Bedeutung des nukleären Faktors kappaB für das primäre Offenwinkelglaukom – eine Hypothese

Zusammenfassung

Das primäre Offenwinkelglaukom (POWG) ist eine multifaktoriell bedingte Optikusneuropathie, die durch viele verschiedene Risikofaktoren begünstigt wird. Einige der Risikofaktoren wirken sich auf den Transkriptionsfaktor NF-κB aus, ein Kernprotein, das an spezifische DNS-Abschnitte bindet und zahlreiche Gene beeinflussen kann. Durch einen erhöhten Augeninnendruck, ein erhöhtes Lebensalter, vaskuläre Störungen und durch einen erhöhten oxidativen Streß kann NF-κB aktiviert werden. Denkbar ist eine Überstimulation von NF-κB beim POWG mit der Folge zahlreicher biochemischer Entgleisungen. Durch Augendrucksenkung, aber auch durch die Therapie mit Statinen, omega-3-Fettsäuren sowie mit α-Liponsäure kann NF-κB gehemmt und somit positiv auf das POWG Einfluss genommen werden. Dieses Modell ist eine Hypothese und möchte als Grundlage für Diskussionen dienen.

Abstract

The primary open-angle glaucoma (POAG) is an optic neuropathy which is influenced by a number of different risk factors. Some of them can induce the transcriptional factor NF-κB, a nuclear protein which binds to specific areas of the DNA to stimulate different genes. NF-κB can be activated by increased intraocular pressure, increased age, vascular diseases and by oxidative stress. In the case of POAG NF-κB might be overstimulated with the induction of uncontrolled biochemical reactions. Treatment strategies for reducing NF-κB are to reduce intraocular pressure as well as therapies with statins, omega-3-fatty acids and α-lipoic acid. This model is a hypothesis and is intende to provide a basis for further discussions and basic research.

Schlüsselwörter

NF-κB - Glaukom - oxidativer Stress - Endothelin-1

Key words

NF-κB - glaucoma - oxidative stress - endothelin-1

Literatur

• 1 Leske M C, Heijl A, Hyman L. et al . Predictors of long-term progression in the early manifest glaucoma trial.  Ophthalmology. 2007;  114 1965-1972
• 2 Sultan M B, Mansberger S L, Lee P P. Understanding the importance of IOP variables in glaucoma: a systematic review.  Surv Ophthalmol. 2009;  54 643-662
• 3 Sergi M, Salerno D E, Rizzi M. et al . Prevalence of normal tension glaucoma in obstructive sleep apnea syndrome patients.  J Glaucoma. 2007;  16 42-46
• 4 Kargi S H, Altin R, Koksai M. et al . Retinal nerve fibre layer measurements are reduced in patients with obstructive sleep apnoea syndrome.  Eye. 2005;  19 575-579
• 5 Tsang C S, Chong S L, Ho C K. et al . Moderate to severe obstructive sleep apnoea patients is associated with a higher incidence of visual field defect.  Eye. 2006;  20 38-42
• 6 Gallardo M J, Aggarwal N, Cavanagh H D. et al . Progression of glaucoma associated with the Sirsasana (headstand) yoga posture.  Adv Ther. 2006;  23 921-925
• 7 Schuman J S, Massicotte E C, Connolly S. et al . Increased intraocular pressure and visual field defects in high resistance wind instrument players.  Ophthalmology. 2000;  107 127-133
• 8 Aydin P, Oram O, Akman A. et al . Effect of wind instrument playing on intraocular pressure.  J Glaucoma. 2000;  9 322-324
• 9 Flammer J, Orgül S, Costa V P. et al . The impact of ocular blood flow in glaucoma.  Prog Retin Eye Res. 2002;  21 359-393
• 10 Grieshaber M C, Mozaffarieh M, Flammer J. What is the link between vascular dysregulation and glaucoma?.  Surv Ophthalmol. 2007;  52 S144-S154
• 11 Chauhan B C, Mikelberg F S, Balaszi A G. et al . Canadian Glaucoma Study: 2. risk factors for the progression of open-angle glaucoma.  Arch Ophthalmol. 2008;  126 1030-1036
• 12 Grus F H, Joachim S C, Hoffmann E M. et al . Complex autoantibody repertoires in patients with glaucoma.  Molecular Vision. 2004;  10 132-137
