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. 1999 Aug;83(8):980–986. doi: 10.1136/bjo.83.8.980

Ganglion cell death in glaucoma: what do we really know?

N OSBORNE 1, J WOOD 1, G CHIDLOW 1, J BAE 1, J MELENA 1, M NASH 1
PMCID: PMC1723166  PMID: 10413706

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Figure 1  .

Figure 1  

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Three hypothetical views of how retinal ganglion cell death may occur in glaucoma. In (A), all ganglion cells are initiated to die at more or less the same time but individual cells die at variable rates. In (B), a series of acute insults occurs at different periods and this leads to the death of subsets of ganglion cells all dying at similar rates. In (C), an acute insult leads to the death of a subset of ganglion cells: the other ganglion cells then die because of secondary degeneration rather than because of a defined insult, at variable rates.

Figure 2  .

Figure 2  

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Immunohistochemical staining showing the presence of brain derived neurotrophic growth factor (BDNF) (A) and the TrkB receptor (B) in the retina. Clearly the immunofluorescence is associated with the ganglion cells in each case.

Figure 3  .

Figure 3  

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A schematic representation of how ganglion cells may die by overexcitation as would occur in hypoxia/ischaemia. In the normal healthy retina (A-C) the degree of excitation of a ganglion cell will be a balance between the level of excitatory and inhibitory neurotransmitters (solid and open circles, respectively) and the complement of excitatory (for example, ionotropic glutamate) and inhibitory (for example, GABAA) receptors (grey and black buckets, respectively). The degree of stimulation will depend on the complement of receptors. However, the cells are not overstimulated whether they have the equivalent number of excitatory and inhibitory (A), more excitatory (B), or more inhibitory (C) receptors, because the level of neurotransmitters are at a low and controlled level. In hypoxia/ischaemia (D-F), extracellular neurotransmitters are elevated and the potential for overstimulation of receptors can occur. Cells that contain equivalent numbers of excitatory and inhibitory receptors can become slightly overexcited (that is, suffer slightly more excitatory than inhibitory input than normal) and may therefore become sick or unhealthy (D). In contrast, cells that have very much more excitatory than inhibitory receptors (E) will be overstimulated to a greater extent and this could lead to immediate death. Theoretically, neurons that have more inhibitory than excitatory receptors will not be overexcited in hypoxia/ischaemia (F) and are therefore less likely to suffer from the insult.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aguayo A. J., Rasminsky M., Bray G. M., Carbonetto S., McKerracher L., Villegas-Pérez M. P., Vidal-Sanz M., Carter D. A. Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci. 1991 Mar 29;331(1261):337–343. doi: 10.1098/rstb.1991.0025. [DOI] [PubMed] [Google Scholar]
  2. Anderson D. R., Hendrickson A. Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve. Invest Ophthalmol. 1974 Oct;13(10):771–783. [PubMed] [Google Scholar]
  3. Brandstätter J. H., Hartveit E., Sassoè-Pognetto M., Wässle H. Expression of NMDA and high-affinity kainate receptor subunit mRNAs in the adult rat retina. Eur J Neurosci. 1994 Jul 1;6(7):1100–1112. doi: 10.1111/j.1460-9568.1994.tb00607.x. [DOI] [PubMed] [Google Scholar]
