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 multi-step 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. dce bc2 f41 fed da7 ab0 dad d87 d87 d87 d87 e0c ea4 c8a d87 f8f aef f6b bc0 b6f b6f b6f f35 abd bd3 fce da7 c0d ef0 d81 spinal cord disease DOID:319 Human Disease Ontology astrocyte of the spinal cord CL:0002606 Cell Ontology disease pathway PW:0000013 Pathway Ontology traumatic neurosis DOID:2055 Human Disease Ontology 21673720 PubMed Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011 David S Kroner A 21868473 PubMed Phospholipase A2 superfamily members play divergent roles after spinal cord injury. FASEB J 2011 Lopez-Vales R Ghasemlou N Redensek A Kerr BJ Barbayianni E Antonopoulou G Baskakis C Rathore KI Constantinou-Kokotou V Stephens D Shimizu T Dennis EA Kokotos G David S 11553680 PubMed A neutrophil elastase inhibitor (ONO-5046) reduces neurologic damage after spinal cord injury in rats. J Neurochem 2001 Tonai T Shiba K Taketani Y Ohmoto Y Murata K Muraguchi M Ohsaki H Takeda E Nishisho T 19932745 PubMed 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. Brain Behav Immun 2010 Pineau I Sun L Bastien D Lacroix S 19770517 PubMed Pathogenic antibodies are active participants in spinal cord injury. J Clin Invest 2009 Dekaban GA Thawer S 16623828 PubMed Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion. Eur J Neurosci 2006 Fabes J Anderson P Yanez-Munoz RJ Thrasher A Brennan C Bolsover S 20202079 PubMed Eph receptor tyrosine kinases regulate astrocyte cytoskeletal rearrangement and focal adhesion formation. J Neurochem 2010 Puschmann TB Turnley AM 12666113 PubMed Gene profiling in spinal cord injury shows role of cell cycle in neuronal death. Ann Neurol 2003 Di Giovanni S Knoblach SM Brandoli C Aden SA Hoffman EP Faden AI 21957482 PubMed Activated microglia inhibit axonal growth through RGMa. PLoS One 2011 Kitayama M Ueno M Itakura T Yamashita T 10094148 PubMed Improved recovery after spinal cord trauma in ICAM-1 and P-selectin knockout mice. Neuroreport 1999 Farooque M Isaksson J Olsson Y 11059815 PubMed Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res 2000 Eng LF Ghirnikar RS Lee YL 17706365 PubMed The p75 neurotrophin receptor is essential for neuronal cell survival and improvement of functional recovery after spinal cord injury. Neuroscience 2007 Chu GK Yu W Fehlings MG 20304963 PubMed The LTB4-BLT1 axis mediates neutrophil infiltration and secondary injury in experimental spinal cord injury. Am J Pathol 2010 Saiwai H Ohkawa Y Yamada H Kumamaru H Harada A Okano H Yokomizo T Iwamoto Y Okada S 17698296 PubMed Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons. Neuroscience 2007 Adjan VV Hauser KF Bakalkin G Yakovleva T Gharibyan A Scheff SW Knapp PE 22564823 PubMed PlexinA2 limits recovery from corticospinal axotomy by mediating oligodendrocyte-derived Sema6A growth inhibition. Mol Cell Neurosci 2012 Shim SO Cafferty WB Schmidt EC Kim BG Fujisawa H Strittmatter SM 21168495 PubMed CD47 knockout mice exhibit improved recovery from spinal cord injury. Neurobiol Dis 2011 Myers SA DeVries WH Andres KR Gruenthal MJ Benton RL Hoying JB Hagg T Whittemore SR 18267965 PubMed Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Brain 2008 Saadoun S Bell BA Verkman AS Papadopoulos MC 21657851 PubMed Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. J Neurotrauma 2011 Lee SM Rosen S Weinstein P van Rooijen N Noble-Haeusslein LJ 17917587 PubMed Annexin A1 reduces inflammatory reaction and tissue damage through inhibition of phospholipase A2 activation in adult rats following spinal cord injury. J Neuropathol Exp Neurol 2007 Liu NK Zhang YP Han S Pei J Xu LY Lu PH Shields CB Xu XM 17629414 PubMed Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury. Neuroscience 2007 Terayama R Bando Y Murakami K Kato K Kishibe M Yoshida S 23035104 PubMed p53 Regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. J Neurosci 2012 Floriddia EM Rathore KI Tedeschi A Quadrato G Wuttke A Lueckmann JM Kigerl KA Popovich PG Di Giovanni S 16602711 PubMed Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity. J Proteome Res 2006 Woods AS Kaminski R Oz M Wang Y Hauser K Goody R Wang HY Jackson SN Zeitz P Zeitz KP Zolkowska D Schepers R Nold M Danielson J Graeslund A Vukojevic V Bakalkin G Basbaum A Shippenberg T 12861073 PubMed Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc Natl Acad Sci U S A 2003 Menet V Prieto M Privat A Gimenez y Ribotta M 22771695 PubMed Immunosuppressant FK506: focusing on neuroprotective effects following brain and spinal cord injury. Life Sci 2012 Saganova K Galik J Blasko J Korimova A Racekova E Vanicky I 19350383 PubMed Effects of long-term FK506 administration on functional and histopathological outcome after spinal cord injury in adult rat. Cell Mol Neurobiol 2009 Saganova K Orendacova J Sulla I Jr Filipci­k P Cizkova D Vanicky I 21640756 PubMed Current and future therapeutic strategies for functional repair of spinal cord injury. Pharmacol Ther 2011 Tohda C Kuboyama T 9872457 PubMed Role of cyclooxygenase 2 in acute spinal cord injury. J Neurotrauma 1998 Resnick DK Graham SH Dixon CE Marion DW 17482149 PubMed Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model. Brain Res 2007 Tian DS Dong Q Pan DJ He Y Yu ZY Xie MJ Wang W 16295699 PubMed Stimulation of production of glial cell line-derived neurotrophic factor and nitric oxide by lipopolysaccharide with different dose-responsiveness in cultured rat macrophages. Biomed Res 2005 Hashimoto M Ito T Fukumitsu H Nomoto H Furukawa Y Furukawa S 22399755 PubMed Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury. J Neurosci 2012 Huang C Han X Li X Lam E Peng W Lou N Torres A Yang M Garre JM Tian GF Bennett MV Nedergaard M Takano T 23152062 PubMed Molecular targeting of NOX4 for neuropathic pain after traumatic injury of the spinal cord. Cell Death Dis 2012 Im YB Jee MK Choi JI Cho HT Kwon OH Kang SK