• 13 Abu-Amero K K, Morales J, Bosley T M. Mitochondrial abnormalities in patients with primary open-angle glaucoma.  Invest Ophthalmol Vis Sci. 2006;  47 2533-2541
• 14 Sen R, Baltimore D. Inducibility of the immunglobulin enhancer-binding protein NF-κB by a posttranslational mechanism.  Cell. 1986;  47 921-928
• 15 Ghosh S, May M J, Kopp E B. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses.  Annu Rev Immunol. 1998;  16 225-260
• 16 Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B.  Annu Rev Cell Biol. 1994;  10 405-455
• 17 DiDonato J, Mercurio F, Rosette C. et al . Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation.  Mol Cell Biol. 1996;  16 1295-1304
• 18 Baeuerle P A, Baltimore D. NF-κB: a specific inhibitor of the NF-&kappaB transcription factor.  Science. 1988;  242 540-546
• 19 Zhong H, Voll R E, Ghosh S. Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300.  Mol Cell. 1998;  1 661-671
• 20 Rothwarf D M, Karin M. The NF-κB-Activation Pathway: A paradigm in information transfer from membrane to nucleus.  Science. 1999;  5 RE1
• 21 Senftleben U, Cao Y, Xiao G. et al . Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway.  Science. 2001;  293 1495-1499
• 22 Sun Z, Anderson R. NF-kB activation and inhibition: a review.  Shock. 2002;  18 99-106
• 23 Keates S, Hitti Y S, Upton M. et al . Helicobacter pylori infection activates NF-κB in gastric epithelial cells.  Gastroenterology. 1997;  113 1099-1109
• 24 Münzenmaier A, Lange C, Glocker E. et al . A secreted/shed product of Helicobacter pylori activates transcription factor nuclear factor-κB.  J Immunology. 1997;  159 6140-6147
• 25 Trede N S, Castigli E, Geha R S. et al . Microbial superantigens induce NF-κB in the human monocytic cell line THP-1.  J Immunology. 1993;  150 5604-5613
• 26 Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-κB.  Annu Rev Cell Biol. 1994;  10 405-455
• 27 Baeuerle P A, Henkel T. Function and activation of NF-κB in the immune system.  Annu Rev Immunol. 1994;  12 141-179
• 28 Malek R, Borowicz K K, Jargiello M. et al . Role of nuclear factor κB in the central nervous system.  Pharmacological Reports. 2007;  59 25-33
• 29 Kass M A, Heuer D K, Higginbotham E J. et al . The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma.  Arch Ophthalmol. 2002;  120 701-713
• 30 Weinreb R N, Friedman D S, Fechtner R D. et al . Risk assessment in the managemnet of patients with ocular hypertension.  Am J Ophthalmol. 2004;  138 458-467
• 31 Sappington R M, Calkins D J. Pressure-induced regulation of Il-6 in retinal glial cells: Involvement of the Ubiquitin/Proteasome pathway and NF-κB.  Invest Ophthalmol Vis Sci. 2006;  47 3860-3869
• 32 Sappington R M, Calkins D J. Contribution of TRPV1 to mikroglia-derived Il-6 and NF-κB translocation with elevated hydrostatic pressure.  Invest Ophthalmol Vis Sci. 2008;  49 3004-3017
• 33 Agapova O A, Kaufman P L, Hernandez M R. Androgen receptor and NF-κB expression in human normal and glaucomatous optic nerve head astrocytes in vitro and in experimental glaucoma.  Exp Eye Res. 2006;  82 1053-1059
• 34 Zhou L, Li Y, Yue B Y. Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue: the trabecular meshwork.  J Cell Physiol. 1999;  180 182-189
• 35 Wang N, Chintala S K, Fini M E. et al . Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype.  Nature Medicine. 2001;  7 304-309
• 36 Zhou X, Li F, Kong L. et al . Involvement of inflammation, degradation, and apoptosis in a mouse model of glaucoma.  J Biol Chemistry. 2005;  280 31 240-31 248
• 37 Lan Y Q, Zhang C, Xiao J H. et al . Suppression of I κBα increases the expression of matrix metalloproteinase-2 in human ciliary muscle cells.  Molecular Vision. 2009;  15 1977-1987
