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Glaucoma and optic nerve repair

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Abstract

Glaucoma is a leading cause of irreversible blindness worldwide and causes progressive visual impairment attributable to the dysfunction and death of retinal ganglion cells (RGCs). Progression of visual field damage is slow and typically painless. Thus, glaucoma is often diagnosed after a substantial percentage of RGCs has been damaged. To date, clinical interventions are mainly restricted to the reduction of intraocular pressure (IOP), one of the major risk factors for this disease. However, the lowering of IOP is often insufficient to halt or reverse the progress of visual loss, underlining the need for the development of alternative treatment strategies. Several lines of evidence suggest that axonal damage of RGCs occurs primary at the optic nerve head, where axons appear to be most vulnerable. Axonal injury leads to the functional loss of RGCs and subsequently induces the death of the neurons. However, the detailed molecular mechanism(s) underlying IOP-induced optic nerve injury remain poorly understood. Moreover, whether glaucoma pathophysiology is primarily axonal, glial, or vascular remains unclear. Therefore, protective strategies to prevent further axonal and subsequent soma degeneration are of great importance to limit the progression of sight loss. In addition, strategies that stimulate injured RGCs to regenerate and reconnect axons with their central targets are necessary for functional restoration. The present review provides an overview of the context of glaucoma pathogenesis and surveys recent findings regarding potential strategies for axonal regeneration of RGCs and optic nerve repair, focusing on the role of cytokines and their downstream signaling pathways.

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References

  • Abe N, Cavalli V (2008) Nerve injury signaling. Curr Opin Neurobiol 18:276–283

    Article  PubMed  CAS  Google Scholar 

  • Abu-Amero KK, Bosley TM (2006) Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Invest Ophthalmol Vis Sci 47:4211–4220

    Article  PubMed  Google Scholar 

  • Ahmed Z, Berry M, Logan A (2009) ROCK inhibition promotes adult retinal ganglion cell neurite outgrowth only in the presence of growth promoting factors. Mol Cell Neurosci 42:128–133

    Article  PubMed  CAS  Google Scholar 

  • Ahmed Z, Aslam M, Lorber B, Suggate EL, Berry M, Logan A (2010) Optic nerve and vitreal inflammation are both RGC neuroprotective but only the latter is RGC axogenic. Neurobiol Dis 37:441–454

    Article  PubMed  CAS  Google Scholar 

  • Anderson DR (1999) Introductory comments on blood flow autoregulation in the optic nerve head and vascular risk factors in glaucoma. Surv Ophthalmol 43 (Suppl 1):S5–S9

    Article  PubMed  Google Scholar 

  • Anderson DR, Davis EB (1996) Glaucoma, capillaries and pericytes. 5. Preliminary evidence that carbon dioxide relaxes pericyte contractile tone. Ophthalmologica 210:280–284

    Article  PubMed  CAS  Google Scholar 

  • Anderson DR, Hendrickson A (1974) Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve. Invest Ophthalmol 13:771–783

    PubMed  CAS  Google Scholar 

  • Atwal JK, Pinkston-Gosse J, Syken J, Stawicki S, Wu Y, Shatz C, Tessier-Lavigne M (2008) PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322:967–970

    Article  PubMed  CAS  Google Scholar 

  • Bahr M, Vanselow J, Thanos S (1989) Ability of adult rat ganglion cells to regrow axons in vitro can be influenced by fibroblast growth factor and gangliosides. Neurosci Lett 96:197–201

    Article  PubMed  CAS  Google Scholar 

  • Baltan S, Inman DM, Danilov CA, Morrison RS, Calkins DJ, Horner PJ (2010) Metabolic vulnerability disposes retinal ganglion cell axons to dysfunction in a model of glaucomatous degeneration. J Neurosci 30:5644–5652

    Article  PubMed  CAS  Google Scholar 

  • Barron MJ, Griffiths P, Turnbull DM, Bates D, Nichols P (2004) The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head. Br J Ophthalmol 88:286–290

