Skip to main content

Advertisement

Log in

Neuroprotection by Ulinastatin in Experimental Autoimmune Encephalomyelitis

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Ulinastatin has previously been used as a drug for patients with acute inflammatory disorders. The goal of the present study was to investigate the protective effects of ulinastatin on myelin sheaths and oligodendrocytes in experimental autoimmune encephalomyelitis (EAE), and to explore the possible underlying mechanism. Mice were divided into an ulinastatin treatment group, a normal saline treatment group, and a normal control group. EAE was induced in the mice with and without ulinastatin treatment. Demyelination was evaluated, as was the number of oligodendrocytes. The ulinastatin treatment group had a significantly lower clinical score, demyelinating score, and large numbers of oligodendrocytes compared with the group without ulinastatin treatment. Furthermore, ulinastatin treatment increased the expression of nerve growth factor and brain-derived neurotrophic factor, and protected against oligodendrocyte apoptosis. Thus, ulinastatin is shown to have a protective effect against EAE.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

UTI:

Ulinastatin

OLG:

Oligodendrocytes

MBP:

Myelin basic protein

IF:

Immunofluorescence

NGF:

Nerve growth factor

BDNF:

Brain-derived neurotrophic factor

CNPase:

2′,3′-cyclic nucleotide 3′-phosphodiesterase

proNGF:

The precursor form of NGF

TUNEL:

Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate nick-end labeling

BBB:

Blood-brain barrier

References

  1. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712

    Article  PubMed  Google Scholar 

  2. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717

    Article  PubMed  CAS  Google Scholar 

  3. Bjartmar C, Wujek JR, Trapp BD (2003) Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 206:165–171

    Article  PubMed  CAS  Google Scholar 

  4. Cudrici C, Niculescu T, Niculescu F, Shin ML, Rus H (2006) Oligodendrocyte cell death in pathogenesis of multiple sclerosis: protection of oligodendrocytes from apoptosis by complement. J Rehabil Res Dev 43:123–132

    Article  PubMed  Google Scholar 

  5. Hisahara S, Araki T, Sugiyama F, Yagami K, Suzuki M, Abe K, Yamamura K, Miyazaki J, Momoi T, Saruta T, Bernard CC, Okano H, Miura M (2000) Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune-mediated demyelination. EMBO J 19:341–348

    Article  PubMed  CAS  Google Scholar 

  6. Skihar V, Silva C, Chojnacki A, Doring A, Stallcup WB, Weiss S, Yong VW (2009) Promoting oligodendrogenesis and myelin repair using the multiple sclerosis medication glatiramer acetate. Proc Natl Acad Sci USA 106:17992–17997

    Article  PubMed  CAS  Google Scholar 

  7. Chen CC, Wang SS, Lee FY (2007) Action of antiproteases on the inflammatory response in acute pancreatitis. JOP 8:488–494

    PubMed  Google Scholar 

  8. Abe H, Sugino N, Matsuda T, Kanamaru T, Oyanagi S, Mori H (1996) Effect of ulinastatin on delayed neuronal death in the gerbil hippocampus. Masui 45:38–43

    PubMed  CAS  Google Scholar 

  9. Yano T, Anraku S, Nakayama R, Ushijima K (2003) Neuroprotective effect of urinary trypsin inhibitor against focal cerebral ischemia-reperfusion injury in rats. Anesthesiology 98:465–473

    Article  PubMed  CAS  Google Scholar 

  10. Koga Y, Fujita M, Tsuruta R, Koda Y, Nakahara T, Yagi T, Aoki T, Kobayashi C, Izumi T, Kasaoka S, Yuasa M, Maekawa T (2010) Urinary trypsin inhibitor suppresses excessive superoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats. Neurol Res 32:925–932

    Article  PubMed  CAS  Google Scholar 

  11. Tamatani M, Ogawa S, Nunez G, Tohyama M (1998) Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide. Cell Death Differ 5:911–919

