Skip to main content
SpringerLink
Log in

Targeting ERK1/2-calpain 1-NF-κB signal transduction in secondary tissue damage and astrogliosis after spinal cord injury

  • Research Article
  • Published:
Frontiers in Biology

Abstract

Neuronal damage, glial inflammation, and astrogliosis/astroglial scar formation are major secondary injury mechanisms that are significant contributors to functional deficits after spinal cord injury (SCI). The objectives of the study were to evaluate the distinct roles of ERK2 vs. ERK1/2 and ERK1/2-calpain 1–NF-κB signal transduction in the tissue damage and astrogliosis/astroglial scar formation following SCI in rats. RNAi approaches, pharmacological intervention (U0126), Western blot analysis, immunofluorescence analysis, and histological assessment were used to target ERK1/2-calpain 1-NF-κB signal transduction pathway for neuroprotection. Histological staining analysis demonstrated that selectively reducing pERK2 using ERK2 siRNA, but not inhibition of pERK1/2 with U0126, significantly reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing in spinal cord two weeks after contusive SCI. An ERK1/2-calpain 1-NF-κB signal transduction pathway was involved in the astroglial scar formation after SCI. Blockade of ERK1/2 by U0126 decreased calpain 1 expression 4 h following SCI. Selective calpain 1 reduction by lentiviral shRNA attenuated astroglial NF-κB activity and astroglial scar formation after SCI in rats. Taken together, these results demonstrate the involvement of individual ERK2 and calpain 1 signaling pathways in tissue damage and astrogliosis/astroglial scar formation in animal models of SCI. Therefore, targeting individual ERK and its downstream signal transduction of calpain 1-NF-κB may provide greater potential as novel therapeutics for minimizing tissue damage and astroglial scar formation following SCI.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Agrawal A, Dillon S, Denning T L, Pulendran B (2006). ERK1-/- mice exhibit Th1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis. J Immunol, 176(10): 5788–5796

    Article  CAS  PubMed  Google Scholar 

  • Aigner A (2006). Gene silencing through RNA interference (RNAi) in vivo: strategies based on the direct application of siRNAs. J Biotechnol, 124(1): 12–25

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Brambilla R, Hurtado A, Persaud T, Esham K, Pearse D D, Oudega M, Bethea J R (2009). Transgenic inhibition of astroglial NF-kappa B leads to increased axonal sparing and sprouting following spinal cord injury. J Neurochem, 110(2): 765–778

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bramlett H M, Dietrich W D (2007). Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies. Prog Brain Res, 161: 125–141

    Article  PubMed  Google Scholar 

  • Cargnello M, Roux P P (2011). Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev, 75(1): 50–83

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Colak A, Kaya M, Karaoglan A, Sagmanligil A, Akdemir O, Sahan E, Celik O (2009). Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats. Neurocirugia (Astur), 20(3): 245–254

    Article  CAS  Google Scholar 

  • Doshi S, Lynch D R (2009). Calpain and the glutamatergic synapse. Front Biosci (Schol Ed), 1(1): 466–476

    Article  Google Scholar 

  • Drake C R, Aissaoui A, Argyros O, Serginson J M, Monnery B D, Thanou M, Steinke J H, Miller A D (2010). Bioresponsive small molecule polyamines as noncytotoxic alternative to polyethylenimine. Mol Pharm, 7(6): 2040–2055

    Article  CAS  PubMed  Google Scholar 

  • Geddes J W, Saatman K E (2010). Targeting individual calpain isoforms for neuroprotection. Exp Neurol, 226(1): 6–7

    Article  PubMed Central  PubMed  Google Scholar 

  • Hetman M, Gozdz A (2004). Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. Eur J Biochem, 271(11): 2050–2055

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa T, Suzuki H, Ishikawa K, Yasuda S, Matsui T, Yamamoto M, Kakeda T, Yamamoto S, Owada Y, Yaksh T L (2014). Spinal cord ischemia/injury. Curr Pharm Des, 20(36): 5738–5743