    Article  PubMed  CAS  Google Scholar 

  • Berry M, Ahmed Z, Lorber B, Douglas M, Logan A (2008) Regeneration of axons in the visual system. Restor Neurol Neurosci 26:147–174

    PubMed  Google Scholar 

  • Bertrand J, Winton MJ, Rodriguez-Hernandez N, Campenot RB, McKerracher L (2005) Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats. J Neurosci 25:1113–1121

    Article  PubMed  CAS  Google Scholar 

  • Buckingham BP, Inman DM, Lambert W, Oglesby E, Calkins DJ, Steele MR, Vetter ML, Marsh-Armstrong N, Horner PJ (2008) Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J Neurosci 28:2735–2744

    Article  PubMed  CAS  Google Scholar 

  • Burgoyne CF (2011) A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma. Exp Eye Res 93:120–132

    Article  PubMed  CAS  Google Scholar 

  • Cai X, Yuan R, Hu Z, Chen C, Yu J, Zheng Z, Ye J (2012) Expression of PirB protein in intact and injured optic nerve and retina of mice. Neurochem Res 37:647–654

    Article  PubMed  CAS  Google Scholar 

  • Chang EE, Goldberg JL (2012) Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology 119:979–986

    Article  PubMed  Google Scholar 

  • Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403:434–439

    Article  PubMed  CAS  Google Scholar 

  • Cheng L, Sapieha P, Kittlerova P, Hauswirth WW, Di Polo A (2002) TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J Neurosci 22:3977–3986

    PubMed  CAS  Google Scholar 

  • Chidlow G, Ebneter A, Wood JP, Casson RJ (2011) The optic nerve head is the site of axonal transport disruption, axonal cytoskeleton damage and putative axonal regeneration failure in a rat model of glaucoma. Acta Neuropathol 121:737–751

    Article  PubMed  CAS  Google Scholar 

  • Chierzi S, Strettoi E, Cenni MC, Maffei L (1999) Optic nerve crush: axonal responses in wild-type and bcl-2 transgenic mice. J Neurosci 19:8367–8376

    PubMed  CAS  Google Scholar 

  • Cohen A, Bray GM, Aguayo AJ (1994) Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro. J Neurobiol 25:953–959

    Article  PubMed  CAS  Google Scholar 

  • Conde C, Caceres A (2009) Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci 10:319–332

    Article  PubMed  CAS  Google Scholar 

  • Corredor RG, Goldberg JL (2009) Electrical activity enhances neuronal survival and regeneration. J Neural Eng 6:055001

    Article  PubMed  Google Scholar 

  • Cui Q, Yip HK, Zhao RC, So KF, Harvey AR (2003) Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. Mol Cell Neurosci 22:49–61

    Article  PubMed  CAS  Google Scholar 

  • Dandona L, Hendrickson A, Quigley HA (1991) Selective effects of experimental glaucoma on axonal transport by retinal ganglion cells to the dorsal lateral geniculate nucleus. Invest Ophthalmol Vis Sci 32:1593–1599

    PubMed  CAS  Google Scholar 

  • Danias J, Lee KC, Zamora MF, Chen B, Shen F, Filippopoulos T, Su Y, Goldblum D, Podos SM, Mittag T (2003) Quantitative analysis of retinal ganglion cell (RGC) loss in aging DBA/2NNia glaucomatous mice: comparison with RGC loss in aging C57/BL6 mice. Invest Ophthalmol Vis Sci 44:5151–5162

    Article  PubMed  Google Scholar 

  • Derry WB, Wilson L, Jordan MA (1995) Substoichiometric binding of taxol suppresses microtubule dynamics. Biochemistry 34:2203–2211

    Article  PubMed  CAS  Google Scholar 

  • Derry WB, Wilson L, Khan IA, Luduena RF, Jordan MA (1997) Taxol differentially modulates the dynamics of microtubules assembled from unfractionated and purified beta-tubulin isotypes. Biochemistry 36:3554–3562

