Pathophysiology of primary open-angle glaucoma from a neuroinflammatory and neurotoxicity perspective: a review of the literature

  • Karine Evangelho
  • Maria Mogilevskaya
  • Monica Losada-Barragan
  • Jeinny Karina Vargas-SanchezEmail author



Glaucoma is the leading cause of blindness in humans, affecting 2% of the population. This disorder can be classified into various types including primary, secondary, glaucoma with angle closure and with open angle. The prevalence of distinct types of glaucoma differs for each particular region of the world. One of the most common types of this disease is primary open-angle glaucoma (POAG), which is a complex inherited disorder characterized by progressive retinal ganglion cell death, optic nerve head excavation and visual field loss. Nowadays, POAG is considered an optic neuropathy, while intraocular pressure is proposed to play a fundamental role in its pathophysiology and especially in optic disk damage. However, the exact mechanism of optic nerve head damage remains a topic of debate. This literature review aims to bring together the information on the pathophysiology of primary open-angle glaucoma, particularly focusing on neuroinflammatory mechanisms leading to the death of the retinal ganglion cell.


A literature search was done on PubMed using key words including primary open-angle glaucoma, retinal ganglion cells, Müller cells, glutamate, glial cells, ischemia, hypoxia, exitotoxicity, neuroinflammation, axotomy and neurotrophic factors. The literature was reviewed to collect the information published about the pathophysiologic mechanisms of RGC death in the POAG, from a neuroinflammatory and neurotoxicity perspective.


Proposed mechanisms for glaucomatous damage are a result of pressure in RGC followed by ischemia, hypoxia of the ONH, and consequently death due to glutamate-induced excitotoxicity, deprivation of energy and oxygen, increase in levels of inflammatory mediators and alteration of trophic factors flow. These events lead to blockage of anterograde and retrograde axonal transport with ensuing axotomy and eventually blindness.


The damage to ganglion cells and eventually glaucomatous injury can occur via various mechanisms including baric trauma, ischemia and impact of metabolic toxins, which triggers an inflammatory process and secondary degeneration in the ONH.


Glaucoma Retinal ganglion cells Cell death Glutamate Intraocular pressure Neuroinflammation 



We would like to Acknowledge to the Editorial Universidad ECCI.

Compliance with ethical standards

Conflict of interest

All authors certify that they have no affiliation with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

This article does not contain any studies with human participants and animals performed directly by any of the authors.

Informed consent

As this article does not contain any studies with human participants, the concept of informed consent is not applicable.


