中华眼底病杂志

中华眼底病杂志

亟待加强视神经损伤修复基础研究成果的临床转化

查看全文

视神经属中枢神经。由于中枢神经系统微环境内缺少神经营养因子并且存在髓鞘和胶质瘢痕相关抑制分子以及中枢神经元内在的再生潜能低于周围神经元等原由,视神经损伤后难以自发再生。保护受损的视网膜神经节细胞(节细胞)、补充神经营养因子、拮抗轴突再生抑制因子、上调节细胞内在的再生潜力均能有效促进视神经的再生与修复。基础研究已取得包括视觉功能部分恢复等重要进展,但临床应用转化仍存在大量未解难题,至今尚无治疗视神经损伤的理想方法。亟待加强基础与临床研究合作,促进基础研究成果尽快向临床应用转化,早日改变不尽如人意的临床研究现状。

The optic nerve belongs to the central nervous system (CNS). Because of the lack of neurotrophic factors in the microenvironment of the CNS and the presence of myelin and glial scar-related inhibitory molecules, and the inherent low renewal potentials of CNS neurons comparing to the peripheral nerve system, it is difficult to spontaneously regenerate the optic nerve after injury. Protecting damaged retinal ganglion cells (RGCs), supplementing neurotrophic factor, antagonizing axon regeneration inhibitory factor, and regulating the inherent regeneration potential of RGCs can effectively promote the regeneration and repair of optic nerve. Basic research has made important progress, including the restoration of visual function, but there are still a lot of unsolved problems in clinical translation of these achievements, so far there is no ideal method of treatment of optic nerve injury. Therefore, it is rather urgent to strengthen the cooperation between basic and clinical research, to promote the transformation of basic research to the clinical applications as soon as possible, which will change the unsatisfactory clinical application status.

关键词: 视神经损伤; 视网膜神经节细胞; 轴突; 述评

Key words: Optic nerve injury; Retinal ganglion cells; Axons; Editorial

引用本文: 游思维, 胡丹, 王雨生. 亟待加强视神经损伤修复基础研究成果的临床转化. 中华眼底病杂志, 2017, 33(6): 569-572. doi: 10.3760/cma.j.issn.1005-1015.2017.06.003 复制