• 38 Wang J J, Mitchell P, Smith W. Is there an association between migraine headache and open-angle glaucoma? Findings from the Blue Mountains Eye Study.  Ophthalmology. 1997;  104 1714-1719
• 39 Kriete A, Mayo K L. Atypical pathways of NF-kappaB activation and aging.  Exp Gerontol. 2009;  44 250-255
• 40 Ungvari Z, Orosz Z, Labinskyy N. et al . Increased mitochondrial H₂O₂ production promotes endothelial NF-kappaB activation in aged rat arteries.  Am J Physiol Heart Circ Physiol. 2007;  293 H37-47
• 41 Csiszar A, Wang M, Lakatta E G. et al . Inflammation and endothelial dysfunction during aging:role of NF-kappaB.  J Appl Physiol. 2008;  105 1333-1341
• 42 Schleicher E, Friess U. Oxidative stress, AGE, and atherosclerosis.  Kidney Int Suppl. 2007;  106 S17-26
• 43 Büchi E R, Schiller P, Felice M. et al . Common histopathological changes in aged human orbital arteries.  Int Ophthalmol. 1993;  17 37-42
• 44 Hayreh S S. The role of age and cardiovascular disease in glaucomatous optic neuropathy.  Surv Ophthalmol. 1999;  43 (Suppl 1) S27-S42
• 45 Graham S L, Drance S M. Nocturnal Hypotension: Role in glaucoma progression.  Surv Ophthalmol. 1999;  43 (Suppl 1) S10-S16
• 46 Osborne N N, Ugarte M, Chidlow G. et al . Neuroprotection in relation to retinal ischemia and relevance to glaucoma.  Surv Ophthalmol. 1999;  43 (Suppl 1) S102-S128
• 47 Taylor C T. Interdependent roles for hypoxia inducible factor and nuclear factor-κB in hypoxic inflammation.  J Physiol. 2008;  586 4055-4059
• 48 Cummins E P, Comerford K M, Scholz C. et al . Hypoxic regulation of NF-kappaB signaling.  Methods Enzymol. 2007;  435 479-492
• 49 Nanduri J, Yuan G, Kumar G K. et al . Trancriptional responses to intermittent hypoxia.  Respir Physiol Neurobiol. 2008;  164 277-281
• 50 Tezel G, Wax M B. Hypoxia-inducible factor 1 alpha in the glaucomatous retina and optic nerve head.  Arch Ophthalmol. 2004;  122 1348-1356
• 51 Ohkita M, Takaoka M, Matsumura Y. Endothelin-1 production and its involvement in cardiovascular diseases.  Yakugaku Zasshi. 2007;  127 1319-1329
• 52 Takaoka M, Ohkita M, Matsumura Y. Pathophysiological role of proteasome-dependent proteolytic pathway in endothelin-1-related cardiovascular disease.  Curr Vasc Pharmacol. 2003;  1 19-26
• 53 Chauhan B C. Endothelin and its potential role in glaucoma.  Can J Ophthalmol. 2008;  43 356-360
• 54 Orgül S, Cioffi G A, Wilson D J. et al . An endothelin-1 induced model of optic nerve ischemia in the rabbit.  Invest Ophthalmol Vis Sci. 1996;  37 1860-1869
• 55 Kim T W, Kim D M, Park K H. et al . Neuroprotective effect of memantine in a rabbit model of optic nerve ischemia.  Korean J Ophthalmol. 2002;  16 1-7
• 56 Phillips L, Toledo A H, Lopez-Neblina F. et al . Nitric oxide mechanism of protection in ischemia and reperfusion injury.  J Invest Surg. 2009;  22 46-55
• 57 Wiederholt M, Sturm A, Lepple-Wienhues A. Relaxation of trabecular meshwork and ciliary muscle by release of nitric oxide.  Invest Ophthalmol Vis Sci. 1994;  35 2515-2520
• 58 Nathanson J A, McKee M. Alterations of ocular nitric oxide synthase in human glaucoma.  Invest Ophthalmol Vis Sci. 1995;  36 1774-1784
• 59 Neufeld A H, Hernandez M R, Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head.  Arch Ophthalmol. 1997;  115 497-503
• 60 Crow J P, Beckman J S. Reactions between nitric oxide, superoxide, abd peroxynitrite: footprints of peroxynitrite in vivo.  Adv Pharmacol. 1995;  34 17-43
• 61 Hattori Y, Kasai K, Gross S S. NO suppresses while peroxynitrite sustains NF-κB: a paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.  Cardiovascular Research. 2004;  63 31-40
• 62 Franco-Bourland R E, Guizar-Sahagun G, Garcia G A. et al . Retinal vulnerability to glutamate excitotoxicity in canine glaucoma: induction of neuronal nitric oxide synthase in retinal ganglion cells.  Proc West Pharmacol Soc. 1998;  41 201-204