  1. 1.
    Osborne NN, Melena J, Chidlow G, Wood JP (2001) A hypothesis to explain ganglion cell death caused by vascular insults at the optic nerve head: possible implication for the treatment of glaucoma. Br J Ophthalmol 85(10):1252–1259PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M, Early Manifest Glaucoma Trial G (2002) Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 120(10):1268–1279PubMedCrossRefGoogle Scholar
  3. 3.
    Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S (2017) Glaucoma. Lancet. Scholar
  4. 4.
    Casson RJ (2006) Possible role of excitotoxicity in the pathogenesis of glaucoma. Clin Exp Ophthalmol 34(1):54–63. Scholar
  5. 5.
    Anderson DR, Drance SM, Schulzer M, Collaborative Normal-Tension Glaucoma Study G (2003) Factors that predict the benefit of lowering intraocular pressure in normal tension glaucoma. Am J Ophthalmol 136(5):820–829PubMedCrossRefGoogle Scholar
  6. 6.
    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. Investig Ophthalmol Vis Sci 41(11):3460–3466Google Scholar
  7. 7.
    Abe RY, Gracitelli CP, Diniz-Filho A, Tatham AJ, Medeiros FA (2015) Lamina cribrosa in glaucoma: diagnosis and monitoring. Curr Ophthalmol Rep 3(2):74–84. Scholar
  8. 8.
    Anderson DR, Hendrickson A (1974) Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve. Investig Ophthalmol 13(10):771–783Google Scholar
  9. 9.
    Bellezza AJ, Rintalan CJ, Thompson HW, Downs JC, Hart RT, Burgoyne CF (2003) Deformation of the lamina cribrosa and anterior scleral canal wall in early experimental glaucoma. Investig Ophthalmol Vis Sci 44(2):623–637CrossRefGoogle Scholar
  10. 10.
    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(4):635–649PubMedCrossRefGoogle Scholar
  11. 11.
    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(5):673–691PubMedCrossRefGoogle Scholar
  12. 12.
    Yang H, Downs JC, Girkin C, Sakata L, Bellezza A, Thompson H, Burgoyne CF (2007) 3-D histomorphometry of the normal and early glaucomatous monkey optic nerve head: lamina cribrosa and peripapillary scleral position and thickness. Investig Ophthalmol Vis Sci 48(10):4597–4607. Scholar
  13. 13.
    Ozcan AA, Ozdemir N, Canataroglu A (2004) The aqueous levels of TGF-beta2 in patients with glaucoma. Int Ophthalmol 25(1):19–22PubMedCrossRefGoogle Scholar
  14. 14.
    Naskar R, Dreyer EB (2001) New horizons in neuroprotection. Surv Ophthalmol 45(suppl 3):S250–S255 (discussion S273–S256)PubMedCrossRefGoogle Scholar
  15. 15.
    Morrison JC, Moore CG, Deppmeier LM, Gold BG, Meshul CK, Johnson EC (1997) A rat model of chronic pressure-induced optic nerve damage. Exp Eye Res 64(1):85–96. Scholar
  16. 16.
    Garcia-Valenzuela E, Shareef S, Walsh J, Sharma SC (1995) Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res 61(1):33–44PubMedCrossRefGoogle Scholar
  17. 17.
    Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A (2012) The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 31(2):152–181. Scholar
  18. 18.
    Klein BE, Klein R, Sponsel WE, Franke T, Cantor LB, Martone J, Menage MJ (1992) Prevalence of glaucoma. The beaver dam eye study. Ophthalmology 99(10):1499–1504PubMedCrossRefGoogle Scholar
  19. 19.
    Flammer J, Orgul S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, Renard JP, Stefansson E (2002) The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 21(4):359–393PubMedCrossRefGoogle Scholar
  20. 20.
    Bui BV, Edmunds B, Cioffi GA, Fortune B (2005) The gradient of retinal functional changes during acute intraocular pressure elevation. Investig Ophthalmol Vis Sci 46(1):202–213. Scholar
  21. 21.
    Holcombe DJ, Lengefeld N, Gole GA, Barnett NL (2008) The effects of acute intraocular pressure elevation on rat retinal glutamate transport. Acta Ophthalmol 86(4):408–414. Scholar
  22. 22.
    Yu DY, Cringle SJ, Balaratnasingam C, Morgan WH, Yu PK, Su EN (2013) Retinal ganglion cells: energetics, compartmentation, axonal transport, cytoskeletons and vulnerability. Prog Retin Eye Res 36:217–246. Scholar
