Targeting endothelin receptors A and B attenuates the inflammatory response and improves locomotor function following spinal cord injury in mice

Guo,Jian; Li,Yiqiao; He,Zhennian; Zhang,Bin; Li,Yonghuan; Hu,Jianghua; Han,Mingyuan; Xu,Yuanlin; Li,Yongfu; Gu,Jie; Dai,Bo; Chen,Zhong

doi:10.3892/ijmm.2014.1751

Targeting endothelin receptors A and B attenuates the inflammatory response and improves locomotor function following spinal cord injury in mice

Authors:
- Jian Guo
- Yiqiao Li
- Zhennian He
- Bin Zhang
- Yonghuan Li
- Jianghua Hu
- Mingyuan Han
- Yuanlin Xu
- Yongfu Li
- Jie Gu
- Bo Dai
- Zhong Chen
View Affiliations

Affiliations: Department of Orthopaedic Surgery, Ningbo Beilun People Hospital, Ningbo, Zhejiang 315800, P.R. China, Central Laboratory, Ningbo Beilun People Hospital, Ningbo, Zhejiang 315800, P.R. China, Department of Orthopaedic Surgery, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
Published online on: April 22, 2014 https://doi.org/10.3892/ijmm.2014.1751
Pages: 74-82
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

After spinal cord injury (SCI), the disruption of blood-spinal cord barrier by activation of the endothelin (ET) system is a critical event leading to leukocyte infiltration, inflammatory response and oxidative stress, contributing to neurological disability. In the present study, we showed that blockade of ET receptor A (ETAR) and/or ET receptor B (ETBR) prevented early inflammatory responses directly via the inhibition of neutrophil and monocyte diapedesis and inflammatory mediator production following traumatic SCI in mice. Long-term neurological improvement, based on a series of tests of locomotor performance, occurred only in the spinal cord‑injured mice following blockade of ETAR and ETBR. We also examined the post‑traumatic changes of the microenvironment within the injured spinal cord of mice following blockade of ET receptors. Oxidative stress reflects an imbalance between malondialdehyde and superoxide dismutase in spinal cord‑injured mice treated with vehicle, whereas blockade of ETAR and ETBR reversed the oxidation state imbalance. In addition, hemeoxygenase-1, a protective protease involved in early SCI, was increased in spinal cord‑injured mice following the blockade of ETAR and ETBR, or only ETBR. Matrix metalloproteinase-9, a tissue-destructive protease involved in early damage, was decreased in the injured spinal cord of mice following blockade of ETAR, ETBR or a combination thereof. The findings of the present study therefore suggested an association between ETAR and ETBR in regulating early pathogenesis of SCI and determining the outcomes of long‑term neurological recovery.