    Article  CAS  PubMed  Google Scholar 

  • Karimi-Abdolrezaee S, Billakanti R (2012). Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects. Mol Neurobiol, 46(2): 251–264

    Article  CAS  PubMed  Google Scholar 

  • Kim J Y, Park K J, Kim G H, Jeong E A, Lee D Y, Lee S S, Kim D J, Roh G S, Song J, Ki S H, Kim W H (2013). In vivo activating transcription factor 3 silencing ameliorates the AMPK compensatory effects for ER stress-mediated ß-cell dysfunction during the progression of type-2 diabetes. Cell Signal, 25(12): 2348–2361

    Article  CAS  PubMed  Google Scholar 

  • Kuchay S M, Chishti A H (2007). Calpain-mediated regulation of platelet signaling pathways. Curr Opin Hematol, 14(3): 249–254

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kwon B K, Sekhon L H, Fehlings M G (2010). Emerging repair, regeneration, and translational research advances for spinal cord injury. Spine, 35(21 Suppl): S263–S270

    Article  PubMed  Google Scholar 

  • Li L, Wu Y, Wang C, Zhang W (2012). Inhibition of PAX2 gene expression by siRNA (polyethylenimine) in experimental model of obstructive nephropathy. Ren Fail, 34(10): 1288–1296

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Liu M C, Wang K K (2008). Calpain in the CNS: from synaptic function to neurotoxicity. Sci Signal, 1(14): re1

    Article  Google Scholar 

  • Liu L, Zhang R, Liu K, Zhou H, Tang Y, Su J, Yu X, Yang X, Tang M, Dong Q (2009). Tissue kallikrein alleviates glutamate-induced neurotoxicity by activating ERK1. J Neurosci Res, 87(16): 3576–3590

    Article  CAS  PubMed  Google Scholar 

  • Lu P Y, Woodle MC (2008). Delivering small interfering RNA for novel therapeutics. Methods Mol Biol, 437: 93–107

    Article  CAS  PubMed  Google Scholar 

  • Luo M C, Zhang D Q, Ma S W, Huang Y Y, Shuster S J, Porreca F, Lai J (2005). An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons. Mol Pain, 1(1): 29

    Article  PubMed Central  PubMed  Google Scholar 

  • Nakazawa T, Shimura M, Ryu M, Nishida K, Pagès G, Pouysségur J, Endo S (2008). ERK1 plays a critical protective role against Nmethyl- D-aspartate-induced retinal injury. J Neurosci Res, 86(1): 136–144

    Article  CAS  PubMed  Google Scholar 

  • Rabchevsky A G, Fugaccia I, Sullivan P G, Blades D A, Scheff S W (2002). Efficacy of methylprednisolone therapy for the injured rat spinal cord. J Neurosci Res, 68(1): 7–18

    Article  CAS  PubMed  Google Scholar 

  • Ray S K, Hogan E L, Banik N L (2003). Calpain in the pathophysiology of spinal cord injury: neuroprotection with calpain inhibitors. Brain Res Brain Res Rev, 42(2): 169–185

    Article  CAS  PubMed  Google Scholar 

  • Saatman K E, Creed J, Raghupathi R (2010). Calpain as a therapeutic target in traumatic brain injury. Neurotherapeutics, 7(1): 31–42

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schumacher P A, Siman R G, Fehlings M G (2000). Pretreatment with calpain inhibitor CEP-4143 inhibits calpain I activation and cytoskeletal degradation, improves neurological function, and enhances axonal survival after traumatic spinal cord injury. J Neurochem, 74(4): 1646–1655

    Article  CAS  PubMed  Google Scholar 

  • Springer J E, Azbill R D, Kennedy S E, George J, Geddes J W (1997). Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatment. J Neurochem, 69(4): 1592–1600

    Article  CAS  PubMed  Google Scholar 

  • Sribnick E A, Samantaray S, Das A, Smith J, Matzelle D D, Ray S K, Banik N L (2010). Postinjury estrogen treatment of chronic spinal cord injury improves locomotor function in rats. J Neurosci Res, 88 (8): 1738–1750