• 63 Kremmer S, Kreuzfelder E, Klein R. et al . Antiphosphatidylserine antibodies are elevated in normal tension glaucoma.  Clin Exp Immunol. 2001;  125 211-215
• 64 Dunoyer-Geindre S, Moerloose de P, Galve-Rochemonteix de B. et al . NFkappaB is an essential intermediate in the activation of endothelial cells by anti-beta(2)-glycoprotein 1 antibodies.  Thromb Haemost. 2002;  88 851-857
• 65 Meroni P L, Raschi E, Testoni C. et al . Endothelial cell activation by antiphospholipid antibodies.  Clin Immunol. 2004;  112 169-174
• 66 Sies H. Oxidative stress: oxidants and antioxidans. London; Academic Press 1991
• 67 Jones D P. Disruption of mitochondrial redox circuitry in oxidative stress.  Chem Biol Interact. 2006;  163 38-53
• 68 Ferreira S M, Lerner S F, Brunzini R. et al . Oxidative stress markers in aqueous humour of glaucoma patients.  Am J Ophthalmol. 2004;  137 62-69
• 69 Aleksidze A T, Beradze I N, Golovachev O G. Effect of the ascorbic acid of the aqueous humor on the lipid peroxidation process in the eye in primary open-angle glaucoma.  Oftalmol Zh. 1989;  2 114-116
• 70 Bunin A I, Filina A A, Erichev V P. A glutathione deficiency in open-angle glaucoma and the approaches to its correction.  Vestn Oftalmol. 1992;  108 13-15
• 71 Erb C. Oxidativer Stress beim primären Offenwinkelglaukom. Erb C Oxidativer Stress beim Glaukom Amsterdam; Search on Glaukoma, Excerpta medica 2007: 44-55
• 72 Izzotti A, Bagnis A, Saccà S C. The role of oxidative stress in glaucoma.  Mutation Research. 2006;  612 105-114
• 73 Mozaffarieh M, Grieshaber M C, Flammer J. Oxygen and blood flow: players in the pathogenesis of glaucoma.  Molecular Vision. 2008;  14 224-233
• 74 Feilchenfeld Z, Yücel Y H, Gupta N. Oxidative injury to blood vessels and glia of the pre-laminar optic nerve head in human glaucoma.  Exp Eye Res. 2008;  87 409-414
• 75 Osborne N N. Pathogenesis of ganglion „cell death” in glaucoma and neuroprotection: focus on ganglion cell axonal mitochondria.  Prog Brain Res. 2008;  173 339-352
• 76 Ohia S E, Opere C A, leDay A M. Pharmacological consequences of oxidative stress in ocular tissues.  Mutation Res. 2005;  579 22-36
• 77 Kahn M G, Giblin F J, Epstein D L. Gluthatione in calf trabecular meshwork and its relation to aqueous humor outflow facility.  Invest Ophthalmol Vis Sci. 1983;  24 1283-1287
• 78 Zhou L, Li Y, Yue B Y. Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue: the trabecular meshwork.  J Cell Physiol. 1999;  180 182-189
• 79 Li G, Luna C, Liton P B. et al . Sustained stress response after oxidative stress in trabecular meshwork cells.  Molecular Vision. 2007;  13 2282-2288
• 80 Izzotti A, Sacca S C, Cartiglia C. et al . Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients.  Am J Med. 2003;  114 638-646
• 81 Sacca S C, Pascotto A, Camicione P. et al . Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma.  Arch Ophthalmol. 2005;  123 458-463
• 82 Karin M. How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex.  Oncogene. 1999;  18 6867-6874
• 83 Moreno M C, Campanelli J, Sande P. et al . Retinal oxidative stress induced by high intraocular pressure.  Free Radic Biol Med. 2004;  37 803-812
• 84 Liu B, Neufeld B. Nitric oxide synthase-2 in human optic nerve head astrocytes induced by elevated pressure in vitro.  Arch Ophthalmol. 2001;  119 240-245
• 85 De la Fuente M. Role of neuroimmunomodulation in aging.  Neuroimmunomodulation. 2008;  15 213-223
• 86 Csiszar A, Wang M, Lakatta E G. et al . Inflammation and endothelial dysfunction during aging: role of NF-kappaB.  J Appl Physiol. 2008;  105 1333-1341
• 87 Selmi C, Montano N, Furlan R. et al . Inflammation and oxidative stress in obstructive sleep apnea syndrome.  Exp Biol Med. 2007;  232 1409-1413