  4. Bray G. M., Villegas-Pérez M. P., Vidal-Sanz M., Carter D. A., Aguayo A. J. Neuronal and nonneuronal influences on retinal ganglion cell survival, axonal regrowth, and connectivity after axotomy. Ann N Y Acad Sci. 1991;633:214–228. doi: 10.1111/j.1749-6632.1991.tb15613.x. [DOI] [PubMed] [Google Scholar]
  5. Cellerino A., Carroll P., Thoenen H., Barde Y. A. Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor. Mol Cell Neurosci. 1997;9(5-6):397–408. doi: 10.1006/mcne.1997.0641. [DOI] [PubMed] [Google Scholar]
  6. Charriaut-Marlangue C., Ben-Ari Y. A cautionary note on the use of the TUNEL stain to determine apoptosis. Neuroreport. 1995 Dec 29;7(1):61–64. [PubMed] [Google Scholar]
  7. DeGirolami U., Zivin J. A. Neuropathology of experimental spinal cord ischemia in the rabbit. J Neuropathol Exp Neurol. 1982 Mar;41(2):129–149. doi: 10.1097/00005072-198203000-00004. [DOI] [PubMed] [Google Scholar]
  8. Douglas G. R. Pathogenetic mechanisms of glaucoma not related to intraocular pressure. Curr Opin Ophthalmol. 1998 Apr;9(2):34–38. doi: 10.1097/00055735-199804000-00007. [DOI] [PubMed] [Google Scholar]
  9. Dreyer E. B., Zurakowski D., Schumer R. A., Podos S. M., Lipton S. A. Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol. 1996 Mar;114(3):299–305. doi: 10.1001/archopht.1996.01100130295012. [DOI] [PubMed] [Google Scholar]
  10. Ernest J. T. Optic disc blood flow. Trans Ophthalmol Soc U K. 1976 Sep;96(3):348–351. [PubMed] [Google Scholar]
  11. Flammer J., Orgül S. Optic nerve blood-flow abnormalities in glaucoma. Prog Retin Eye Res. 1998 Apr;17(2):267–289. doi: 10.1016/s1350-9462(97)00006-2. [DOI] [PubMed] [Google Scholar]
  12. Galzi J. L., Changeux J. P. Neuronal nicotinic receptors: molecular organization and regulations. Neuropharmacology. 1995 Jun;34(6):563–582. doi: 10.1016/0028-3908(95)00034-4. [DOI] [PubMed] [Google Scholar]
  13. Glovinsky Y., Quigley H. A., Pease M. E. Foveal ganglion cell loss is size dependent in experimental glaucoma. Invest Ophthalmol Vis Sci. 1993 Feb;34(2):395–400. [PubMed] [Google Scholar]
  14. Gupta N., Weinreb R. N. New definitions of glaucoma. Curr Opin Ophthalmol. 1997 Apr;8(2):38–41. doi: 10.1097/00055735-199704000-00007. [DOI] [PubMed] [Google Scholar]
  15. Hernandez M. R., Andrzejewska W. M., Neufeld A. H. Changes in the extracellular matrix of the human optic nerve head in primary open-angle glaucoma. Am J Ophthalmol. 1990 Feb 15;109(2):180–188. doi: 10.1016/s0002-9394(14)75984-7. [DOI] [PubMed] [Google Scholar]
  16. Hernandez M. R., Pena J. D. The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol. 1997 Mar;115(3):389–395. doi: 10.1001/archopht.1997.01100150391013. [DOI] [PubMed] [Google Scholar]
  17. Kalloniatis M., Harwerth R. S., Smith E. L., 3rd, DeSantis L. Colour vision anomalies following experimental glaucoma in monkeys. Ophthalmic Physiol Opt. 1993 Jan;13(1):56–67. doi: 10.1111/j.1475-1313.1993.tb00427.x. [DOI] [PubMed] [Google Scholar]
  18. Kerrigan L. A., Zack D. J., Quigley H. A., Smith S. D., Pease M. E. TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol. 1997 Aug;115(8):1031–1035. doi: 10.1001/archopht.1997.01100160201010. [DOI] [PubMed] [Google Scholar]
  19. Koroshetz W. J., Moskowitz M. A. Emerging treatments for stroke in humans. Trends Pharmacol Sci. 1996 Jun;17(6):227–233. doi: 10.1016/0165-6147(96)10020-1. [DOI] [PubMed] [Google Scholar]
  20. Kroemer G., Petit P., Zamzami N., Vayssière J. L., Mignotte B. The biochemistry of programmed cell death. FASEB J. 1995 Oct;9(13):1277–1287. doi: 10.1096/fasebj.9.13.7557017. [DOI] [PubMed] [Google Scholar]