    Article  PubMed  CAS  Google Scholar 

  • Di Polo A, Aigner LJ, Dunn RJ, Bray GM, Aguayo AJ (1998) Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells. Proc Natl Acad Sci USA 95:3978–3983

    Article  PubMed  Google Scholar 

  • Domeniconi M, Cao Z, Spencer T, Sivasankaran R, Wang K, Nikulina E, Kimura N, Cai H, Deng K, Gao Y, He Z, Filbin M (2002) Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35:283–290

    Article  PubMed  CAS  Google Scholar 

  • Ebadi M, Bashir RM, Heidrick ML, Hamada FM, Refaey HE, Hamed A, Helal G, Baxi MD, Cerutis DR, Lassi NK (1997) Neurotrophins and their receptors in nerve injury and repair. Neurochem Int 30:347–374

    Article  PubMed  CAS  Google Scholar 

  • Ernst M, Jenkins BJ (2004) Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet 20:23–32

    Article  PubMed  CAS  Google Scholar 

  • Filippopoulos T, Danias J, Chen B, Podos SM, Mittag TW (2006) Topographic and morphologic analyses of retinal ganglion cell loss in old DBA/2NNia mice. Invest Ophthalmol Vis Sci 47:1968–1974

    Article  PubMed  Google Scholar 

  • Findl O, Strenn K, Wolzt M, Menapace R, Vass C, Eichler HG, Schmetterer L (1997) Effects of changes in intraocular pressure on human ocular haemodynamics. Curr Eye Res 16:1024–1029

    Article  PubMed  CAS  Google Scholar 

  • Fischer D (2008) CNTF, a key factor mediating the beneficial effects of inflammatory reactions in the eye. Brain 131:e97

    Article  Google Scholar 

  • Fischer D, Leibinger M (2012) Promoting optic nerve regeneration. Progress in retinal and eye research 31(6):688–701

    Google Scholar 

  • Fischer D, Pavlidis M, Thanos S (2000) Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture. Invest Ophthalmol Vis Sci 41:3943–3954

    PubMed  CAS  Google Scholar 

  • Fischer D, Heiduschka P, Thanos S (2001) Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats. Exp Neurol 172:257–272

    Article  PubMed  CAS  Google Scholar 

  • Fischer D, He Z, Benowitz LI (2004a) Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J Neurosci 24:1646–1651

    Article  PubMed  CAS  Google Scholar 

  • Fischer D, Petkova V, Thanos S, Benowitz LI (2004b) Switching mature retinal ganglion cells to a robust growth state in vivo: gene expression and synergy with RhoA inactivation. J Neurosci 24:8726–8740

    Article  PubMed  CAS  Google Scholar 

  • Fischer D, Hauk TG, Muller A, Thanos S (2008) Crystallins of the beta/gamma-superfamily mimic the effects of lens injury and promote axon regeneration. Mol Cell Neurosci 37:471–479

    Article  PubMed  CAS  Google Scholar 

  • Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K, Hirano T (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5:449–460

    Article  PubMed  CAS  Google Scholar 

  • Gaasterland D, Tanishima T, Kuwabara T (1978) Axoplasmic flow during chronic experimental glaucoma. 1. Light and electron microscopic studies of the monkey optic nerve head during development of glaucomatous cupping. Invest Ophthalmol Vis Sci 17:838–846

    PubMed  CAS  Google Scholar 

  • Goldberg JL (2011) Optic nerve. In: Levin LA, Nilsson SFE, Ver Hoeve J, Wu S, Kaufman PL, Alm A (eds) Adler’s physiology of the eye, 11th edn. Elsevier, New York, Chapter 28

    Google Scholar 

  • Goldberg JL, Barres BA (2000) The relationship between neuronal survival and regeneration. Annu Rev Neurosci 23:579–612

    Article  PubMed  CAS  Google Scholar 

  • Gupta N, Fong J, Ang LC, Yucel YH (2008) Retinal tau pathology in human glaucomas. Can J Ophthalmol 43:53–60