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tian D S, Yu Z Y, Xie M J, Bu B T, Witte O W, Wang W (2006). Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor olomoucine. J Neurosci Res, 84(5): 1053–1063

    Article  CAS  PubMed  Google Scholar 

  • Wall E A, Zavzavadjian J R, Chang M S, Randhawa B, Zhu X, Hsueh R C, Liu J, Driver A, Bao X R, Sternweis P C, Simon M I, Fraser I D (2009). Suppression of LPS-induced TNF-alpha production in macrophages by cAMP is mediated by PKA-AKAP95-p105. Sci Signal, 2(75): ra28

    Article  Google Scholar 

  • Wittrup A, Lieberman J (2015). Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet, 16(9): 543–552

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Pajoohesh-Ganji A, Stoica B A, Dinizo M, Guanciale K, Faden A I (2012). Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion. J Neuroinflammation, 9(1): 169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yiu G, He Z (2006). Glial inhibition of CNS axon regeneration. Nat Rev Neurosci, 7(8): 617–627

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yu C G (2012). Distinct roles for ERK1 and ERK2 in pathophysiology of CNS. Front Biol, 7 (3): 267–276

    Article  CAS  Google Scholar 

  • Yu C G, Geddes J W (2007). Sustained calpain inhibition improves locomotor function and tissue sparing following contusive spinal cord injury. Neurochem Res, 32(12): 2046–2053

    Article  CAS  PubMed  Google Scholar 

  • Yu C G, Li Y, Raza K, Yu X X, Ghoshal S, Geddes J W (2013). Calpain 1 knockdown improves tissue sparing and functional outcomes after spinal cord injury in rats. J Neurotrauma, 30(6): 427–433

    Article  PubMed Central  PubMed  Google Scholar 

  • Yu C G, Singh R, Crowdus C, Raza K, Kincer J, Geddes J W (2014). Fenbendazole improves pathological and functional recovery following traumatic spinal cord injury. Neuroscience, 256: 163–169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yu C G, Yezierski R P (2005). Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury. Brain Res Mol Brain Res, 138(2): 244–255

    Article  CAS  PubMed  Google Scholar 

  • Yu C G, Yezierski R P, Joshi A, Raza K, Li Y, Geddes J W (2010). Involvement of ERK2 in traumatic spinal cord injury. J Neurochem, 113(1): 131–142

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yuan Y M, He C (2013). The glial scar in spinal cord injury and repair. Neurosci Bull, 29(4): 421–435

    Article  PubMed  Google Scholar 

  • Zhang S X, Underwood M, Landfield A, Huang F F, Gison S, Geddes J W (2000). Cytoskeletal disruption following contusion injury to the rat spinal cord. J Neuropathol Exp Neurol, 59(4): 287–296

    CAS  PubMed  Google Scholar 

  • Zhao P, Waxman S G, Hains B C (2007). Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci, 27(9): 2357–2368

    Article  CAS  PubMed  Google Scholar 

  • Zhuang S, Schnellmann R G (2006). A death-promoting role for extracellular signal-regulated kinase. J Pharmacol Exp Ther, 319(3): 991–997

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Xin Xin Yu

    Present address: Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, USA

Authors and Affiliations

  1. Spinal Cord and Brain Injury Research Center, Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, KY, 40536-0509, USA

    Xin Xin Yu, Vimala Bondada, Colin Rogers, Carolyn A. Meyer & Chen Guang Yu

Authors
  1. Xin Xin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vimala Bondada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Colin Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carolyn A. Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Guang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chen Guang Yu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, X.X., Bondada, V., Rogers, C. et al. Targeting ERK1/2-calpain 1-NF-κB signal transduction in secondary tissue damage and astrogliosis after spinal cord injury. Front. Biol. 10, 427–438 (2015). https://doi.org/10.1007/s11515-015-1373-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-015-1373-z

Keywords

Search

Navigation