  23. 23.
    Yu DY, Cringle SJ, Alder VA, Su EN (1994) Intraretinal oxygen distribution in rats as a function of systemic blood pressure. Am J Physiol 267(6 Pt 2):H2498–H2507PubMedGoogle Scholar
  24. 24.
    Chang EE, Goldberg JL (2012) Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology 119(5):979–986. Scholar
  25. 25.
    Bereiter-Hahn J, Voth M (1994) Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27(3):198–219. Scholar
  26. 26.
    Yu DY, Cringle SJ (2001) Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Retin Eye Res 20(2):175–208PubMedCrossRefGoogle Scholar
  27. 27.
    Andrews RM, Griffiths PG, Johnson MA, Turnbull DM (1999) Histochemical localisation of mitochondrial enzyme activity in human optic nerve and retina. Br J Ophthalmol 83(2):231–235PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Delyfer MN, Forster V, Neveux N, Picaud S, Leveillard T, Sahel JA (2005) Evidence for glutamate-mediated excitotoxic mechanisms during photoreceptor degeneration in the rd1 mouse retina. Mol Vis 11:688–696PubMedGoogle Scholar
  29. 29.
    Hernandez MR (2000) The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res 19(3):297–321PubMedCrossRefGoogle Scholar
  30. 30.
    Varela HJ, Hernandez MR (1997) Astrocyte responses in human optic nerve head with primary open-angle glaucoma. J Glaucoma 6(5):303–313PubMedCrossRefGoogle Scholar
  31. 31.
    Plange N, Bienert M, Remky A, Arend KO (2012) Optic disc fluorescein leakage and intraocular pressure in primary open-angle glaucoma. Curr Eye Res 37(6):508–512. Scholar
  32. 32.
    Yao H, Wang T, Deng J, Liu D, Li X, Deng J (2014) The development of blood-retinal barrier during the interaction of astrocytes with vascular wall cells. Neural Regen Res 9(10):1047–1054. Scholar
  33. 33.
    Chong RS, Martin KR (2015) Glial cell interactions and glaucoma. Curr Opin Ophthalmol 26(2):73–77. Scholar
  34. 34.
    Newman E, Reichenbach A (1996) The Muller cell: a functional element of the retina. Trends Neurosci 19(8):307–312PubMedCrossRefGoogle Scholar
  35. 35.
    Simo R, Villarroel M, Corraliza L, Hernandez C, Garcia-Ramirez M (2010) The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier—implications for the pathogenesis of diabetic retinopathy. J Biomed Biotechnol 2010:190724. Scholar
  36. 36.
    Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845–881. Scholar
  37. 37.
    Gugleta K, Orgul S, Hasler PW, Picornell T, Gherghel D, Flammer J (2003) Choroidal vascular reaction to hand-grip stress in subjects with vasospasm and its relevance in glaucoma. Investig Ophthalmol Vis Sci 44(4):1573–1580CrossRefGoogle Scholar
  38. 38.
    Chung HS, Harris A, Evans DW, Kagemann L, Garzozi HJ, Martin B (1999) Vascular aspects in the pathophysiology of glaucomatous optic neuropathy. Surv Ophthalmol 43(Suppl 1):S43–S50PubMedCrossRefGoogle Scholar
  39. 39.
    Balaratnasingam C, Ye L, Morgan WH, Bass L, Cringle SJ, Yu DY (2009) Protective role of endothelial nitric oxide synthase following pressure-induced insult to the optic nerve. Brain Res 1263:155–164. Scholar
  40. 40.
    Kawai Y, Yokoyama Y, Kaidoh M, Ohhashi T (2010) Shear stress-induced ATP-mediated endothelial constitutive nitric oxide synthase expression in human lymphatic endothelial cells. Am J Physiol Cell Physiol 298(3):C647–C655. Scholar
  41. 41.
    Neufeld AH, Hernandez MR, Gonzalez M (1997) Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol 115(4):497–503PubMedCrossRefGoogle Scholar
  42. 42.
    Liu B, Neufeld AH (2000) Expression of nitric oxide synthase-2 (NOS-2) in reactive astrocytes of the human glaucomatous optic nerve head. Glia 30(2):178–186PubMedCrossRefGoogle Scholar
  43. 43.
    Kaufman PL (1999) Nitric-oxide synthase and neurodegeneration/neuroprotection. Proc Natl Acad Sci USA 96(17):9455–9456PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Osborne NN (2010) Mitochondria: their role in ganglion cell death and survival in primary open angle glaucoma. Exp Eye Res 90(6):750–757. Scholar
