Mechanisms of retinal ganglion cell injury and defense in glaucoma.

Glaucoma is a disease in which retinal ganglion cells (RGCs) die leading ultimately to blindness. Over the past decade and a half, information has begun to emerge regarding specific molecular responses of the retina to conditions of elevated intraocular pressure (IOP). It is now clear that the state of the RGC in glaucoma depends on a balance of pro-survival and pro-death pathways in the retina and details of these responses are still being worked out. In this review, we will discuss the evidence supporting the involvement of specific apoptotic cascades as well as the insults that trigger RGC apoptosis. In addition, we will present evidence supporting the existence of endogenous protective mechanisms as well as exogenous neuroprotective strategies.

[1]  M. Vidal-Sanz,et al.  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 , 1999 .

[2]  Hwa Sun Kim,et al.  Retinal ganglion cell death is delayed by activation of retinal intrinsic cell survival program , 2005, Brain Research.

[3]  William Cepurna,et al.  Understanding mechanisms of pressure-induced optic nerve damage , 2005, Progress in Retinal and Eye Research.

[4]  M. Wax,et al.  Matrix metalloproteinases and tumor necrosis factor α in glaucomatous optic nerve head , 2000 .

[5]  D. Zack,et al.  Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. , 1995, Investigative ophthalmology & visual science.

[6]  T. Oka,et al.  Amelioration of retinal degeneration and proteolysis in acute ocular hypertensive rats by calpain inhibitor ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester , 2006, Neuroscience.

[7]  M. Hüll,et al.  Regulation of immediate-early gene expression in rat retinal ganglion cells after axotomy and during regeneration through a peripheral nerve graft. , 1994, Journal of neurobiology.

[8]  S. Sagar,et al.  Long‐term induction of c‐jun mRNA and jun protein in rabbit retinal ganglion cells following axotomy or colchicine treatment , 1993, Journal of neuroscience research.

[9]  P. Kaufman,et al.  Vitreous glutamate concentration and axon loss in monkeys with experimental glaucoma. , 2005, Archives of ophthalmology.

[10]  L. Zangwill,et al.  Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, II: Structural measures. , 2004, Investigative ophthalmology & visual science.

[11]  D. Lucas,et al.  The toxic effect of sodium L-glutamate on the inner layers of the retina. , 1957, A.M.A. archives of ophthalmology.

[12]  A. Weber,et al.  BDNF preserves the dendritic morphology of alpha and beta ganglion cells in the cat retina after optic nerve injury. , 2008, Investigative ophthalmology & visual science.

[13]  E. Woldemussie,et al.  Müller cell response to laser‐induced increase in intraocular pressure in rats , 2004, Glia.

[14]  H. Quigley,et al.  Measurement of amino acid levels in the vitreous humor of rats after chronic intraocular pressure elevation or optic nerve transection. , 2002, Journal of glaucoma.

[15]  G. Risuleo,et al.  Degenerative and apoptotic events at retinal and optic nerve level after experimental induction of ocular hypertension , 2007, Molecular and Cellular Biochemistry.

[16]  J C Reed,et al.  Mitochondria and apoptosis. , 1998, Science.

[17]  Po-ki Ho,et al.  Mammalian initiator apoptotic caspases , 2005, The FEBS journal.

[18]  N. Agarwal,et al.  Oxidative Stress in Glaucoma: A Burden of Evidence , 2007, Journal of glaucoma.

[19]  Earl L. Smith,et al.  Vitreal glutamate concentration in monkeys with experimental glaucoma. , 2002, Investigative ophthalmology & visual science.

[20]  V. Hänninen,et al.  Activation of caspase 9 in a rat model of experimental glaucoma , 2002, Current eye research.

[21]  H. Quigley,et al.  The transcription factor c-jun is activated in retinal ganglion cells in experimental rat glaucoma. , 2005, Experimental eye research.

[22]  G. Tezel Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences , 2006, Progress in Retinal and Eye Research.