View Figures

View References

1	Hawkins B and Davis T: The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 57:173–185. 2005. View Article : Google Scholar : PubMed/NCBI
2	Abbott N, Rönnbäck L and Hansson E: Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 7:41–53. 2006. View Article : Google Scholar : PubMed/NCBI
3	Bao F, Chen Y, Schneider K and Weaver L: An integrin inhibiting molecule decreases oxidative damage and improves neurological function after spinal cord injury. Exp Neurol. 214:160–167. 2008. View Article : Google Scholar : PubMed/NCBI
4	Goldbaum O and Richter-Landsberg C: Stress proteins in oligodendrocytes: differential effects of heat shock and oxidative stress. J Neurochem. 78:1233–1242. 2001. View Article : Google Scholar : PubMed/NCBI
5	Lin Q, Weis S, Yang G, et al: Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress. J Biol Chem. 282:20621–20633. 2007. View Article : Google Scholar : PubMed/NCBI
6	Lindsey M, Wedin K, Brown M, et al: Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischernia/reperfusion. Circulation. 103:2181–2187. 2001. View Article : Google Scholar : PubMed/NCBI
7	Liu D, Li L and Augustus L: Prostaglandin release by spinal cord injury mediates production of hydroxyl radical, malondialdehyde and cell death: a site of the neuroprotective action of methylprednisolone. J Neurochem. 77:1036–1047. 2001. View Article : Google Scholar
8	Liu Y, Tachibana T, Dai Y, et al: Heme oxygenase-1 expression after spinal cord injury: the induction in activated neutrophils. J Neurotrauma. 19:479–490. 2002. View Article : Google Scholar : PubMed/NCBI
9	Nguyen H, O’Barr T and Anderson A: Polymorphonuclear leukocytes promote neurotoxicity through release of matrix metalloproteinases, reactive oxygen species, and TNF-alpha. J Neurochem. 102:900–912. 2007. View Article : Google Scholar
10	Dang A, Tay B, Kim H, Nauth A, Alfonso-Jaume M and Lovett D: Inhibition of MMP2/MMP9 after spinal cord trauma reduces apoptosis. Spine (Phila Pa 1976). 33:E576–E579. 2008. View Article : Google Scholar : PubMed/NCBI
11	Dehouck M, Vigne P, Torpier G, Breittmayer J, Cecchelli R and Frelin C: Endothelin-1 as a mediator of endothelial cell-pericyte interactions in bovine brain capillaries. J Cereb Blood Flow Metab. 17:464–469. 1997. View Article : Google Scholar : PubMed/NCBI
12	Hama H, Kasuya Y, Sakurai T, et al: Role of endothelin-1 in astrocyte responses after acute brain damage. J Neurosci Res. 47:590–602. 1997. View Article : Google Scholar : PubMed/NCBI
13	Siren A, Knerlich F, Schilling L, Kamrowski-Kruck H, Hahn A and Ehrenreich H: Differential glial and vascular expression of endothelins and their receptors in rat brain after neurotrauma. Neurochem Res. 25:957–969. 2000. View Article : Google Scholar : PubMed/NCBI
14	Martin D, Schoenen J, Delrée P, et al: Experimental acute traumatic injury of the adult rat spinal cord by a subdural inflatable balloon: methodology, behavioral analysis, and histopathology. J Neurosci Res. 32:539–550. 1992. View Article : Google Scholar
15	Lampl Y, Fleminger G, Gilad R, Galron R, Sarova-Pinhas I and Sokolovsky M: Endothelin in cerebrospinal fluid and plasma of patients in the early stage of ischemic stroke. Stroke. 28:1951–1955. 1997. View Article : Google Scholar : PubMed/NCBI
16	Reijerkerk A, Lakeman K, Drexhage J, et al: Brain endothelial barrier passage by monocytes is controlled by the endothelin system. J Neurochem. 121:730–737. 2012. View Article : Google Scholar : PubMed/NCBI
17	Leonard M, Briyal S and Gulati A: Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats. Brain Res. 1420:48–58. 2011. View Article : Google Scholar : PubMed/NCBI
18	Chou A, Chen T, Winardi W, et al: Functional neuroprotective effect of CGS 26303, a dual ECE inhibitor, on ischemic-reperfusion spinal cord injury in rats. Exp Biol Med (Maywood). 232:214–218. 2007.PubMed/NCBI
