Neurochemical Research

, Volume 38, Issue 7, pp 1333–1340 | Cite as

The Effect of an NgR1 Antagonist on the Neuroprotection of Cortical Axons After Cortical Infarction in Rats

  • Hong Zhan
  • Shu-Jie Sun
  • Jie Cai
  • Ying-Qing Li
  • Chun-Lin Hu
  • Daniel H. S. Lee
  • Kwok-Fai So
  • Xin Li
Original Paper
First Online:
Received:
Revised:
Accepted:

Abstract

We investigated the effect of the soluble Nogo66 receptor (sNgR-Fc) on the protection of cortical axons after cortical infarction in rats. The cortical infarction was induced by photothrombotic cortical injury (PCI) in Sprague–Dawley rats, after which sNgR-Fc was injected into the lateral ventricle. The ipsilesional cortices were harvested for analyses using histochemical and transmission-electron microscope techniques. The involved signaling pathways, which include RhoA, JNK, c-JUN and ATF-2, were detected by Western blot. Serious pathologies were found in the brains of the rats after injury, including edemas in the axoplasms of axons that have no medulla sheath and a thickening or shrinkage in the sheath of the axons that have medulla sheathes. However, these pathologies improved after sNgR-Fc treatment. The levels of GTP-RhoA, p-JNK, p–c-JUN and p-ATF-2 in the PCI group were increased when compared with their levels in the sham-operation group (P < 0.05), and animals receiving the sNgR-Fc treatment showed lower expression levels of these proteins when compared with the sham-operation group (P < 0.05). Our results suggest that sNgR-Fc can alleviate the pathological changes of axons following cortical infarction via decreasing the activation of RhoA/JNK signaling pathways.

Keywords

Nogo-66 receptor Axon Cortical infarction Regeneration Signal pathway 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

This study was supported by funding from the NSFC (81272062, 81071030), Science and Technology Foundation of Guangdong Province, China (2012B031800286, 2010B031600089) and the Fundamental Research Funds for the Central Universities (09ykpy31). The funders had no role in the study design, data collection, analysis, decision to publish or the preparation of the manuscript. Biogen Idec, Inc. provided the sNgR-Fc in the study.

Conflict of interest

The authors indicate no potential conflicts of interest.