[23]  C. L. Schlamp,et al.  Involvement of the Bcl2 gene family in the signaling and control of retinal ganglion cell death. , 2008, Progress in brain research.

[24]  H. Gao,et al.  Elevated mRNA expression of brain-derived neurotrophic factor in retinal ganglion cell layer after optic nerve injury. , 1997, Investigative ophthalmology & visual science.

[25]  Michael G. Anderson,et al.  Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. , 2005, Visual neuroscience.

[26]  D. Zack,et al.  Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. , 2009, Investigative ophthalmology & visual science.

[27]  Rajendra K. Sharma,et al.  Localization and characterization of calcineurin in bovine eye. , 2002, Investigative ophthalmology & visual science.

[28]  M. Ingelsson,et al.  Transcriptional up-regulation and activation of initiating caspases in experimental glaucoma. , 2005, The American journal of pathology.

[29]  L. Levin,et al.  Identification of the bcl-2 family of genes in the rat retina. , 1997, Investigative ophthalmology & visual science.

[30]  Xiu-Huai Liu,et al.  Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein* , 2001, The Journal of Biological Chemistry.

[31]  Sheng-tian Li,et al.  Critical Role of Calpain-mediated Cleavage of Calcineurin in Excitotoxic Neurodegeneration* , 2004, Journal of Biological Chemistry.

[32]  C. L. Schlamp,et al.  Experimental induction of retinal ganglion cell death in adult mice. , 1999, Investigative ophthalmology & visual science.

[33]  A. Neufeld,et al.  Expression of nitric oxide synthase‐2 (NOS‐2) in reactive astrocytes of the human glaucomatous optic nerve head , 2000, Glia.

[34]  D. Zack,et al.  Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. , 2000, Investigative ophthalmology & visual science.

[35]  Rebecca M. Sappington,et al.  TRPV1: contribution to retinal ganglion cell apoptosis and increased intracellular Ca2+ with exposure to hydrostatic pressure. , 2009, Investigative ophthalmology & visual science.

[36]  M. Wax,et al.  TNF-a and TNF-a Receptor-1 in the Retina of Normal and Glaucomatous Eyes , 2001 .

[37]  T. Shearer,et al.  The role of calcium-activated protease calpain in experimental retinal pathology. , 2008, Survey of ophthalmology.

[38]  M. Wax,et al.  Inhibition of caspase activity in retinal cell apoptosis induced by various stimuli in vitro. , 1999, Investigative ophthalmology & visual science.

[39]  A. Clark,et al.  Neurotrophin and neurotrophin receptor expression by cells of the human lamina cribrosa. , 2001, Investigative ophthalmology & visual science.

[40]  N. Harizman,et al.  Regulation of cell death and survival pathways in experimental glaucoma. , 2007, Experimental eye research.

[41]  M. Wax,et al.  Hypoxia-inducible factor 1α in the glaucomatous retina and optic nerve head , 2004 .

[42]  Donald J Zack,et al.  Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model. , 2003, Investigative ophthalmology & visual science.

[43]  Andreas Fischer,et al.  Reversible Membrane Interaction of BAD Requires two C-terminal Lipid Binding Domains in Conjunction with 14-3-3 Protein Binding* , 2006, Journal of Biological Chemistry.

[44]  C. L. Schlamp,et al.  Bax-dependent and independent pathways of retinal ganglion cell death induced by different damaging stimuli. , 2000, Experimental eye research.

[45]  L. Chang,et al.  Mitochondrial involvement in the point of no return in neuronal apoptosis. , 2002, Biochimie.

[46]  S. Sharma,et al.  Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats , 2001, Neuroscience Letters.

[47]  G. Tezel TNF-alpha signaling in glaucomatous neurodegeneration. , 2008, Progress in brain research.

[48]  D. Zack,et al.  Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. , 2002, Investigative ophthalmology & visual science.

[49]  D. B. Clarke,et al.  Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[50]  E. Slee,et al.  Serial killers: ordering caspase activation events in apoptosis , 1999, Cell Death and Differentiation.