• 88 Frei B, Forte T M, Ames B N. et al . Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properities in human blood plasma. Protective effects of ascorbic acid.  Biochem J. 1991;  277 133-138
• 89 Bar-Shai M, Hasnis E, Wiener-Megnazi Z. et al . The role of reactive nitrogen species and cigarette smoke in activation of transcription factor NF-kappaB and implication to inflammatory processes.  J Physiol Pharmacol. 2006;  57 (Suppl 4) 39-44
• 90 Thurberg B L, Collins T. The nuclear factor kappaB/inhibitor of kappaB autoregulatory system and atherosclerosis.  Curr Opin Lipidol. 2007;  9 387-396
• 91 Hsiai T, Berliner J A. Oxidative stress as a regulator of murine atherosclerosis.  Curr Drug Targets. 2007;  8 1222-1229
• 92 Di Lisa F, Kaludercic N, Carpi A. et al . Mitochondria and vascular pathology.  Pharmacological Reports. 2009;  61 123-130
• 93 Harrison D G, Gongora M C. Oxidative stress and hypertension.  Med Clin North Am. 2009;  93 621-635
• 94 Friederich M, Hansell P, Palm F. Diabetes, oxidative stress, nitric oxide and mitochondrial function.  Curr Diabetes Rev. 2009;  5 120-144
• 95 Mariappan N, Elks C M, Sriamula S. et al . NF-kappaB-induced oxidative stress contributes to mitochondrial and cardic dysfunction in type II diabetes.  Cardiovasc Res Sep. 2009;  25 Epub ahead of print
• 96 Elks C M, Mariappan N, Haque M. et al . Chronic NF-kappaB blockade reduces cytosolic and mitochondrial oxidative stress and attenuates renal injury and hypertension in SHR.  Am J Physiol Renal Physiol. 2009;  296 F298-F305
• 97 Arend K O, Redbrake C. Vitamincocktail für Glaukom-Patienten?. Erb C Oxidativer Stress beim Glaukom Amsterdam; Search on Glaukoma, Excerpta medica 2007: 122-133
• 98 Jasinska M, Owczarek J, Orszulak-Michalak D. Statins: a new insight into their mechanisms of action and consequent pleiotropic effects.  Pharmacological Reports. 2007;  59 483-499
• 99 Sironi L, Banfi C, Brioschi. et al . Activation of NF-kB and ERK1 / 2 after permanent focal ischemia is abolished by simvastatin treatment.  Neurobiol Dis. 2006;  22 445-451
• 100 Kim Y S, Ahn Y, Hong M H. et al . Rosuvastatin suppresses the inflammatory responses through inhibition of c-Jun N-terminal kinase and nuclear factor-kappaB in endothelial cells.  J Cardiovasc Pharmacol. 2007;  49 376-383
• 101 Chauhan A, Hahn S, Gartner S. et al . Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins.  FASEB J. 2007;  21 777-789
• 102 McGwin Jr G, McNeal S, Owsley C. et al . Statins and other cholesterol-lowering medications and the presence of glaucoma.  Arch Ophthalmol. 2004;  122 822-826
• 103 De Castro D K, Punjabi O S, Bostrom A G. et al . Effect of statin drugs and aspirin on progression in open-angle glaucoma suspects using confocal scanning laser ophthalmoscopy.  Clin Experiment Ophthalmol. 2007;  35 506-513
• 104 Song J, Deng P F, Stinnett S S. et al . Effects of cholesterol-lowering statins on the aqueous humor outflow pathway.  Invest Ophthalmol Vis Sci. 2005;  46 2424-2432
• 105 Ren H, Magulike N, Ghebremeskel K. et al . Primary open-angle glaucoma patients have reduced levels of blood docosahexaenoic and eicosapentaenoic acids.  Prostaglandins Leukot Essent Fatty Acids. 2006;  74 157-163
• 106 Mancino M, Ohia E, Kulkarni P. A comparative study between cod liver oil and liquid lard intake on intraocular pressare on rabbits.  Prostaglandins Leukot Essent Fatty Acids. 1992;  45 239-243
• 107 Nguyen C T, Bui B V, Sinclair A J. et al . Dietary omega 3 fatty acids decrease intraocular pressure with age by increasing aqueous outflow.  Invest Ophthalmol Vis Sci. 2007;  48 756-762