    Article  PubMed  Google Scholar 

  • Hauk TG, Leibinger M, Muller A, Andreadaki A, Knippschild U, Fischer D (2010) Stimulation of axon regeneration in the mature optic nerve by intravitreal application of the toll-like receptor 2 agonist Pam3Cys. Invest Ophthalmol Vis Sci 51:459–464

    Article  PubMed  Google Scholar 

  • Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20

    Article  PubMed  CAS  Google Scholar 

  • Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ, Umlauf M, Kapitein LC, Strikis D, Lemmon V, Bixby J, Hoogenraad CC, Bradke F (2011) Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331:928–931

    Article  PubMed  CAS  Google Scholar 

  • Hellstrom M, Pollett MA, Harvey AR (2011) Post-injury delivery of rAAV2-CNTF combined with short-term pharmacotherapy is neuroprotective and promotes extensive axonal regeneration after optic nerve trauma. J Neurotrauma 28:2475–2483

    Article  PubMed  Google Scholar 

  • Hemmann U, Gerhartz C, Heesel B, Sasse J, Kurapkat G, Grotzinger J, Wollmer A, Zhong Z, Darnell JE Jr, Graeve L, Heinrich PC, Horn F (1996) Differential activation of acute phase response factor/Stat3 and Stat1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. II. Src homology SH2 domains define the specificity of Stat factor activation. J Biol Chem 271:12999–13007

    Article  PubMed  CAS  Google Scholar 

  • Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SW (2007) Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol 179:1523–1537

    Article  PubMed  CAS  Google Scholar 

  • Inoue T, Hosokawa M, Morigiwa K, Ohashi Y, Fukuda Y (2002) Bcl-2 overexpression does not enhance in vivo axonal regeneration of retinal ganglion cells after peripheral nerve transplantation in adult mice. J Neurosci 22:4468–4477

    PubMed  CAS  Google Scholar 

  • Jakobs TC, Libby RT, Ben Y, John SW, Masland RH (2005) Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. J Cell Biol 171:313–325

    Article  PubMed  CAS  Google Scholar 

  • Jo SA, Wang E, Benowitz LI (1999) Ciliary neurotrophic factor is an axogenesis factor for retinal ganglion cells. Neuroscience 89:579–591

    Article  PubMed  CAS  Google Scholar 

  • Jo D, Liu D, Yao S, Collins RD, Hawiger J (2005) Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nat Med 11:892–898

    Article  PubMed  CAS  Google Scholar 

  • Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR (2010) Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci 51:2051–2059

    Article  PubMed  Google Scholar 

  • Ju WK, Kim KY, Lindsey JD, Angert M, Duong-Polk KX, Scott RT, Kim JJ, Kukhmazov I, Ellisman MH, Perkins GA, Weinreb RN (2008) Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve. Invest Ophthalmol Vis Sci 49:4903–4911

    Article  PubMed  Google Scholar 

  • Kim H, Baumann H (1999) Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Mol Cell Biol 19:5326–5338

    PubMed  CAS  Google Scholar 

  • Koeberle PD, Ball AK (1998) Effects of GDNF on retinal ganglion cell survival following axotomy. Vis Res 38:1505–1515

    Article  PubMed  CAS  Google Scholar 

  • Lagord C, Berry M, Logan A (2002) Expression of TGFbeta2 but not TGFbeta1 correlates with the deposition of scar tissue in the lesioned spinal cord. Mol Cell Neurosci 20:69–92

    Article  PubMed  CAS  Google Scholar 

  • Leaver SG, Cui Q, Plant GW, Arulpragasam A, Hisheh S, Verhaagen J, Harvey AR (2006) AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells. Gene Ther 13:1328–1341

    Article  PubMed  CAS  Google Scholar 

  • Lehmann M, Fournier A, Selles-Navarro I, Dergham P, Sebok A, Leclerc N, Tigyi G, McKerracher L (1999) Inactivation of Rho signaling pathway promotes CNS axon regeneration. J Neurosci 19:7537–7547

