwai H, Ohkawa Y, Yamada H, Kumamaru H, Harada A, Okano H, et al. Am J Pathol. 2010 May;176(5):2352–66. PubMed Europe PMC Scholia
  26. 2-Methoxyestradiol inhibits the up-regulation of AQP4 and AQP1 expression after spinal cord injury. Wang Y feng, Fan Z kai, Cao Y, Yu D shui, Zhang Y qiang, Wang Y song. Brain Res. 2011 Jan 25;1370:220–6. PubMed Europe PMC Scholia
  27. CD47 knockout mice exhibit improved recovery from spinal cord injury. Myers SA, DeVries WH, Andres KR, Gruenthal MJ, Benton RL, Hoying JB, et al. Neurobiol Dis. 2011 Apr;42(1):21–34. PubMed Europe PMC Scholia
  28. Sustained delivery of activated Rho GTPases and BDNF promotes axon growth in CSPG-rich regions following spinal cord injury. Jain A, McKeon RJ, Brady-Kalnay SM, Bellamkonda RV. PLoS One. 2011 Jan 24;6(1):e16135. PubMed Europe PMC Scholia
  29. Current and future therapeutic strategies for functional repair of spinal cord injury. Tohda C, Kuboyama T. Pharmacol Ther. 2011 Oct;132(1):57–71. PubMed Europe PMC Scholia
  30. Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. Lee SM, Rosen S, Weinstein P, van Rooijen N, Noble-Haeusslein LJ. J Neurotrauma. 2011 Sep;28(9):1893–907. PubMed Europe PMC Scholia
  31. Repertoire of microglial and macrophage responses after spinal cord injury. David S, Kroner A. Nat Rev Neurosci. 2011 Jun 15;12(7):388–99. PubMed Europe PMC Scholia
  32. Phospholipase A2 superfamily members play divergent roles after spinal cord injury. López-Vales R, Ghasemlou N, Redensek A, Kerr BJ, Barbayianni E, Antonopoulou G, et al. FASEB J. 2011 Dec;25(12):4240–52. PubMed Europe PMC Scholia
  33. Activated microglia inhibit axonal growth through RGMa. Kitayama M, Ueno M, Itakura T, Yamashita T. PLoS One. 2011;6(9):e25234. PubMed Europe PMC Scholia
  34. Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury. Huang C, Han X, Li X, Lam E, Peng W, Lou N, et al. J Neurosci. 2012 Mar 7;32(10):3333–8. PubMed Europe PMC Scholia
  35. Acute leptin treatment enhances functional recovery after spinal cord injury. Fernández-Martos CM, González P, Rodriguez FJ. PLoS One. 2012;7(4):e35594. PubMed Europe PMC Scholia
  36. PlexinA2 limits recovery from corticospinal axotomy by mediating oligodendrocyte-derived Sema6A growth inhibition. Shim SO, Cafferty WBJ, Schmidt EC, Kim BG, Fujisawa H, Strittmatter SM. Mol Cell Neurosci. 2012 Jun;50(2):193–200. PubMed Europe PMC Scholia
  37. Immunosuppressant FK506: focusing on neuroprotective effects following brain and spinal cord injury. Saganová K, Gálik J, Blaško J, Korimová A, Račeková E, Vanický I. Life Sci. 2012 Aug 21;91(3–4):77–82. PubMed Europe PMC Scholia
  38. Induction of neuronal phenotypes from NG2+ glial progenitors by inhibiting epidermal growth factor receptor in mouse spinal cord injury. Ju P, Zhang S, Yeap Y, Feng Z. Glia. 2012 Nov;60(11):1801–14. PubMed Europe PMC Scholia
  39. Characterization of inflammatory gene expression and galectin-3 function after spinal cord injury in mice. Pajoohesh-Ganji A, Knoblach SM, Faden AI, Byrnes KR. Brain Res. 2012 Sep 26;1475:96–105. PubMed Europe PMC Scholia
  40. FOXO3a/p27kip1 expression and essential role after acute spinal cord injury in adult rat. Zhang S, Huan W, Wei H, Shi J, Fan J, Zhao J, et al. J Cell Biochem. 2013 Feb;114(2):354–65. PubMed Europe PMC Scholia
  41. p53 Regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. Floriddia EM, Rathore KI, Tedeschi A, Quadrato G, Wuttke A, Lueckmann JM, et al. J Neurosci. 2012 Oct 3;32(40):13956–70. PubMed Europe PMC Scholia
  42. Molecular targeting of NOX4 for neuropathic pain after traumatic injury of the spinal cord. Im YB, Jee MK, Choi JI, Cho HT, Kwon OH, Kang SK. Cell Death Dis. 2012 Nov 15;3(11):e426. PubMed Europe PMC Scholia