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

doi:10.1007/s11515-015-1373-z

Frontiers in Biology

2015, Vol. 10

Issue (5): 427-438 https://doi.org/10.1007/s11515-015-1373-z

本期目录

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

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

)

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

全文: PDF(1394 KB) HTML

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.

Key words： calpain 1 ERK1/2 RNAi neurodegeneration astrogliosis spinal cord injury

收稿日期: 2015-09-03 出版日期: 2015-10-30

Corresponding Author(s): Chen Guang Yu

引用本文:

. [J]. Frontiers in Biology, 2015, 10(5): 427-438.
Xin Xin Yu,Vimala Bondada,Colin Rogers,Carolyn A. Meyer,Chen Guang Yu. Targeting ERK1/2-calpain 1-NF-κB signal transduction in secondary tissue damage and astrogliosis after spinal cord injury. Front. Biol., 2015, 10(5): 427-438.

链接本文:

https://academic.hep.com.cn/fib/CN/10.1007/s11515-015-1373-z
https://academic.hep.com.cn/fib/CN/Y2015/V10/I5/427

Fig.1

Fig.2

Fig.3

Fig.4

Fig.5

Fig.6

Fig.7

1	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 https://doi.org/10.4049/jimmunol.176.10.5788 pmid: 16670284
2	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 https://doi.org/10.1016/j.jbiotec.2005.12.003 pmid: 16413079
3	Borgens R B, Liu-Snyder P (2012). Understanding secondary injury. Q Rev Biol, 87(2): 89–127 https://doi.org/10.1086/665457 pmid: 22696939
4	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 https://doi.org/10.1111/j.1471-4159.2009.06190.x pmid: 19522780
5	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 https://doi.org/10.1016/S0079-6123(06)61009-1 pmid: 17618974
6	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 https://doi.org/10.1128/MMBR.00031-10 pmid: 21372320
7	Colak A, Kaya M, Karaoğlan A, Sağmanligil 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 https://doi.org/10.1016/S1130-1473(09)70163-0 pmid: 19575128
8	Doshi S, Lynch D R (2009). Calpain and the glutamatergic synapse. Front Biosci (Schol Ed), 1(1): 466–476 https://doi.org/10.2741/s38 pmid: 19482714
9	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 https://doi.org/10.1021/mp9002249 pmid: 20929266
10	Geddes J W, Saatman K E (2010). Targeting individual calpain isoforms for neuroprotection. Exp Neurol, 226(1): 6–7 https://doi.org/10.1016/j.expneurol.2010.07.025 pmid: 20682310
11	Hetman M, Gozdz A (2004). Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. Eur J Biochem, 271(11): 2050–2055 https://doi.org/10.1111/j.1432-1033.2004.04133.x pmid: 15153093
12	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 https://doi.org/10.2174/1381612820666140204113252 pmid: 24502574
13	Karimi-Abdolrezaee S, Billakanti R (2012). Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects. Mol Neurobiol, 46(2): 251–264 https://doi.org/10.1007/s12035-012-8287-4 pmid: 22684804
14	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 β-cell dysfunction during the progression of type-2 diabetes. Cell Signal, 25(12): 2348–2361 https://doi.org/10.1016/j.cellsig.2013.07.028 pmid: 23916985
15	Kuchay S M, Chishti A H (2007). Calpain-mediated regulation of platelet signaling pathways. Curr Opin Hematol, 14(3): 249–254 https://doi.org/10.1097/MOH.0b013e3280ef68f8 pmid: 17414215
16	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 https://doi.org/10.1097/BRS.0b013e3181f3286d pmid: 20881470
17	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 https://doi.org/10.3109/0886022X.2012.723662 pmid: 23078635
18	Liu J, Liu M C, Wang K K (2008). Calpain in the CNS: from synaptic function to neurotoxicity. Sci Signal, 1(14): re1 https://doi.org/10.1126/stke.114re1 pmid: 18398107
19	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 https://doi.org/10.1002/jnr.22151 pmid: 19598250
20	Lu P Y, Woodle M C (2008). Delivering small interfering RNA for novel therapeutics. Methods Mol Biol, 437: 93–107 https://doi.org/10.1007/978-1-59745-210-6_3 pmid: 18369963
21	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 https://doi.org/10.1186/1744-8069-1-29 pmid: 16191203
22	Nakazawa T, Shimura M, Ryu M, Nishida K, Pagès G, Pouysségur J, Endo S (2008). ERK1 plays a critical protective role against N-methyl-D-aspartate-induced retinal injury. J Neurosci Res, 86(1): 136–144 https://doi.org/10.1002/jnr.21472 pmid: 17722069
23	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 https://doi.org/10.1002/jnr.10187 pmid: 11933044
24	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 https://doi.org/10.1016/S0165-0173(03)00152-8 pmid: 12738057
25	Saatman K E, Creed J, Raghupathi R (2010). Calpain as a therapeutic target in traumatic brain injury. Neurotherapeutics, 7(1): 31–42 https://doi.org/10.1016/j.nurt.2009.11.002 pmid: 20129495
26	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 https://doi.org/10.1046/j.1471-4159.2000.0741646.x pmid: 10737623
27	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 https://doi.org/10.1046/j.1471-4159.1997.69041592.x pmid: 9326288
28	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 pmid: 20091771
29	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 https://doi.org/10.1002/jnr.20999 pmid: 16862564
30	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 https://doi.org/10.1126/scisignal.2000202 pmid: 19531803
31	Wittrup A, Lieberman J (2015). Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet, 16(9): 543–552 https://doi.org/10.1038/nrg3978 pmid: 26281785
32	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 https://doi.org/10.1186/1742-2094-9-169 pmid: 22784881
33	Yiu G, He Z (2006). Glial inhibition of CNS axon regeneration. Nat Rev Neurosci, 7(8): 617–627 https://doi.org/10.1038/nrn1956 pmid: 16858390
34	Yu C G (2012). Distinct roles for ERK1 and ERK2 in pathophysiology of CNS. Front Biol, 7 (3): 267–276
35	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 https://doi.org/10.1007/s11064-007-9347-4 pmid: 17476592
36	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 https://doi.org/10.1089/neu.2012.2561 pmid: 23102374
37	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 https://doi.org/10.1016/j.neuroscience.2013.10.039 pmid: 24183965
38	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 https://doi.org/10.1016/j.molbrainres.2005.04.013 pmid: 15922485
39	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 https://doi.org/10.1111/j.1471-4159.2010.06579.x pmid: 20067580
40	Yuan Y M, He C (2013). The glial scar in spinal cord injury and repair. Neurosci Bull, 29(4): 421–435 https://doi.org/10.1007/s12264-013-1358-3 pmid: 23861090
41	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 pmid: 10759184
42	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 https://doi.org/10.1523/JNEUROSCI.0138-07.2007 pmid: 17329433
43	Zhuang S, Schnellmann R G (2006). A death-promoting role for extracellular signal-regulated kinase. J Pharmacol Exp Ther, 319(3): 991–997 https://doi.org/10.1124/jpet.106.107367 pmid: 16801453

Viewed

Full text

Abstract

Cited

Shared

Discussed