    PubMed  CAS  Google Scholar 

  • Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, Behrmann I, Tsiaris W, Sasaki A, Schneider-Mergener J, Yoshimura A, Neel BG, Heinrich PC, Schaper F (2003) SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem 278:661–671

    Article  PubMed  CAS  Google Scholar 

  • Leibinger M, Muller A, Andreadaki A, Hauk TG, Kirsch M, Fischer D (2009) Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor. J Neurosci 29:14334–14341

    Article  PubMed  Google Scholar 

  • Leibinger M, Andreadaki A, Fischer D (2012) Role of mTOR in neuroprotection and axon regeneration after inflammatory stimulation. Neurobiol Dis 46:314–324

    Article  PubMed  CAS  Google Scholar 

  • Leon S, Yin Y, Nguyen J, Irwin N, Benowitz LI (2000) Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci 20:4615–4626

    PubMed  CAS  Google Scholar 

  • Levy NS (1974) The effects of elevated intraocular pressure on slow axonal protein flow. Invest Ophthalmol 13:691–695

    PubMed  CAS  Google Scholar 

  • Libby RT, Li Y, Savinova OV, Barter J, Smith RS, Nickells RW, John SW (2005) Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet 1:17–26

    Article  PubMed  CAS  Google Scholar 

  • Lingor P, Teusch N, Schwarz K, Mueller R, Mack H, Bahr M, Mueller BK (2007) Inhibition of Rho kinase (ROCK) increases neurite outgrowth on chondroitin sulphate proteoglycan in vitro and axonal regeneration in the adult optic nerve in vivo. J Neurochem 103:181–189

    PubMed  CAS  Google Scholar 

  • Lingor P, Tonges L, Pieper N, Bermel C, Barski E, Planchamp V, Bahr M (2008) ROCK inhibition and CNTF interact on intrinsic signalling pathways and differentially regulate survival and regeneration in retinal ganglion cells. Brain 131:250–263

    PubMed  Google Scholar 

  • Logan A, Berry M (2002) Cellular and molecular determinants of glial scar formation. Adv Exp Med Biol 513:115–158

    Article  PubMed  CAS  Google Scholar 

  • Lukas TJ, Wang AL, Yuan M, Neufeld AH (2009) Early cellular signaling responses to axonal injury. Cell Commun Signal 7:5

    Article  PubMed  CAS  Google Scholar 

  • Mabuchi F, Aihara M, Mackey MR, Lindsey JD, Weinreb RN (2004) Regional optic nerve damage in experimental mouse glaucoma. Invest Ophthalmol Vis Sci 45:4352–4358

    Article  PubMed  Google Scholar 

  • Mansour-Robaey S, Clarke DB, Wang YC, Bray GM, Aguayo AJ (1994) Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci USA 91:1632–1636

    Article  PubMed  CAS  Google Scholar 

  • McKeon RJ, Schreiber RC, Rudge JS, Silver J (1991) Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci 11:3398–3411

    PubMed  CAS  Google Scholar 

  • McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE (1994) Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13:805–811

    Article  PubMed  CAS  Google Scholar 

  • Mey J, Thanos S (1993) Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res 602:304–317

    Article  PubMed  CAS  Google Scholar 

  • Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB (2004) LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci 7:221–228

    Article  PubMed  CAS  Google Scholar 

  • Mimura F, Yamagishi S, Arimura N, Fujitani M, Kubo T, Kaibuchi K, Yamashita T (2006) Myelin-associated glycoprotein inhibits microtubule assembly by a Rho-kinase-dependent mechanism. J Biol Chem 281:15970–15979

    Article  PubMed  CAS  Google Scholar 

  • Minckler DS, Bunt AH, Johanson GW (1977) Orthograde and retrograde axoplasmic transport during acute ocular hypertension in the monkey. Invest Ophthalmol Vis Sci 16:426–441

    PubMed  CAS  Google Scholar 

  • Morgan JE (2004) Circulation and axonal transport in the optic nerve. Eye (Lond) 18:1089–1095