19	Barnes K and Turner A: The endothelin system and endothelin-converting enzyme in the brain: molecular and cellular studies. Neurochem Res. 22:1033–1040. 1997. View Article : Google Scholar : PubMed/NCBI
20	Kallakuri S, Kreipke C, Schafer P, Schafer S and Rafols J: Brain cellular localization of endothelin receptors A and B in a rodent model of diffuse traumatic brain injury. Neuroscience. 168:820–830. 2010. View Article : Google Scholar : PubMed/NCBI
21	McKenzie A, Hall J, Aihara N, Fukuda K and Noble L: Immunolocalization of endothelin in the traumatized spinal cord: relationship to blood-spinal cord barrier breakdown. J Neurotrauma. 12:257–268. 1995. View Article : Google Scholar : PubMed/NCBI
22	MacCumber M, Ross C and Snyder S: Endothelin in brain: receptors, mitogenesis, and biosynthesis in glial cells. Proc Natl Acad Sci USA. 87:2359–2363. 1990. View Article : Google Scholar : PubMed/NCBI
23	Peters C, Rogers S, Pomonis J, et al: Endothelin receptor expression in the normal and injured spinal cord: potential involvement in injury-induced ischemia and gliosis. Exp Neurol. 180:1–13. 2003. View Article : Google Scholar
24	Huggins J, Pelton J and Miller R: The structure and specificity of endothelin receptors: their importance in physiology and medicine. Pharmacol Ther. 59:55–123. 1993. View Article : Google Scholar : PubMed/NCBI
25	Koyama Y, Takemura M, Fujiki K, Ishikawa N, Shigenaga Y and Baba A: BQ788, an endothelin ET(B) receptor antagonist, attenuates stab wound injury-induced reactive astrocytes in rat brain. Glia. 26:268–271. 1999. View Article : Google Scholar : PubMed/NCBI
26	Noble L, Donovan F, Igarashi T, Goussev S and Werb Z: Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci. 22:7526–7535. 2002.PubMed/NCBI
27	Fu L, Guo Z and Longhurst J: Endogenous endothelin stimulates cardiac sympathetic afferents during ischaemia. J Physiol. 588:2473–2486. 2010. View Article : Google Scholar : PubMed/NCBI
28	Douglas SA, Vickery-Clark LM, Louden C and Ohlstein EH: Selective ETA receptor antagonism with BQ-123 is insufficient to inhibit angioplasty induced neointima formation in the rat. Cardiovasc Res. 29:641–646. 1995. View Article : Google Scholar : PubMed/NCBI
29	Okada M and Nishikibe M: BQ-788, a selective endothelin ET(B) receptor antagonist. Cardiovasc Drug Rev. 20:53–66. 2002. View Article : Google Scholar
30	Lee J, Kim H, Choi H, Oh T and Yune T: Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury. Brain. 135:2375–2389. 2012. View Article : Google Scholar : PubMed/NCBI
31	Basso D, Fisher L, Anderson A, Jakeman L, McTigue D and Popovich P: Basso mouse scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma. 23:635–659. 2006. View Article : Google Scholar : PubMed/NCBI
32	Lee S, Rosen S, Weinstein P, van Rooijen N and Noble-Haeusslein L: Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. J Neurotrauma. 28:1893–1907. 2011. View Article : Google Scholar : PubMed/NCBI
33	Xu W, Chi L, Xu R, et al: Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury. Spinal Cord. 43:204–213. 2005. View Article : Google Scholar : PubMed/NCBI
34	Cuadrado A and Rojo A: Heme oxygenase-1 as a therapeutic target in neurodegenerative diseases and brain infections. Curr Pharm Des. 14:429–442. 2008. View Article : Google Scholar : PubMed/NCBI
35	Salzman S, Acosta R, Beck G, Madden J, Boxer B and Ohlstein E: Spinal endothelin content is elevated after moderate local trauma in the rat to levels associated with locomotor dysfunction after intrathecal injection. J Neurotrauma. 13:93–101. 1996. View Article : Google Scholar
36	Nagasaka J, Tsuji M, Takeda H and Matsumiya T: Role of endothelin receptor subtypes in the behavioral effects of the intracerebroventricular administration of endothelin-1 in conscious rats. Pharmacol Biochem Behav. 64:171–176. 1999. View Article : Google Scholar : PubMed/NCBI