[51]  J. Caprioli,et al.  Induction of heat shock protein 72 protects retinal ganglion cells in a rat glaucoma model. , 2001, Investigative ophthalmology & visual science.

[52]  Joan W. Miller,et al.  Tumor Necrosis Factor-α Mediates Oligodendrocyte Death and Delayed Retinal Ganglion Cell Loss in a Mouse Model of Glaucoma , 2006, The Journal of Neuroscience.

[53]  S. Sharma,et al.  Programmed cell death of retinal ganglion cells during experimental glaucoma. , 1995, Experimental eye research.

[54]  J. Caprioli,et al.  Expression of phosphorylated c-Jun N-terminal protein kinase (JNK) in experimental glaucoma in rats. , 2006, Experimental eye research.

[55]  G. A. Robinson Immediate early gene expression in axotomized and regenerating retinal ganglion cells of the adult rat. , 1994, Brain research. Molecular brain research.

[56]  M. Wax,et al.  Increased Production of Tumor Necrosis Factor-a by Glial Cells Exposed to Simulated Ischemia or Elevated Hydrostatic Pressure Induces Apoptosis in Cocultured Retinal Ganglion Cells , 2000 .

[57]  T. Shearer,et al.  Presence of calpain‐induced proteolysis in retinal degeneration and dysfunction in a rat model of acute ocular hypertension , 2006, Journal of neuroscience research.

[58]  V. Dixit,et al.  Death receptors: signaling and modulation. , 1998, Science.

[59]  G. Núñez,et al.  Caspases: the proteases of the apoptotic pathway , 1998, Oncogene.

[60]  Richard S. Smith,et al.  Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model , 2007, BMC Neuroscience.

[61]  K. Brown,et al.  Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure. , 2004, Investigative ophthalmology & visual science.

[62]  Jacek Kuznicki,et al.  Calcium ions in neuronal degeneration , 2008, IUBMB life.

[63]  S. Kügler,et al.  Excess Bcl-XL increases the intrinsic growth potential of adult CNS neurons in vitro , 2004, Molecular and Cellular Neuroscience.

[64]  H. Arai,et al.  Localization of Calcineurin in the Mature and Developing Retina , 2001, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[65]  Y. Ng,et al.  Factors contributing to neuronal degeneration in retinas of experimental glaucomatous rats , 2005, Journal of neuroscience research.

[66]  H. Yip,et al.  c-Jun expression in surviving and regenerating retinal ganglion cells: effects of intravitreal neurotrophic supply. , 2003, Investigative ophthalmology & visual science.

[67]  A. Weber,et al.  BDNF enhances retinal ganglion cell survival in cats with optic nerve damage. , 2001, Investigative ophthalmology & visual science.

[68]  A. Di Polo,et al.  Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Müller cells temporarily rescues injured retinal ganglion cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[69]  J. Morrison,et al.  Evaluation of inducible nitric oxide synthase in glaucomatous optic neuropathy and pressure-induced optic nerve damage. , 2005, Investigative ophthalmology & visual science.

[70]  E. Ling,et al.  Müller glial cells express nestin coupled with glial fibrillary acidic protein in experimentally induced glaucoma in the rat retina , 2006, Neuroscience.

[71]  S. Srinivasula,et al.  Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. , 1998, Molecular cell.

[72]  D. Zack,et al.  Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. , 2000, Investigative ophthalmology & visual science.

[73]  E. Freeman,et al.  The effects of FK506 on retinal ganglion cells after optic nerve crush. , 2000, Investigative ophthalmology & visual science.

[74]  Emad S. Alnemri,et al.  Ordering the Cytochrome c–initiated Caspase Cascade: Hierarchical Activation of Caspases-2, -3, -6, -7, -8, and -10 in a Caspase-9–dependent Manner , 1999, The Journal of cell biology.