• 108 Novak T E, Babcock T A, Jho D H. et al . NF-kB inhibition by w-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription.  Am J Physiol Lung Cell Mol Physiol. 2003;  284 L84-L89
• 109 Mishra A, Chaudhary A, Sethi S. Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway.  Arterioscler Thromb Vasc Biol. 2004;  24 1621-1627
• 110 Petersen Shay K, Moreau R F, Smith E J. et al . Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity.  IUBMB Life. 2008;  60 362-367
• 111 Filina A A, Sporova N A. Effect of lipoic acid on tyrosine metabolism in patients with open-angle glaucoma.  Vestn Oftalmol. 1991;  107 19-21
• 112 Filina A A, Davydova N G, Endrihovskij S N. et al . Lipoic acid as a means of metabolic therapy of open-angle glaucoma.  Vestn Oftalmol. 1995;  111 6-8
• 113 Voloboueva L A, Liu J, Suh J H. et al . Alpha-lipoic acid protects retinal pigment epithelial cells from oxidative damage.  Invest Ophthalmol Vis Sci. 2005;  46  4302-4310
• 114 Packer L. Alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury.  Drug Metab Rev. 1998;  30 245-275
• 115 Kim H S, Kim H J, Parl K G. et al . α-Lipoic acid inhibits matrix metalloproteinase-9 expression by inhibiting NF-kB transcriptional activity.  Exp Mol Med. 2007;  39 106-113
• 116 Lee C K, Lee E Y, Kim Y G. et al . Alpha-lipoic acid inhibits TNF-alpha induced NF-kappa B activation through blocking of MEKK1-MKK4-IKK signalling cascades.  Int Immunopharmacol. 2008;  8 362-370
• 117 Ebadi M, Sharma S K, Wanpen S. et al . Coenzyme Q 10 inhibits mitochondrial complex-1 down-regulation and nuclear factor-kappa B activation.  J Cell Mol Med. 2004;  8 213-222
• 118 Bae M K, Kim S R, Lee H J. et al . Aspirin-induced blockade of NF-kappaB activity restrains up-regulation of glial fibrillary acidic protein in human astroglial cells.  Biochem Biophys Acta. 2006;  1763 282-289
• 119 Wei Z, Peng Q, Lau B H. et al . Ginkgo biloba inhibits hydrogen peroxide-induced activation of nuclear factor kappa B in vascular endothelial cells.  Gen Pharmacol. 1999;  33 369-375
• 120 Zhu G, Wu C J, Zhao Y. et al . Optineurin negatively regulates TNF&alpha-induced NF-κB activation by competing with NEMO for ubiquitinated RIP.  Current Biology. 2007;  17 1438-1443
• 121 Chalasani M L, Swarup G, Balasubramanian D. Optineurin and its mutants: molecules associated with some forms of glaucoma.  Ophthalmic Res. 2009;  42 176-184
• 122 Erb C, Thiel H J, Flammer J. The psychology of the glaucoma patient.  Curr Opin Ophthalmol. 1998;  9 65-70
• 123 Bierhaus A, Wolf J, Andrassy M. et al . A mechanism converting psychosocial stress into mononuclear cell activation.  Proc Nat Acad Sci USA. 2003;  100 1920-1925
• 124 Madrigal J L, Hurtado O, Moro M A. et al . The increase in TNF-alpha levels is implicated in NF-kappaB activation and inducile nitric oxide synthase expression in brain cortex after immobilization stress.  Neuropsychopharmacology. 2002;  26 155-163
• 125 Lütjen-Drecoll E. Morphological changes in glaucomatous eyes and the role of TGFbeta2 for the pathogenesis of the disease.  Exp Eye Res. 2005;  81 1-4
• 126 Osborne N N, Lascaratos G, Bron A J. et al . A hypothesis to suggest that light is a risk factor in glaucoma and the mitochondrial optic neuropathies.  Br J Ophthalmol. 2006;  90 237-241
• 127 Takuma K, Baba A, Matsuda T. Astrocyte apoptosis: implications for neuroprotection.  Prog Neurobiol. 2004;  72 111-127
• 128 Ando A, Yamazaki Y, Kaneko S. et al . Cytoprotection by nipradilol, an anti-glaucomatous agent, via down-regulation of apoptosis related gene expression and activation of NF-kappaB.  Exp Eye Res. 2005;  80 501-507
• 129 Takahashi Y, Katai N, Murata T. et al . Development of spontaneous optic neuropathy in NF-κBetap50-deficient mice: requirement for NF-κBetap50 in ganglion cell survival.  Neuropathol Appl Neurobiol. 2007;  33 692-705