    Article  PubMed  CAS  Google Scholar 

  12. Villoslada P, Hauser SL, Bartke I, Unger J, Heald N, Rosenberg D, Cheung SW, Mobley WC, Fisher S, Genain CP (2000) Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J Exp Med 191:1799–1806

    Article  PubMed  CAS  Google Scholar 

  13. Flugel A, Matsumuro K, Neumann H, Klinkert WE, Birnbacher R, Lassmann H, Otten U, Wekerle H (2001) Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration. Eur J Immunol 31:11–22

    Article  PubMed  CAS  Google Scholar 

  14. Althaus HH, Kloppner S, Schmidt-Schultz T, Schwartz P (1992) Nerve growth factor induces proliferation and enhances fiber regeneration in oligodendrocytes isolated from adult pig brain. Neurosci Lett 135:219–223

    Article  PubMed  CAS  Google Scholar 

  15. McTigue DM, Horner PJ, Stokes BT, Gage FH (1998) Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 18:5354–5365

    PubMed  CAS  Google Scholar 

  16. Cohen RI, Marmur R, Norton WT, Mehler MF, Kessler JA (1996) Nerve growth factor and neurotrophin-3 differentially regulate the proliferation and survival of developing rat brain oligodendrocytes. J Neurosci 16:6433–6442

    PubMed  CAS  Google Scholar 

  17. Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948

    Article  PubMed  CAS  Google Scholar 

  18. Beattie MS, Harrington AW, Lee R, Kim JY, Boyce SL, Longo FM, Bresnahan JC, Hempstead BL, Yoon SO (2002) ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36:375–386

    Article  PubMed  CAS  Google Scholar 

  19. Coulson EJ, Reid K, Murray SS, Cheema SS, Bartlett PF (2000) Role of neurotrophin receptor p75NTR in mediating neuronal cell death following injury. Clin Exp Pharmacol Physiol 27:537–541

    Article  PubMed  CAS  Google Scholar 

  20. Zhang J, Brodie C, Li Y, Zheng X, Roberts C, Lu M, Gao Q, Borneman J, Savant-Bhonsale S, Elias SB, Chopp M (2009) Bone marrow stromal cell therapy reduces proNGF and p75 expression in mice with experimental autoimmune encephalomyelitis. J Neurol Sci 279:30–38

    Article  PubMed  CAS  Google Scholar 

  21. Chen X, Pi R, Zou Y, Liu M, Ma X, Jiang Y, Mao X, Hu X (2010) Attenuation of experimental autoimmune encephalomyelitis in C57 BL/6 mice by osthole, a natural coumarin. Eur J Pharmacol 629:40–46

    Article  PubMed  CAS  Google Scholar 

  22. Kuerten S, Kostova-Bales DA, Frenzel LP, Tigno JT, Tary-Lehmann M, Angelov DN, Lehmann PV (2007) MP4- and MOG:35–55-induced EAE in C57BL/6 mice differentially targets brain, spinal cord and cerebellum. J Neuroimmunol 189:31–40

    Article  PubMed  CAS  Google Scholar 

  23. Morimoto T, Sasaki T, Takakura K (1992) Effect of ulinastatin on postischemic brain edema in cats. No To Shinkei 44:337–341

    PubMed  CAS  Google Scholar 

  24. Munakata M, Kato R, Yokoyama H, Haginoya K, Tanaka Y, Kayaba J, Kato T, Takayanagi R, Endo H, Hasegawa R, Ejima Y, Hoshi K, Iinuma K (2000) Combined therapy with hypothermia and anticytokine agents in influenza A encephalopathy. Brain Dev 22:373–377

    Article  PubMed  CAS  Google Scholar 

  25. HG DU, Yin LC, He M, Zhang GJ, Tian Y, Wang C, GA DU (2005) Application of ulinastatin in severe craniocerebral injuries. Chin J Traumatol 8:236–239

    Google Scholar 

  26. Cowan WM (2001) Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor. Annu Rev Neurosci 24:551–600

    Article  PubMed  CAS  Google Scholar 

  27. Sugiki M, Sumi H, Maruyama M, Yoshida E, Mihara H (1989) Clearance and distribution of acid-stable trypsin inhibitor (ASTI). Enzyme 42:31–38