[75]  Wutian Wu,et al.  Up-regulated Endogenous Erythropoietin/Erythropoietin Receptor System and Exogenous Erythropoietin Rescue Retinal Ganglion Cells after Chronic Ocular Hypertension , 2008, Cellular and Molecular Neurobiology.

[76]  Maria-Thereza R. Perez,et al.  Expression of brain-derived neurotrophic factor and of its functional receptor in neonatal and adult rat retina , 1995, Neuroscience Letters.

[77]  D. Clarke,et al.  Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[78]  D. Baltimore,et al.  Autoproteolytic activation of pro-caspases by oligomerization. , 1998, Molecular cell.

[79]  S. Srinivasula,et al.  Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade , 1997, Cell.

[80]  A. Neufeld,et al.  Isoforms of nitric oxide synthase in the optic nerves of rat eyes with chronic moderately elevated intraocular pressure. , 1999, Investigative ophthalmology & visual science.

[81]  Hwa Sun Kim,et al.  Retinal glial cell responses and Fas/FasL activation in rats with chronic ocular hypertension , 2006, Brain Research.

[82]  S. Kügler,et al.  Long-term in vivo inhibition of CNS neurodegeneration by Bcl-XL gene transfer. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[83]  M. Forbes,et al.  Intravitreal Administration of Erythropoietin and Preservation of Retinal Ganglion Cells in an Experimental Rat Model of Glaucoma , 2005, Current eye research.

[84]  R. Segal,et al.  Action in the axon: generation and transport of signaling endosomes , 2008, Current Opinion in Neurobiology.

[85]  C. Ibáñez Message in a bottle: long-range retrograde signaling in the nervous system. , 2007, Trends in cell biology.

[86]  T. Cotter,et al.  A key role for calpains in retinal ganglion cell death. , 2007, Investigative ophthalmology & visual science.

[87]  K. Kaneda,et al.  Mechanism of the pathogenesis of glutamate neurotoxicity in retinal ischemia , 1998, Graefe's Archive for Clinical and Experimental Ophthalmology.

[88]  L. Maffei,et al.  Protection of Retinal Ganglion Cells from Natural and Axotomy-Induced Cell Death in Neonatal Transgenic Mice Overexpressing bcl-2 , 1996, The Journal of Neuroscience.

[89]  S. Sharma,et al.  Caspase inhibitors block the retinal ganglion cell death following optic nerve transection. , 1999, Brain research. Molecular brain research.

[90]  Y. Ng,et al.  An immunohistochemical study of neuronal and glial cell reactions in retinae of rats with experimental glaucoma , 2000, Experimental Brain Research.

[91]  V. Hänninen,et al.  FK506 blocks activation of the intrinsic caspase cascade after optic nerve crush. , 2005, Experimental eye research.

[92]  David J. Calkins,et al.  Microarray analysis of retinal gene expression in the DBA/2J model of glaucoma. , 2006, Investigative ophthalmology & visual science.

[93]  S M Podos,et al.  Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. , 1996, Archives of ophthalmology.

[94]  Z. Darżynkiewicz,et al.  Apoptosis in adult retinal ganglion cells after axotomy. , 1994, Journal of neurobiology.

[95]  J. Karlsson,et al.  Immunohistochemical localization of calpains and calpastatin in the rabbit eye , 1993, Brain Research.

[96]  Young H. Kwon,et al.  Primary open-angle glaucoma. , 2009, The New England journal of medicine.

[97]  D. B. Clarke,et al.  Prolonged administration of NT-4/5 fails to rescue most axotomized retinal ganglion cells in adult rats , 1998, Vision Research.

[98]  D. Dhanasekaran,et al.  JNK signaling in apoptosis , 2008, Oncogene.

[99]  L. Maffei,et al.  Long‐term Survival of Retina Optic Nerve Section in Adult Ganglion Cells Following bcl‐2 Transgenic Mice , 1996 .

[100]  John Calvin Reed,et al.  Caspase-9: involvement in secondary death of axotomized rat retinal ganglion cells in vivo. , 2000, Brain research. Molecular brain research.