  45. 45.
    Kobayashi M, Kuroiwa T, Shimokawa R, Okeda R, Tokoro T (2000) Nitric oxide synthase expression in ischemic rat retinas. Jpn J Ophthalmol 44(3):235–244PubMedCrossRefGoogle Scholar
  46. 46.
    Adalbert R, Coleman MP (2013) Review: axon pathology in age-related neurodegenerative disorders. Neuropathol Appl Neurobiol 39(2):90–108. Scholar
  47. 47.
    Munemasa Y, Kitaoka Y (2012) Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection. Front Cell Neurosci 6:60. Scholar
  48. 48.
    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. Scholar
  49. 49.
    Ousman SS, Kubes P (2012) Immune surveillance in the central nervous system. Nat Neurosci 15(8):1096–1101. Scholar
  50. 50.
    Chi W, Li F, Chen H, Wang Y, Zhu Y, Yang X, Zhu J, Wu F, Ouyang H, Ge J, Weinreb RN, Zhang K, Zhuo Y (2014) Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1beta production in acute glaucoma. Proc Natl Acad Sci USA 111(30):11181–11186. Scholar
  51. 51.
    Schroder K, Tschopp J (2010) The inflammasomes. Cell 140(6):821–832. Scholar
  52. 52.
    Crowder RN, El-Deiry WS (2012) Caspase-8 regulation of TRAIL-mediated cell death. Exp Oncol 34(3):160–164PubMedGoogle Scholar
  53. 53.
    Innocenti B, Parpura V, Haydon PG (2000) Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes. J Neurosci Off J Soc Neurosci 20(5):1800–1808CrossRefGoogle Scholar
  54. 54.
    Voloboueva LA, Suh SW, Swanson RA, Giffard RG (2007) Inhibition of mitochondrial function in astrocytes: implications for neuroprotection. J Neurochem 102(4):1383–1394. Scholar
  55. 55.
    Martins-Ferreira H, Nedergaard M, Nicholson C (2000) Perspectives on spreading depression. Brain Res Brain Res Rev 32(1):215–234PubMedCrossRefGoogle Scholar
  56. 56.
    Singh M, Savitz SI, Hoque R, Gupta G, Roth S, Rosenbaum PS, Rosenbaum DM (2001) Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia. J Neurochem 77(2):466–475PubMedCrossRefGoogle Scholar
  57. 57.
    Katai N, Yoshimura N (1999) Apoptotic retinal neuronal death by ischemia-reperfusion is executed by two distinct caspase family proteases. Investig Ophthalmol Vis Sci 40(11):2697–2705Google Scholar
  58. 58.
    Sumioka K, Shirai Y, Sakai N, Hashimoto T, Tanaka C, Yamamoto M, Takahashi M, Ono Y, Saito N (2000) Induction of a 55-kDa PKN cleavage product by ischemia/reperfusion model in the rat retina. Investig Ophthalmol Vis Sci 41(1):29–35Google Scholar
  59. 59.
    Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A (2006) Muller cells in the healthy and diseased retina. Prog Retin Eye Res 25(4):397–424. Scholar
  60. 60.
    Bringmann A, Wiedemann P (2012) Muller glial cells in retinal disease. Ophthalmologica 227(1):1–19. Scholar
  61. 61.
    Provis JM (2001) Development of the primate retinal vasculature. Prog Retin Eye Res 20(6):799–821PubMedCrossRefGoogle Scholar
  62. 62.
    Stone J, Itin A, Alon T, Pe’er J, Gnessin H, Chan-Ling T, Keshet E (1995) Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci Off J Soc Neurosci 15(7 Pt 1):4738–4747CrossRefGoogle Scholar
  63. 63.
    Balaratnasingam C, Morgan WH, Bass L, Ye L, McKnight C, Cringle SJ, Yu DY (2008) Elevated pressure induced astrocyte damage in the optic nerve. Brain Res 1244:142–154. Scholar
  64. 64.
    Prasanna G, Krishnamoorthy R, Yorio T (2011) Endothelin, astrocytes and glaucoma. Exp Eye Res 93(2):170–177. Scholar
  65. 65.
    Bringmann A, Iandiev I, Pannicke T, Wurm A, Hollborn M, Wiedemann P, Osborne NN, Reichenbach A (2009) Cellular signaling and factors involved in Muller cell gliosis: neuroprotective and detrimental effects. Prog Retin Eye Res 28(6):423–451. Scholar
  66. 66.
    Bringmann A, Reichenbach A, Wiedemann P (2004) Pathomechanisms of cystoid macular edema. Ophthalmic Res 36(5):241–249. Scholar
  67. 67.
    Francke M, Pannicke T, Biedermann B, Faude F, Wiedemann P, Reichenbach A, Reichelt W (1997) Loss of inwardly rectifying potassium currents by human retinal glial cells in diseases of the eye. Glia 20(3):210–218PubMedCrossRefGoogle Scholar