    PubMed  CAS  Google Scholar 

  28. Keegan BM, Noseworthy JH (2002) Multiple sclerosis. Annu Rev Med 53:285–302

    Article  PubMed  CAS  Google Scholar 

  29. Weiss N, Miller F, Cazaubon S, Couraud PO (2009) The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta 1788:842–857

    Article  PubMed  CAS  Google Scholar 

  30. Ma X, Jiang Y, Wu A, Chen X, Pi R, Liu M, Liu Y (2010) Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice. PLoS One 5:e13489

    Article  PubMed  Google Scholar 

  31. Lassmann H, Schwerer B, Kitz K, Egghart M, Bernheimer H (1983) Pathogenetic aspects of demyelinating lesions in chronic relapsing experimental allergic encephalomyelitis: possible interaction of cellular and humoral immune mechanisms. Prog Brain Res 59:305–315

    Article  PubMed  CAS  Google Scholar 

  32. Wu YJ, Ling Q, Zhou XH, Wang Y, Xie HY, Yu JR, Zheng SS (2009) Urinary trypsin inhibitor attenuates hepatic ischemia-reperfusion injury by reducing nuclear factor-kappa B activation. Hepatobiliary Pancreat Dis Int 8:53–58

    PubMed  CAS  Google Scholar 

  33. Li XK, Matin AF, Suzuki H, Uno T, Yamaguchi T, Harada Y (1993) Effect of protease inhibitor on ischemia/reperfusion injury of the rat liver. Transplantation 56:1331–1336

    Article  PubMed  CAS  Google Scholar 

  34. Chen CC, Liu ZM, Wang HH, He W, Wang Y, Wu WD (2004) Effects of ulinastatin on renal ischemia-reperfusion injury in rats. Acta Pharmacol Sin 25:1334–1340

    PubMed  CAS  Google Scholar 

  35. Ren B, Wu H, Zhu J, Li D, Shen Y, Ying R, Dong G, Jing H (2006) Ulinastatin attenuates lung ischemia-reperfusion injury in rats by inhibiting tumor necrosis factor alpha. Transplant Proc 38:2777–2779

    Article  PubMed  CAS  Google Scholar 

  36. Kobayashi H, Suzuki M, Tanaka Y, Hirashima Y, Terao T (2001) Suppression of urokinase expression and invasiveness by urinary trypsin inhibitor is mediated through inhibition of protein kinase C- and MEK/ERK/c-Jun-dependent signaling pathways. J Biol Chem 276:2015–2022

    Article  PubMed  CAS  Google Scholar 

  37. Shikimi T, Hattori K, Takaori S (1992) Existence of a human urinary trypsin inhibitor (urinastatin)-like substance in the rat brain. Jpn J Pharmacol 60:97–103

    Article  PubMed  CAS  Google Scholar 

  38. Shikimi T, Wessel T, Joh TH, Takahashi M, Kaneto H, Hattori K, Takaori S (1993) Demonstration of a human urinary trypsin inhibitor (urinastatin)-like substance in the murine brain. Brain Res 616:230–235

    Article  PubMed  CAS  Google Scholar 

  39. Iwama H, Ohmori S, Tsutsumi T (2000) Detectable concentrations of urinary trypsin inhibitor in cerebrospinal fluid. J Neurosurg Anesthesiol 12:29–32

    Article  PubMed  CAS  Google Scholar 

  40. Monard D (1988) Cell-derived proteases and protease inhibitors as regulators of neurite outgrowth. Trends Neurosci 11:541–544

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the Science and Technology Program of Guangdong Province (No. 2008A030201027).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xueqiang Hu.

Additional information

Yaqing Shu and Yu Yang are contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shu, Y., Yang, Y., Qiu, W. et al. Neuroprotection by Ulinastatin in Experimental Autoimmune Encephalomyelitis. Neurochem Res 36, 1969–1977 (2011). https://doi.org/10.1007/s11064-011-0520-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0520-4

Keywords

Navigation