登录后 ,请手动点击刷新查看全文内容。 没有账号,
1. So KF, Aguayo AJ. Lengthy regrowth of cut axons from ganglion cells after peripheral nerve transplantation into the retina of adult rats[J]. Brain Res, 1985, 328(2): 349-354.
2. van Niekerk EA, Tuszynski MH, Lu P, et al. Molecular and cellular mechanisms of axonal regeneration after spinal cord injury[J]. Mol Cell Proteomics, 2016, 15(2): 394-408. DOI: 10.1074/mcp.R115.053751. Epub 2015 Dec 22.
3. Yiu G, He Z. Glial inhibition of CNS axon regeneration[J]. Nat Rev Neurosci, 2006, 7(8): 617-627. DOI:10.1038/nrn1956.
4. Wang X, Hasan O, Arzeno A, et al. Axonal regeneration induced by blockade of glial inhibitors coupled with activation of intrinsic neuronal growth pathways[J]. Exp Neurol, 2012, 237(1): 55-69. DOI:10.1016/j.expneurol.2012.06.009.
5. Ohtake Y, Li S. Molecular mechanisms of scar-sourced axon growth inhibitors[J]. Brain Res, 2015, 1619: 22-35. DOI:10.1016/j.brainres.2014.08.064.
6. Wang KC, Kim JA, Sivasankaran R, et al. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp[J]. Nature, 2002, 420(6911): 74-78. DOI:10.1038/nature01176.
7. Mi S, Lee X, Shao Z, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex[J]. Nat Neurosci, 2004, 7(3): 221-228. DOI:10.1038/nn1188.
8. Tang X, Davies JE, Davies SJ. Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, versican V2, and tenascin-C during acute to chronic maturation of spinal cord scar tissue[J]. J Neurosci Res, 2003, 71(3): 427-444. DOI: 10.1002/jnr.10523.
9. Mar FM, Bonni A, Sousa MM. Cell intrinsic control of axon regeneration[J]. EMBO Rep, 2014, 15(3): 254-263. DOI: 10.1002/embr.201337723.
10. Nickells RW. Variations in the rheostat model of apoptosis: What studies of retinal ganglion cell death tell us about the functions of the Bcl2 family proteins[J]. Exp Eye Res, 2010, 91(1): 2-8. DOI:10.1016/j.exer.2010.03.004.
11. van Kesteren RE, Mason MR, Macgillavry HD, et al. A gene network perspective on axonal regeneration[J]. Front Mol Neurosci, 2011, 4(1): 46. DOI:10.3389/fnmol.2011.00046.
12. Kimura A, Namekata K, Guo X, et al. Neuroprotection, growth factors and BDNF-TrkB signalling in retinal degeneration[J/OL]. Int J Mol Sci, 2016, 17(9): 1584[2016-07-27]. http://www.mdpi.com/1422-0067/17/9/1584. DOI:10.3390/ijms17091584.
13. Aloe L, Rocco ML, Bianchi P, et al. Nerve growth factor: from the early discoveries to the potential clinical use[J]. J Transl Med, 2012, 10: 239. DOI:10.1186/1479-5876-10-239.
14. Blanco RE, Soto I, Duprey-Díaz M, et al. Upregulation of brain-derived neurotrophic factor by application of fibroblast growth factor-2 to the cut optic nerve is important for long term survival of retinal ganglion cells[J]. J Neurosci Res, 2008, 15, 86(15): 3382-3392. DOI:10.1002/jnr.21793.
15. Mathews MK, Guo Y, Langenberg P, et al. Ciliary neurotrophic factor-mediated ganglion cell survival in a rodent model of non-arteritic anterior ischaemic optic neuropathy[J]. Br J Ophthalmol, 2015, 99(1): 133-137.DOI:10.1136/bjophthalmol-2014-305969.
16. Schuettauf F, Vorwerk C, Naskar R, et al. Adeno-associated viruses containing bFGF or BDNF are neuroprotective against excitotoxicity[J]. Curr Eye Res, 2004, 29(6): 379-386.
17. Johnson EC, Guo Y, Cepurna WO, et al. Neurotrophin roles in retinal ganglion cell survival: lessons from rat glaucoma models[J]. Exp Eye Res, 2009, 88(4): 808-815. DOI:10.1016/j.exer.2009.02.004.
18. Wu MM, Fan DG, Tadmori I, et al. Death of axotomized retinal ganglion cells delayed after intraoptic nerve transplantation of olfactory ensheathing cells in adult rats[J]. Cell Transplant, 2010, 19(2): 159-166. DOI: 10.3727/096368910X492625.
19. West EL, Pearson RA, MacLaren RE, et al. Cell transplantation strategies for retinal repair[J]. Prog Brain Res, 2009, 175(1): 3-21.DOI:10.1016/S0079-6123(09)17501-5.
20. Seki M, Soussou W, Manabe S, et al. Protection of retinal ganglion cells by caspase substrate-binding peptide IQACRG from N-methyl-D-aspartate receptor-mediated excitotoxicity [J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1198-1207. DOI:10.1167/iovs.09-4102.
21. Schuettauf F, Naskar R, Vorwerk CK, et al. Ganglion cell loss after optic nerve crush mediated by AMPA-kainate and NMDA receptors[J]. Invest Ophthalmol Vis Sci, 2000, 41(13): 4313-4316.
22. Wu MM, Zhu TT, Wang P, et al. Dose-dependent protective effect of lithium chloride on retinal ganglion cells is interrelated with an upregulated intraretinal BDNF after optic nerve transection in adult rats[J]. Int J Mol Sci, 2014, 15(8): 13550-13563.DOI:10.3390/ijms150813550.
23. Li N, Li Y, Duan X. Heat shock protein 72 confers protection in retinal ganglion cells and lateral geniculate nucleus neurons via blockade of the SAPK/JNK pathway in a chronic ocular-hypertensive rat model[J]. Neural Regen Res, 2014, 9(14): 1395-1401. DOI:10.4103/1673-5374.137595.