  68. 68.
    Lewis GP, Fisher SK (2003) Up-regulation of glial fibrillary acidic protein in response to retinal injury: its potential role in glial remodeling and a comparison to vimentin expression. Int Rev Cytol 230:263–290PubMedCrossRefGoogle Scholar
  69. 69.
    Lu YB, Franze K, Seifert G, Steinhauser C, Kirchhoff F, Wolburg H, Guck J, Janmey P, Wei EQ, Kas J, Reichenbach A (2006) Viscoelastic properties of individual glial cells and neurons in the CNS. Proc Natl Acad Sci USA 103(47):17759–17764. Scholar
  70. 70.
    Ambati J, Chalam KV, Chawla DK, D’Angio CT, Guillet EG, Rose SJ, Vanderlinde RE, Ambati BK (1997) Elevated gamma-aminobutyric acid, glutamate, and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol 115(9):1161–1166PubMedCrossRefGoogle Scholar
  71. 71.
    Naskar R, Vorwerk CK, Dreyer EB (2000) Concurrent downregulation of a glutamate transporter and receptor in glaucoma. Investig Ophthalmol Vis Sci 41(7):1940–1944Google Scholar
  72. 72.
    Lucas DR, Newhouse JP (1957) The toxic effect of sodium l-glutamate on the inner layers of the retina. AMA Arch Ophthalmol 58(2):193–201PubMedCrossRefGoogle Scholar
  73. 73.
    Asensio Sanchez VM, Corral Azor A, Aguirre Aragon B, De Paz Garcia M (2002) Amino acid concentrations in the vitreous body in control subjects. Archivos de la Sociedad Espanola de Oftalmologia 77(11):611–616PubMedGoogle Scholar
  74. 74.
    Choi DW (1988) Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 11(10):465–469PubMedCrossRefGoogle Scholar
  75. 75.
    Huang W, Fileta J, Rawe I, Qu J, Grosskreutz CL (2010) Calpain activation in experimental glaucoma. Investig Ophthalmol Vis Sci 51(6):3049–3054. Scholar
  76. 76.
    Manabe S, Lipton SA (2003) Divergent NMDA signals leading to proapoptotic and antiapoptotic pathways in the rat retina. Investig Ophthalmol Vis Sci 44(1):385–392CrossRefGoogle Scholar
  77. 77.
    Dorado C, Rugerio C, Rivas S (2003) Estrés oxidativo y neurodegeneración. Revista de la Facultad de Medicina 46(6):229–235Google Scholar
  78. 78.
    Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ (1995) Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Investig Ophthalmol Vis Sci 36(5):774–786Google Scholar
  79. 79.
    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 Off J Soc Neurosci 28(2):548–561. Scholar
  80. 80.
    Vidal-Sanz M, Valiente-Soriano FJ, Ortin-Martinez A, Nadal-Nicolas FM, Jimenez-Lopez M, Salinas-Navarro M, Alarcon-Martinez L, Garcia-Ayuso D, Aviles-Trigueros M, Agudo-Barriuso M, Villegas-Perez MP (2015) Retinal neurodegeneration in experimental glaucoma. Prog Brain Res 220:1–35. Scholar
  81. 81.
    Dai C, Khaw PT, Yin ZQ, Li D, Raisman G, Li Y (2012) Structural basis of glaucoma: the fortified astrocytes of the optic nerve head are the target of raised intraocular pressure. Glia 60(1):13–28. Scholar
  82. 82.
    Chaudhary P, Ahmed F, Quebada P, Sharma SC (1999) Caspase inhibitors block the retinal ganglion cell death following optic nerve transection. Brain Res Mol Brain Res 67(1):36–45PubMedCrossRefGoogle Scholar
  83. 83.
    Kermer P, Ankerhold R, Klocker N, Krajewski S, Reed JC, Bahr M (2000) Caspase-9: involvement in secondary death of axotomized rat retinal ganglion cells in vivo. Brain Res Mol Brain Res 85(1–2):144–150PubMedCrossRefGoogle Scholar
  84. 84.
    Kermer P, Klocker N, Labes M, Thomsen S, Srinivasan A, Bahr M (1999) Activation of caspase-3 in axotomized rat retinal ganglion cells in vivo. FEBS Lett 453(3):361–364PubMedCrossRefGoogle Scholar
  85. 85.
    Cheung ZH, Yip HK, Wu W, So KF (2003) Axotomy induces cytochrome c release in retinal ganglion cells. NeuroReport 14(2):279–282. Scholar
  86. 86.
    Quigley HA (1999) Neuronal death in glaucoma. Prog Retin Eye Res 18(1):39–57PubMedCrossRefGoogle Scholar
  87. 87.
    Klocker N, Braunling F, Isenmann S, Bahr M (1997) In vivo neurotrophic effects of GDNF on axotomized retinal ganglion cells. NeuroReport 8(16):3439–3442PubMedCrossRefGoogle Scholar
  88. 88.