    Article  CAS  Google Scholar 

  • Morgan JE, Jeffery G, Foss AJ (1998) Axon deviation in the human lamina cribrosa. Br J Ophthalmol 82:680–683

    Article  PubMed  CAS  Google Scholar 

  • Mueller BK (1999) Growth cone guidance: first steps towards a deeper understanding. Annu Rev Neurosci 22:351–388

    Article  PubMed  CAS  Google Scholar 

  • Muller A, Hauk TG, Fischer D (2007) Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation. Brain 130:3308–3320

    Article  PubMed  Google Scholar 

  • Muller A, Hauk TG, Leibinger M, Marienfeld R, Fischer D (2009) Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF. Mol Cell Neurosci 41:233–246

    Article  PubMed  CAS  Google Scholar 

  • Neufeld AH, Liu B (2003) Glaucomatous optic neuropathy: when glia misbehave. Neuroscientist 9:485–495

    Article  PubMed  CAS  Google Scholar 

  • Neufeld AH, Hernandez MR, Gonzalez M (1997) Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol 115:497–503

    Article  PubMed  CAS  Google Scholar 

  • Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M (2000) Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci USA 97:6493–6498

    Article  PubMed  CAS  Google Scholar 

  • Nickells RW, Howell GR, Soto I, John SW (2012) Under pressure: cellular and molecular responses during glaucoma, a common neurodegeneration with axonopathy. Annu Rev Neurosci 35:153–179

    Article  PubMed  CAS  Google Scholar 

  • Niederost BP, Zimmermann DR, Schwab ME, Bandtlow CE (1999) Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycans. J Neurosci 19:8979–8989

    PubMed  CAS  Google Scholar 

  • Park K, Luo JM, Hisheh S, Harvey AR, Cui Q (2004) Cellular mechanisms associated with spontaneous and ciliary neurotrophic factor-cAMP-induced survival and axonal regeneration of adult retinal ganglion cells. J Neurosci 24:10806–10815

    Article  PubMed  CAS  Google Scholar 

  • Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu B, Connolly L, Kramvis I, Sahin M, He Z (2008) Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322:963–966

    Article  PubMed  CAS  Google Scholar 

  • Park KK, Hu Y, Muhling J, Pollett MA, Dallimore EJ, Turnley AM, Cui Q, Harvey AR (2009) Cytokine-induced SOCS expression is inhibited by cAMP analogue: impact on regeneration in injured retina. Mol Cell Neurosci 41:313–324

    Article  PubMed  CAS  Google Scholar 

  • Pease ME, McKinnon SJ, Quigley HA, Kerrigan-Baumrind LA, Zack DJ (2000) Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci 41:764–774

    PubMed  CAS  Google Scholar 

  • Pernet V, Di Polo A (2006) Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival, but leads to optic nerve dystrophy in vivo. Brain 129:1014–1026

    Article  PubMed  Google Scholar 

  • Pillunat LE, Anderson DR, Knighton RW, Joos KM, Feuer WJ (1997) Autoregulation of human optic nerve head circulation in response to increased intraocular pressure. Exp Eye Res 64:737–744

    Article  PubMed  CAS  Google Scholar 

  • Quigley HA (2011) Glaucoma. Lancet 377:1367–1377

    Article  PubMed  Google Scholar 

  • Quigley H, Anderson DR (1976) The dynamics and location of axonal transport blockade by acute intraocular pressure elevation in primate optic nerve. Invest Ophthalmol 15:606–616

    PubMed  CAS  Google Scholar 

  • Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267

    Article  PubMed  CAS  Google Scholar 

  • Quigley HA, Vitale S (1997) Models of open-angle glaucoma prevalence and incidence in the United States. Invest Ophthalmol Vis Sci 38:83–91

    PubMed  CAS  Google Scholar 

  • Quigley HA, Addicks EM, Green WR, Maumenee AE (1981) Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch Ophthalmol 99:635–649