References

  1. 1.
    Bühnemann C, Scholz A, Bernreuther C, Malik CY, Braun H, Schachner M et al (2006) Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain 129:3238–3248PubMedCrossRefGoogle Scholar
  2. 2.
    Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA et al (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403:434–439PubMedCrossRefGoogle Scholar
  3. 3.
    Domeniconi M, Cao Z, Spencer T, Sivasankaran R, Wang K, Nikulina E et al (2002) Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35:283–290PubMedCrossRefGoogle Scholar
  4. 4.
    Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL et al (2002) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941–944PubMedCrossRefGoogle Scholar
  5. 5.
    GrandPre T, Li S, Strittmatter SM (2002) Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417:547–551PubMedCrossRefGoogle Scholar
  6. 6.
    Harvey PA, Lee DH, Qian F, Weinreb PH, Frank E (2009) Blockade of Nogo receptor ligands promotes functional regeneration of sensory axons after dorsal root crush. J Neurosci 29:6285–6295PubMedCrossRefGoogle Scholar
  7. 7.
    Ji B, Li M, Budel S, Pepinsky RB, Walus L, Engber TM et al (2005) Effect of combined treatment with methylprednisolone and soluble Nogo-66 receptor after rat spinal cord injury. Eur J Neurosci 22:587–594PubMedCrossRefGoogle Scholar
  8. 8.
    Lee JK, Kim JE, Sivula M, Strittmatter SM (2004) Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J Neurosci 24:6209–6217PubMedCrossRefGoogle Scholar
  9. 9.
    Li S, Liu BP, Budel S, Li M, Ji B, Walus L et al (2004) Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury. J Neurosci 24:10511–10520PubMedCrossRefGoogle Scholar
  10. 10.
    MacDermid VE, McPhail LT, Tsang B, Rosenthal A, Davies A, Ramer MS (2004) A soluble Nogo receptor differentially affects plasticity of spinally projecting axons. Eur J Neurosci 20:2567–2579PubMedCrossRefGoogle Scholar
  11. 11.
    Wiessner C, Bareyre FM, Allegrini PR, Mir AK, Frentzel S, Zurini M et al (2003) Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats. J Cereb Blood Flow Metab 23:154–165PubMedCrossRefGoogle Scholar
  12. 12.
    Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD (1985) Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol 17:497–504PubMedCrossRefGoogle Scholar
  13. 13.
    Gao M, Zhu SY, Tan CB, Xu B, Zhang WC, Du GH (2010) Pinocembrin protects the neurovascular unit by reducing inflammation and extracellular proteolysis in MCAO rats. J Asian Nat Prod Res 12:407–418PubMedCrossRefGoogle Scholar
  14. 14.
    Zheng YQ, Liu JX, Wang JN, Xu L (2007) Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. Brain Res 1138:86–94PubMedCrossRefGoogle Scholar
  15. 15.
    Culmsee C, Plesnila N (2006) Targeting Bid to prevent programmed cell death in neurons. Biochem Soc Trans 34:1334–1340PubMedCrossRefGoogle Scholar
  16. 16.
    Plesnila N, Zhu C, Culmsee C, Gröger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466PubMedCrossRefGoogle Scholar
  17. 17.
    Wang F, Liang Z, Hou Q, Xing S, Ling L, He M et al (2007) Nogo-A is involved in secondary axonal degeneration of thalamus in hypertensive rats with focal cortical infarction. Neurosci Lett 417:255–260PubMedCrossRefGoogle Scholar
  18. 18.
    Cheatwood JL, Emerick AJ, Schwab ME, Kartje GL (2008) Nogo-A expression after focal ischemic stroke in the adult rat. Stroke 39:2091–2098PubMedCrossRefGoogle Scholar
  19. 19.
    Kubo T, Hata K, Yamaguchi A, Yamashita T (2007) Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration. Curr Pharm Des 13:2493–2499PubMedCrossRefGoogle Scholar
  20. 20.
    Kubo T, Yamashita T (2007) Rho-ROCK inhibitors for the treatment of CNS injury. Recent Pat CNS Drug Discov 2:173–179PubMedCrossRefGoogle Scholar
  21. 21.
    Schwab TS, Madison BB, Grauman AR, Feldman EL (2005) Insulin-like growth factor-I induces the phosphorylation and nuclear exclusion of forkhead transcription factors in human neuroblastoma cells. Apoptosis 10:831–840PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang HM, Yuan J, Cheung P, Luo H, Yanagawa B, Chau D et al (2003) Overexpression of interferon-gamma-inducible GTPase inhibits coxsackievirus B3-induced apoptosis through the activation of the phosphatidylinositol 3-kinase/Akt pathway and inhibition of viral replication. J Biol Chem 278:33011–33019PubMedCrossRefGoogle Scholar
  23. 23.
    Koh SH, Lee YB, Kim KS, Kim HJ, Kim M, Lee YJ et al (2005) Role of GSK-3beta activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene. Eur J Neurosci 22:301–309PubMedCrossRefGoogle Scholar
  24. 24.
    Yasuda S, Sugiura H, Tanaka H, Takigami S, Yamagata K (2011) p38 MAP kinase inhibitors as potential therapeutic drugs for neural diseases. Cent Nerv Syst Agents Med Chem 11:45–59PubMedCrossRefGoogle Scholar
  25. 25.
    Humar M, Loop T, Schmidt R, Hoetzel A, Roesslein M, Andriopoulos N et al (2007) The mitogen-activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c-Jun. Int J Biochem Cell Biol 39:2278–2288PubMedCrossRefGoogle Scholar
  26. 26.
    Marinissen MJ, Chiariello M, Tanos T, Bernard O, Narumiya S, Gutkind JS (2004) The small GTP-binding protein RhoA regulates c-jun by a ROCK-JNK signaling axis. Mol Cell 14:29–41PubMedCrossRefGoogle Scholar
  27. 27.
    Karin M, Liu Z, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9:240–246PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hong Zhan
    • 1
  • Shu-Jie Sun
    • 4
  • Jie Cai
    • 1
  • Ying-Qing Li
    • 1
  • Chun-Lin Hu
    • 1
  • Daniel H. S. Lee
    • 3
  • Kwok-Fai So
    • 2
    • 5
  • Xin Li
    • 1
  1. 1.Department of Emergency, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouPeople’s Republic of China
  2. 2.The State Key Laboratory of Brain and Cognitive Sciences, Department of AnatomyThe University of Hong KongPokfulamPeople’s Republic of China
  3. 3.Roche R&D Center (China) Ltd.PudongChina
  4. 4.Emergency DepartmentEast Hospital of TongJi UniversityShanghaiPeople’s Republic of China
  5. 5.GHM Institute of CNS RegenerationJinan UniversityGuangzhouPeople’s Republic of China

Personalised recommendations