24. Fisher J, Levkovitch-Verbin H, Schori H, et al. Vaccination for neuroprotection in the mouse optic nerve: implications for optic neuropathies[J]. J Neurosci, 2001, 21(1): 136-142.
25. Watkins TA, Wang B, Huntwork-Rodriguez S, et al. DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury[J]. Proc Natl Acad Sci, 2013, 110(10): 4039-4044. DOI:10.1073/pnas.1211074110.
26. Watanabe M, Tokita Y, Kato M, et al. Intravitreal injections of neurotrophic factors and forskolin enhance survival and axonal regeneration of axotomized beta ganglion cells in cat retina[J]. Neurosci, 2003, 116(3): 733-742. DOI:10.1016/S0306-4522(02)00562-6.
27. Cui Q, Lu Q, So KF, et al. CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters[J]. Invest Ophthalmol Vis Sci, 1999, 40(3): 760-766.
28. You SW, Hellström M, Pollett MA, et al. Large-scale reconstitution of a retina-to-brain pathway in adult rats using gene therapy and bridging grafts: an anatomical and behavioral analysis[J]. Exp Neurol, 2016, 279: 197-211. DOI: 10.1016/j.expneurol.2016.03.006.
29. Li Y, Sauvé Y, Li D, et al. Transplanted olfactory ensheathing cells promote regeneration of cut adult rat optic nerve axons[J]. J Neurosci, 2003, 23(21): 7783-7788.
30. Harvey AR, Hu Y, Leaver SG, et al. Gene therapy and transplantation in CNS repair: the visual system[J]. Prog Retinal Eye Res, 2006, 25(5): 449-489. DOI: 10.1016/j.preteyeres.2006.07.002.
31. Hill AJ, Zwart I, Samaranayake AN, et al. Rat neurosphere cells protect axotomized rat retinal ganglion cells and facilitate their regeneration[J]. J Neurotrauma, 2009, 26(7): 1147-1156. DOI:10.1089/neu.2008-0801.
32. Charalambous P, Hurst LA, Thanos S. Engrafted chicken neural tube-derived stem cells support the innate propensity for axonal regeneration within the rat optic nerve[J]. Invest Ophthalmol Vis Sci, 2008, 49(8): 3513-3524. DOI:10.1167/iovs.07-1473.
33. Nishida A, Takahashi M, Tanihara H, et al. Incorporation and differentiation of hippocampus-derived neural stem cells transplanted in injured adult rat retina[J]. Invest Ophthalmol Vis Sci, 2000, 41(13): 4268-4274.
34. Yin Y, Cui Q, Li Y, et al. Macrophage-derived factors stimulate optic nerve regeneration[J]. J Neurosci, 2003, 23(6): 2284-2293.
35. Urbina M, Schmeer C, Lima L. 5HT1A receptor agonist differentially increases cyclic AMP concentration in intact and lesioned goldfish retina. In vitro inhibition of outgrowth by forskolin[J]. Neurochem Int, 1996, 29(5): 453-460.
36. Cui Q, Cho KS, So KF, et al. Synergistic effect of Nogo-neutralizing antibody IN-1 and ciliary neurotrophic factor on axonal regeneration in adult rodent visual systems[J]. J Neurotrauma, 2004, 21(5): 617-625. DOI: 10.1089/089771504774129946.
37. Yiu G, He Z.Glial inhibition of CNS axon regeneration[J]. Nat Rev Neurosci, 2006, 7(8): 617-627.DOI:10.1038/nrn1956.
38. Cui Z, Kang J, Hu D, et al. Oncomodulin/truncated protamine-mediated Nogo-66 receptor small interference RNA delivery promotes axon regeneration in retinal ganglion cells[J]. Mol Cell, 2014, 37(8): 613-619. DOI:10.14348/molcells.2014.0155.
39. Ahmed Z, Suggate EL, Brown ER, et al. Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro[J]. Brain, 2006, 129(Pt 6): 1517-1533. DOI: 10.1093/brain/awl080.
40. Abdesselem H, Shypitsyna A, Solis GP, et al. Nogo66-and NgR-mediated inhibition of regenerating axons in the zebrafish optic nerve[J]. J Neurosci, 2009, 29(49): 15489-15498. DOI: 10.1523/JNEUROSCI.3561-09.2009.
41. Monnier PP, Sierra A, Schwab JM, et al. The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar[J]. Mol Cell Neurosci, 2003, 22(3): 319-330. DOI: 10.1016/S1044-7431(02)00035-0.
42. Carvalho LS, Vandenberghe LH.Promising and delivering gene therapies for vision loss[J]. Vision Res, 2015, 111(Pt B): 124-133. DOI:10.1016/j.visres.2014.07.013.
43. Petit L, Khanna H, Punzo C.Advances in gene therapy for diseases of the eye[J]. Hum Gene Ther, 2016, 27(8): 563-579. DOI: 10.1089/hum.2016.040.
44. Ellis-Behnke RG, Liang YX, You SW, et al. Nano neuro knitting: Peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision[J]. Proc Natl Acad Sci USA, 2006, 103(13): 5054-5059. DOI:10.1073/pnas.0600559103.
45. Kauper K, McGovern C, Sherman S, et al. Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases[J]. Invest Ophthalmol Vis Sci, 2012, 53(12): 7484-7491. DOI: 10.1167/iovs.12-9970.
46. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report[J]. Lancet, 2012, 379(9817): 713-720. DOI: 10.1016/S0140-6736(12)60028-2.
47. Fields M, Cai H, Gong J, et al. Potential of induced pluripotent stem cells (iPSCs) for treating age-related macular degeneration (AMD)[J/OL]. Cells, 2016, 5(4): 44[2016-12-08]. http://www.mdpi.com/2073-4409/5/4/44. DOI:10.3390/cells5040044.
48. Crair MC, Mason CA.Reconnecting eye to brain[J]. J Neurosci, 2016, 36(42): 10707-10722. DOI:10.1523/JNEUROSCI.1711-16.2016.