  21. Lipton S. A. Spontaneous release of acetylcholine affects the physiological nicotinic responses of rat retinal ganglion cells in culture. J Neurosci. 1988 Oct;8(10):3857–3868. doi: 10.1523/JNEUROSCI.08-10-03857.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ma Y. T., Hsieh T., Forbes M. E., Johnson J. E., Frost D. O. BDNF injected into the superior colliculus reduces developmental retinal ganglion cell death. J Neurosci. 1998 Mar 15;18(6):2097–2107. doi: 10.1523/JNEUROSCI.18-06-02097.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Majno G., Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995 Jan;146(1):3–15. [PMC free article] [PubMed] [Google Scholar]
  24. Mansour-Robaey S., Clarke D. B., Wang Y. C., Bray G. M., Aguayo A. J. Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1632–1636. doi: 10.1073/pnas.91.5.1632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mey J., Thanos S. Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res. 1993 Feb 5;602(2):304–317. doi: 10.1016/0006-8993(93)90695-j. [DOI] [PubMed] [Google Scholar]
  26. Morgan J. E. Selective cell death in glaucoma: does it really occur? Br J Ophthalmol. 1994 Nov;78(11):875–880. doi: 10.1136/bjo.78.11.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Neal M. J., Cunningham J. R., Hutson P. H., Hogg J. Effects of ischaemia on neurotransmitter release from the isolated retina. J Neurochem. 1994 Mar;62(3):1025–1033. doi: 10.1046/j.1471-4159.1994.62031025.x. [DOI] [PubMed] [Google Scholar]
  28. Neufeld A. H., Hernandez M. R., Gonzalez M., Geller A. Cyclooxygenase-1 and cyclooxygenase-2 in the human optic nerve head. Exp Eye Res. 1997 Dec;65(6):739–745. doi: 10.1006/exer.1997.0394. [DOI] [PubMed] [Google Scholar]
  29. Neufeld A. H., Hernandez M. R., Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol. 1997 Apr;115(4):497–503. doi: 10.1001/archopht.1997.01100150499009. [DOI] [PubMed] [Google Scholar]
  30. Neufeld A. H. New conceptual approaches for pharmacological neuroprotection in glaucomatous neuronal degeneration. J Glaucoma. 1998 Dec;7(6):434–438. [PubMed] [Google Scholar]
  31. Okisaka S., Murakami A., Mizukawa A., Ito J. Apoptosis in retinal ganglion cell decrease in human glaucomatous eyes. Jpn J Ophthalmol. 1997 Mar-Apr;41(2):84–88. doi: 10.1016/s0021-5155(97)00013-0. [DOI] [PubMed] [Google Scholar]
  32. Osborne N. N., Cazevieille C., Pergande G., Wood J. P. Induction of apoptosis in cultured human retinal pigment epithelial cells is counteracted by flupirtine. Invest Ophthalmol Vis Sci. 1997 Jun;38(7):1390–1400. [PubMed] [Google Scholar]
  33. Osborne N. N., Chidlow G., Nash M. S., Wood J. P. The potential of neuroprotection in glaucoma treatment. Curr Opin Ophthalmol. 1999 Apr;10(2):82–92. doi: 10.1097/00055735-199904000-00002. [DOI] [PubMed] [Google Scholar]
  34. Pena J. D., Taylor A. W., Ricard C. S., Vidal I., Hernandez M. R. Transforming growth factor beta isoforms in human optic nerve heads. Br J Ophthalmol. 1999 Feb;83(2):209–218. doi: 10.1136/bjo.83.2.209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Quigley H. A., Addicks E. M., Green W. R., Maumenee A. E. Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch Ophthalmol. 1981 Apr;99(4):635–649. doi: 10.1001/archopht.1981.03930010635009. [DOI] [PubMed] [Google Scholar]
  36. Quigley H. A., Dorman-Pease M. E., Brown A. E. Quantitative study of collagen and elastin of the optic nerve head and sclera in human and experimental monkey glaucoma. Curr Eye Res. 1991 Sep;10(9):877–888. doi: 10.3109/02713689109013884. [DOI] [PubMed] [Google Scholar]
  37. Quigley H. A. Ganglion cell death in glaucoma: pathology recapitulates ontogeny. Aust N Z J Ophthalmol. 1995 May;23(2):85–91. doi: 10.1111/j.1442-9071.1995.tb00135.x. [DOI] [PubMed] [Google Scholar]
  38. Quigley H. A., Guy J., Anderson D. R. Blockade of rapid axonal transport. Effect of intraocular pressure elevation in primate optic nerve. Arch Ophthalmol. 1979 Mar;97(3):525–531. doi: 10.1001/archopht.1979.01020010269018. [DOI] [PubMed] [Google Scholar]