    Article  PubMed  CAS  Google Scholar 

  • Quigley HA, Hohman RM, Addicks EM, Massof RW, Green WR (1983) Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol 95:673–691

    PubMed  CAS  Google Scholar 

  • Quigley HA, McKinnon SJ, Zack DJ, Pease ME, Kerrigan-Baumrind LA, Kerrigan DF, Mitchell RS (2000) Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci 41:3460–3466

    PubMed  CAS  Google Scholar 

  • Radius RL, Anderson DR (1981) Rapid axonal transport in primate optic nerve. Distribution of pressure-induced interruption. Arch Ophthalmol 99:650–654

    Article  PubMed  CAS  Google Scholar 

  • Rane SG, Reddy EP (2000) Janus kinases: components of multiple signaling pathways. Oncogene 19:5662–5679

    Article  PubMed  CAS  Google Scholar 

  • Rao VP, Epstein DL (2007) Rho GTPase/Rho kinase inhibition as a novel target for the treatment of glaucoma. BioDrugs 21:167–177

    Article  PubMed  CAS  Google Scholar 

  • Salinas-Navarro M, Alarcon-Martinez L, Valiente-Soriano FJ, Jimenez-Lopez M, Mayor-Torroglosa S, Aviles-Trigueros M, Villegas-Perez MP, Vidal-Sanz M (2010) Ocular hypertension impairs optic nerve axonal transport leading to progressive retinal ganglion cell degeneration. Exp Eye Res 90:168–183

    Article  PubMed  CAS  Google Scholar 

  • Sarup V, Patil K, Sharma SC (2004) Ciliary neurotrophic factor and its receptors are differentially expressed in the optic nerve transected adult rat retina. Brain Res 1013:152–158

    Article  PubMed  CAS  Google Scholar 

  • Schallenberg M, Charalambous P, Thanos S (2009) GM-CSF regulates the ERK1/2 pathways and protects injured retinal ganglion cells from induced death. Exp Eye Res 89:665–677

    Article  PubMed  CAS  Google Scholar 

  • Schlamp CL, Li Y, Dietz JA, Janssen KT, Nickells RW (2006) Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. BMC Neurosci 7:66

    Article  PubMed  CAS  Google Scholar 

  • Semaan SJ, Li Y, Nickells RW (2010) A single nucleotide polymorphism in the Bax gene promoter affects transcription and influences retinal ganglion cell death. ASN Neuro 2:e00032

    Article  PubMed  CAS  Google Scholar 

  • Sengottuvel V, Leibinger M, Pfreimer M, Andreadaki A, Fischer D (2011) Taxol facilitates axon regeneration in the mature CNS. J Neurosci 31:2688–2699

    Article  PubMed  CAS  Google Scholar 

  • Shimazawa M, Inokuchi Y, Ito Y, Murata H, Aihara M, Miura M, Araie M, Hara H (2007) Involvement of ER stress in retinal cell death. Mol Vis 13:578–587

    PubMed  CAS  Google Scholar 

  • Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A (2001) Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 108:1781–1788

    PubMed  CAS  Google Scholar 

  • Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146–156

    Article  PubMed  CAS  Google Scholar 

  • Smith PD, Sun F, Park KK, Cai B, Wang C, Kuwako K, Martinez-Carrasco I, Connolly L, He Z (2009) SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 64:617–623

    Article  PubMed  CAS  Google Scholar 

  • Soto I, Oglesby E, Buckingham BP, Son JL, Roberson ED, Steele MR, Inman DM, Vetter ML, Horner PJ, Marsh-Armstrong N (2008) Retinal ganglion cells downregulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. J Neurosci 28:548–561

    Article  PubMed  CAS  Google Scholar 

  • Soto I, Pease ME, Son JL, Shi X, Quigley HA, Marsh-Armstrong N (2011) Retinal ganglion cell loss in a rat ocular hypertension model is sectorial and involves early optic nerve axon loss. Invest Ophthalmol Vis Sci 52:434–441