37	Ishikawa K, Fukami T, Nagase T, et al: Cyclic pentapeptide endothelin antagonists with high ETA selectivity. Potency- and solubility-enhancing modifications. J Med Chem. 35:2139–2142. 1992. View Article : Google Scholar : PubMed/NCBI
38	Khimji A and Rockey D: Endothelin - biology and disease. Cell Signal. 22:1615–1625. 2010. View Article : Google Scholar
39	Beck K, Nguyen H, Galvan M, Salazar D, Woodruff T and Anderson A: Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain. 133:433–447. 2010. View Article : Google Scholar
40	Letellier E, Kumar S, Sancho-Martinez I, et al: CD95-ligand on peripheral myeloid cells activates Syk kinase to trigger their recruitment to the inflammatory site. Immunity. 32:240–252. 2010. View Article : Google Scholar : PubMed/NCBI
41	Stirling D and Yong V: Dynamics of the inflammatory response after murine spinal cord injury revealed by flow cytometry. J Neurosci Res. 86:1944–1958. 2008. View Article : Google Scholar : PubMed/NCBI
42	Ahnstedt H, Stenman E, Cao L, Henriksson M and Edvinsson L: Cytokines and growth factors modify the upregulation of contractile endothelin ET(A) and ET(B) receptors in rat cerebral arteries after organ culture. Acta Physiol (Oxf). 205:266–278. 2012. View Article : Google Scholar : PubMed/NCBI
43	Zarpelon A, Pinto L, Cunha T, et al: Endothelin-1 induces neutrophil recruitment in adaptive inflammation via TNFα and CXCL1/CXCR2 in mice. Canadian Can J Physiol Pharmacol. 90:187–199. 2012.PubMed/NCBI
44	Tonari M, Kurimoto T, Horie T, Sugiyama T, Ikeda T and Oku H: Blocking endothelin-B receptors rescues retinal ganglion cells from optic nerve injury through suppression of neuroinflammation. Invest Ophthalmol Vis Sci. 53:3490–3500. 2012. View Article : Google Scholar
45	Wang H, Hsieh H and Yang C: Nitric oxide production by endothelin-1 enhances astrocytic migration via the tyrosine nitration of matrix metalloproteinase-9. J Cell Physiol. 226:2244–2256. 2011. View Article : Google Scholar : PubMed/NCBI
46	Gallelli L, Pelaia G, D’Agostino B, et al: Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ET(A) receptor-dependent activation of MAP kinases. J Cell Biochem. 96:858–868. 2005. View Article : Google Scholar : PubMed/NCBI
47	Solini A, Santini E, Madec S, Cuccato S and Ferrannini E: Effects of endothelin-1 on fibroblasts from type 2 diabetic patients: possible role in wound healing and tissue repair. Growth Factors. 25:392–399. 2007. View Article : Google Scholar : PubMed/NCBI
48	Yin X, Yin Y, Cao F, et al: Tanshinone IIA attenuates the inflammatory response and apoptosis after traumatic injury of the spinal cord in adult rats. PLoS One. 7:e383812012. View Article : Google Scholar : PubMed/NCBI
49	Kanno H, Ozawa H, Dohi Y, Sekiguchi A, Igarashi K and Itoi E: Genetic ablation of transcription repressor Bach1 reduces neural tissue damage and improves locomotor function after spinal cord injury in mice. J Neurotrauma. 26:31–39. 2009. View Article : Google Scholar : PubMed/NCBI
50	Goven D, Boutten A, Lecon-Malas V, Boczkowski J and Bonay M: Prolonged cigarette smoke exposure decreases heme oxygenase-1 and alters Nrf2 and Bach1 expression in human macrophages: roles of the MAP kinases ERK(1/2) and JNK. FEBS Lett. 583:3508–3518. 2009. View Article : Google Scholar : PubMed/NCBI
51	Sallum CO, Wilson JL, Rupasinghe C, et al: Enhancing and limiting endothelin-1 signaling with a cell-penetrating peptide mimicking the third intracellular loop of the ETB receptor. Chem Biol Drug Des. 80:374–381. 2012. View Article : Google Scholar : PubMed/NCBI
52	Romanic AM 1, White RF, Arleth AJ, Ohlstein EH and Barone FC: Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 29:1020–1030. 1998. View Article : Google Scholar