[101]  J. Morrison,et al.  Does elevated intraocular pressure reduce retinal TRKB-mediated survival signaling in experimental glaucoma? , 2009, Experimental eye research.

[102]  C. Grosskreutz,et al.  Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental glaucoma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[103]  H. Yip,et al.  Expression of trkA, trkB, and trkC in injured and regenerating retinal ganglion cells of adult rats. , 2002, Investigative ophthalmology & visual science.

[104]  T. Willnow,et al.  p75NTR – live or let die , 2005, Current Opinion in Neurobiology.

[105]  J. Caprioli,et al.  Retinal ganglion cell protection with geranylgeranylacetone, a heat shock protein inducer, in a rat glaucoma model. , 2003, Investigative ophthalmology & visual science.

[106]  Xiaodong Wang,et al.  Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors , 1998, Cell.

[107]  S. Sharma,et al.  Rat retinal ganglion cells co-express brain derived neurotrophic factor (BDNF) and its receptor TrkB , 2002, Vision Research.

[108]  D. E. Goll,et al.  The calpain system. , 2003, Physiological reviews.

[109]  T. Filippopoulos,et al.  Hsp27 phosphorylation in experimental glaucoma. , 2007, Investigative ophthalmology & visual science.

[110]  S. Yonehara,et al.  Caspases Are Activated in a Branched Protease Cascade and Control Distinct Downstream Processes in Fas-induced Apoptosis , 1998, The Journal of experimental medicine.

[111]  E. Huang,et al.  Neurotrophins: roles in neuronal development and function. , 2001, Annual review of neuroscience.

[112]  Yan Li,et al.  Susceptibility to Neurodegeneration in a Glaucoma Is Modified by Bax Gene Dosage , 2005, PLoS genetics.

[113]  J. Caprioli,et al.  Hyperthermia and hypoxia increase tolerance of retinal ganglion cells to anoxia and excitotoxicity. , 1996, Investigative ophthalmology & visual science.

[114]  R. Nixon The calpains in aging and aging-related diseases , 2003, Ageing Research Reviews.

[115]  D. Sisk,et al.  Histologic changes in the inner retina of albino rats following intravitreal injection of monosodiuml-glutamate , 2005, Graefe's Archive for Clinical and Experimental Ophthalmology.

[116]  C. Gravel,et al.  Protection of axotomized retinal ganglion cells by adenovirally delivered BDNF in vivo , 1998, The European journal of neuroscience.

[117]  D. Zack,et al.  TUNEL-positive ganglion cells in human primary open-angle glaucoma. , 1997, Archives of ophthalmology.

[118]  X. Liu,et al.  An APAF-1·Cytochrome c Multimeric Complex Is a Functional Apoptosome That Activates Procaspase-9* , 1999, The Journal of Biological Chemistry.

[119]  C. Grosskreutz,et al.  Calpain activation in experimental glaucoma. , 2010, Investigative ophthalmology & visual science.

[120]  V. Parisi,et al.  Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma , 2009, Proceedings of the National Academy of Sciences.

[121]  David J. Calkins,et al.  Interleukin-6 protects retinal ganglion cells from pressure-induced death. , 2006, Investigative ophthalmology & visual science.

[122]  A. Weber,et al.  Brain-derived neurotrophic factor reduces TrkB protein and mRNA in the normal retina and following optic nerve crush in adult rats , 2004, Brain Research.

[123]  J C Reed,et al.  Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. , 1999, Science.

[124]  Young H. Kwon,et al.  Vitreous amino acid concentrations in patients with glaucoma undergoing vitrectomy. , 2003, Archives of ophthalmology.

[125]  S. Thanos,et al.  Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo , 1993, Brain Research.

[126]  A. Harvey,et al.  AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells , 2006, Gene Therapy.

[127]  S. John,et al.  Glaucoma: Thinking in new ways—a rôle for autonomous axonal self-destruction and other compartmentalised processes? , 2005, Progress in Retinal and Eye Research.