    Article  PubMed  CAS  Google Scholar 

  • Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn BA, Quelle FW, Silvennoinen O, Barbieri G, Pellegrini S et al (1994) Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science 263:92–95

    Article  PubMed  CAS  Google Scholar 

  • Su Y, Wang F, Teng Y, Zhao SG, Cui H, Pan SH (2009) Axonal regeneration of optic nerve after crush in Nogo66 receptor knockout mice. Neurosci Lett 460:223–226

    Article  PubMed  CAS  Google Scholar 

  • Sun F, Park KK, Belin S, Wang D, Lu T, Chen G, Zhang K, Yeung C, Feng G, Yankner BA, He Z (2011) Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480:372–375

    Article  PubMed  CAS  Google Scholar 

  • Tang BL (2003) Inhibitors of neuronal regeneration: mediators and signaling mechanisms. Neurochem Int 42:189–203

    Article  PubMed  Google Scholar 

  • Thylefors B, Negrel AD (1994) The global impact of glaucoma. Bull World Health Organ 72:323–326

    PubMed  CAS  Google Scholar 

  • Tonges L, Ostendorf T, Lamballe F, Genestine M, Dono R, Koch JC, Bahr M, Maina F, Lingor P (2011) Hepatocyte growth factor protects retinal ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in vivo. J Neurochem 117:892–903

    Article  PubMed  CAS  Google Scholar 

  • Vidal-Sanz M, Bray GM, Villegas-Perez MP, Thanos S, Aguayo AJ (1987) Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. J Neurosci 7:2894–2909

    PubMed  CAS  Google Scholar 

  • Vidal-Sanz M, Villegas-Perez MP, Bray GM, Aguayo AJ (1988) Persistent retrograde labeling of adult rat retinal ganglion cells with the carbocyanine dye diI. Exp Neurol 102:92–101

    Article  PubMed  CAS  Google Scholar 

  • Wang KC, Kim JA, Sivasankaran R, Segal R, He Z (2002a) P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420:74–78

    Article  PubMed  CAS  Google Scholar 

  • Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, He Z (2002b) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941–944

    Article  PubMed  CAS  Google Scholar 

  • Weber AJ, Harman CD, Viswanathan S (2008) Effects of optic nerve injury, glaucoma, and neuroprotection on the survival, structure, and function of ganglion cells in the mammalian retina. J Physiol (Lond) 586:4393–4400

    Article  CAS  Google Scholar 

  • World Health Organisation (1997) Blindness and visual disability. World Health Organisation, Geneva

    Google Scholar 

  • Wong ST, Henley JR, Kanning KC, Huang KH, Bothwell M, Poo MM (2002) A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci 5:1302–1308

    Article  PubMed  CAS  Google Scholar 

  • Wu Q, Zhang M, Song BW, Lu B, Hu P (2007) Expression of ciliary neurotrophic factor after induction of ocular hypertension in the retina of rats. Chin Med J (Engl) 120:1825–1829

    CAS  Google Scholar 

  • Yamashita T, Higuchi H, Tohyama M (2002) The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol 157:565–570

    Article  PubMed  CAS  Google Scholar 

  • Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7:617–627

    Article  PubMed  CAS  Google Scholar 

  • Yu-Wai-Man P, Griffiths PG, Chinnery PF (2011) Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies. Prog Retin Eye Res 30:81–114

    Article  PubMed  CAS  Google Scholar 

  • Zheng J, Feng X, Hou L, Cui Y, Zhu L, Ma J, Xia Z, Zhou W, Chen H (2011) Latanoprost promotes neurite outgrowth in differentiated RGC-5 cells via the PI3K-Akt-mTOR signaling pathway. Cell Mol Neurobiol 31:597–604

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We apologize to all colleagues whose important work was not included because of space limitations.

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Correspondence to Dietmar Fischer.

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The work of the authors was supported by the German Research Foundation.

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Diekmann, H., Fischer, D. Glaucoma and optic nerve repair. Cell Tissue Res 353, 327–337 (2013). https://doi.org/10.1007/s00441-013-1596-8

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