    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(2):304–317PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Peinado-Ramon P, Salvador M, Villegas-Perez MP, Vidal-Sanz M (1996) Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study. Investig Ophthalmol Vis Sci 37(4):489–500Google Scholar
  90. 90.
    Klocker N, Kermer P, Weishaupt JH, Labes M, Ankerhold R, Bahr M (2000) Brain-derived neurotrophic factor-mediated neuroprotection of adult rat retinal ganglion cells in vivo does not exclusively depend on phosphatidyl-inositol-3′-kinase/protein kinase B signaling. J Neurosci Off J Soc Neurosci 20(18):6962–6967CrossRefGoogle Scholar
  91. 91.
    Liao R, Yan F, Zeng Z, Farhan M, Little P, Quirion R, Srivastava LK, Zheng W (2016) Amiodarone-induced retinal neuronal cell apoptosis attenuated by IGF-1 via counter regulation of the PI3 k/Akt/FoxO3a pathway. Mol Neurobiol. Scholar
  92. 92.
    Kikuchi M, Tenneti L, Lipton SA (2000) Role of p38 mitogen-activated protein kinase in axotomy-induced apoptosis of rat retinal ganglion cells. J Neurosci Off J Soc Neurosci 20(13):5037–5044CrossRefGoogle Scholar
  93. 93.
    Russelakis-Carneiro M, Silveira LC, Perry VH (1996) Factors affecting the survival of cat retinal ganglion cells after optic nerve injury. J Neurocytol 25(6):393–402PubMedCrossRefGoogle Scholar
  94. 94.
    Yoles E, Muller S, Schwartz M (1997) NMDA-receptor antagonist protects neurons from secondary degeneration after partial optic nerve crush. J Neurotrauma 14(9):665–675. Scholar
  95. 95.
    Yoles E, Schwartz M (1998) Elevation of intraocular glutamate levels in rats with partial lesion of the optic nerve. Arch Ophthalmol 116(7):906–910PubMedCrossRefGoogle Scholar
  96. 96.
    Stys PK (2005) General mechanisms of axonal damage and its prevention. J Neurol Sci 233(1–2):3–13. Scholar
  97. 97.
    Whitmore AV, Libby RT, John SW (2005) Glaucoma: thinking in new ways-a role for autonomous axonal self-destruction and other compartmentalised processes? Prog Retin Eye Res 24(6):639–662. Scholar
  98. 98.
    Ryu M, Yasuda M, Shi D, Shanab AY, Watanabe R, Himori N, Omodaka K, Yokoyama Y, Takano J, Saido T, Nakazawa T (2012) Critical role of calpain in axonal damage-induced retinal ganglion cell death. J Neurosci Res 90(4):802–815. Scholar
  99. 99.
    Stys PK, Jiang Q (2002) Calpain-dependent neurofilament breakdown in anoxic and ischemic rat central axons. Neurosci Lett 328(2):150–154PubMedCrossRefGoogle Scholar
  100. 100.
    Takai Y, Tanito M, Ohira A (2012) Multiplex cytokine analysis of aqueous humor in eyes with primary open-angle glaucoma, exfoliation glaucoma, and cataract. Investig Ophthalmol Vis Sci 53(1):241–247. Scholar
  101. 101.
    Nakazawa T, Tamai M, Mori N (2002) Brain-derived neurotrophic factor prevents axotomized retinal ganglion cell death through MAPK and PI3 K signaling pathways. Investig Ophthalmol Vis Sci 43(10):3319–3326Google Scholar
  102. 102.
    Pervan CL (2017) Smad-independent TGF-beta2 signaling pathways in human trabecular meshwork cells. Exp Eye Res 158:137–145. Scholar
  103. 103.
    Pattabiraman PP, Rao PV (2010) Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells. Am J Physiol Cell Physiol 298(3):C749–C763. Scholar
  104. 104.
    Gauthier AC, Liu J (2017) Epigenetics and signaling pathways in glaucoma. Biomed Res Int 2017:5712341. Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2017

Authors and Affiliations

  • Karine Evangelho
    • 1
  • Maria Mogilevskaya
    • 2
  • Monica Losada-Barragan
    • 3
  • Jeinny Karina Vargas-Sanchez
    • 1
    Email author
  1. 1.Grupo de Investigación en Ciencias Biomédicas GRINCIBIO, Facultad de medicina, Sede BogotáUniversidad Antonio NariñoBogotáColombia
  2. 2.Grupo de Investigación en Ingeniería Clínica – Hospital Universitario la Samaritana GINIC-HUS, Sede BogotáECCIBogotáColombia
  3. 3.Grupo de Biología Celular y Funcional e Ingeniería de Biomoléculas, Facultad de Ciencias, Sede BogotáUniversidad Antonio NariñoBogotáColombia

Personalised recommendations