  39. Quigley H. A. Neuronal death in glaucoma. Prog Retin Eye Res. 1999 Jan;18(1):39–57. doi: 10.1016/s1350-9462(98)00014-7. [DOI] [PubMed] [Google Scholar]
  40. Raffray M., Cohen G. M. Apoptosis and necrosis in toxicology: a continuum or distinct modes of cell death? Pharmacol Ther. 1997 Sep;75(3):153–177. doi: 10.1016/s0163-7258(97)00037-5. [DOI] [PubMed] [Google Scholar]
  41. Rodieck R. W., Brening R. K. Retinal ganglion cells: properties, types, genera, pathways and trans-species comparisons. Brain Behav Evol. 1983;23(3-4):121–164. doi: 10.1159/000121492. [DOI] [PubMed] [Google Scholar]
  42. Russelakis-Carneiro M., Silveira L. C., Perry V. H. Factors affecting the survival of cat retinal ganglion cells after optic nerve injury. J Neurocytol. 1996 Jun;25(6):393–402. doi: 10.1007/BF02284810. [DOI] [PubMed] [Google Scholar]
  43. Schwartz M., Belkin M., Yoles E., Solomon A. Potential treatment modalities for glaucomatous neuropathy: neuroprotection and neuroregeneration. J Glaucoma. 1996 Dec;5(6):427–432. [PubMed] [Google Scholar]
  44. Siesjö B. K. A new perspective on ischemic brain damage? Prog Brain Res. 1993;96:1–9. doi: 10.1016/s0079-6123(08)63255-0. [DOI] [PubMed] [Google Scholar]
  45. Siesjö B. K. Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. J Neurosurg. 1992 Sep;77(3):337–354. doi: 10.3171/jns.1992.77.3.0337. [DOI] [PubMed] [Google Scholar]
  46. Sievers J., Hausmann B., Unsicker K., Berry M. Fibroblast growth factors promote the survival of adult rat retinal ganglion cells after transection of the optic nerve. Neurosci Lett. 1987 May 6;76(2):157–162. doi: 10.1016/0304-3940(87)90708-7. [DOI] [PubMed] [Google Scholar]
  47. Siliprandi R., Canella R., Carmignoto G., Schiavo N., Zanellato A., Zanoni R., Vantini G. N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina. Vis Neurosci. 1992 Jun;8(6):567–573. doi: 10.1017/s0952523800005666. [DOI] [PubMed] [Google Scholar]
  48. Silveira L. C., Russelakis-Carneiro M., Perry V. H. The ganglion cell response to optic nerve injury in the cat: differential responses revealed by neurofibrillar staining. J Neurocytol. 1994 Feb;23(2):75–86. doi: 10.1007/BF01183863. [DOI] [PubMed] [Google Scholar]
  49. Smiddy W. E., Green W. R. Nutritional amblyopia. A histopathologic study with retrospective clinical correlation. Graefes Arch Clin Exp Ophthalmol. 1987;225(5):321–324. doi: 10.1007/BF02153397. [DOI] [PubMed] [Google Scholar]
  50. Thanos Solon, Bähr Mathias, Barde Yves-Alain, Vanselow Jens. Survival and Axonal Elongation of Adult Rat Retinal Ganglion Cells. Eur J Neurosci. 1989 Jan;1(1):19–26. doi: 10.1111/j.1460-9568.1989.tb00770.x. [DOI] [PubMed] [Google Scholar]
  51. Villegas-Pérez M. P., Vidal-Sanz M., Bray G. M., Aguayo A. J. Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats. J Neurosci. 1988 Jan;8(1):265–280. doi: 10.1523/JNEUROSCI.08-01-00265.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Weber A. J., Kaufman P. L., Hubbard W. C. Morphology of single ganglion cells in the glaucomatous primate retina. Invest Ophthalmol Vis Sci. 1998 Nov;39(12):2304–2320. [PubMed] [Google Scholar]
  53. Wyllie A. H., Beattie G. J., Hargreaves A. D. Chromatin changes in apoptosis. Histochem J. 1981 Jul;13(4):681–692. doi: 10.1007/BF01002719. [DOI] [PubMed] [Google Scholar]
  54. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  55. Yoles E., Schwartz M. Potential neuroprotective therapy for glaucomatous optic neuropathy. Surv Ophthalmol. 1998 Jan-Feb;42(4):367–372. doi: 10.1016/s0039-6257(97)00123-9. [DOI] [PubMed] [Google Scholar]

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