Zusammenfassung
Bei vielen Erkrankungen, die mit einer Verschlechterung des Gesichtsfelds und des Sehvermögens einhergehen, sind die Optikusganglienzellen am stärksten gefährdet. Auch beim PCOWG wird der Krankheitsverlauf von dem Grad ihrer Beschädigung bestimmt. Aufgrund ihrer Anatomie sind sie großen metabolischen und mikrozirkulationsbedingten Belastungen unterworfen. So führt das Zusammenspiel von Hypoxie und metabolischer Belastung zur Schädigung retinaler Ganglienzellen. Hinzu kommt oxidativer Stress und eine altersabhängige Vermehrung von „Advanced glycation endproducts“. Im folgenden Beitrag werden Überlegungen zur Verzögerung des Ganglienzelltods—beispielsweise durch Neuroprotektiva—bei PCOWG angestellt. Des Weiteren könnten Wirkstoffe, die den Kalziuminflux in die Zelle reduzieren, den Zelluntergang verhindern. Ebenso könnten Antagonisten des NMDA-Rezeptors wirken, hierbei sind allerdings erhebliche Nebenwirkungen zu befürchten. Auch Antioxidanzien wird bei der Bekämpfung des PCOWG in Form der Verhinderung der Apoptose eine theoretische Bedeutung zugesprochen. Letztlich sollte das ideale Glaukommedikament gut per os verträglich sein, den Untergang retinaler Ganglienzellen verhindern und ein geringes Nebenwirkungsprofil besitzen.
Abstract
In many diseases associated with deterioration of the visual field and eyesight, optic nerve ganglion cells are at the highest risk. The clinical course of primary chronic open-angle glaucoma (PCOAG) is also determined by the degree of damage to these cells. Due to their anatomy, they are subject to extreme stress exerted by metabolic and microcirculatory forces. The interaction between hypoxia and metabolic stress leads to damage of the retinal ganglion cells. This is compounded by oxidative stress and age-dependent increase of advanced glycation end products. The following contribution gives consideration to approaches for delaying ganglion cell death in PCOAG, e.g., with neuroprotective agents. Furthermore, agents that reduce calcium influx into the cells could prevent cell destruction. Likewise, NMDA receptor antagonists could be effective; however, considerable side effects are to be feared. Antioxidants are also attributed with theoretical impact in combating PCOAG by preventing apoptosis. Finally, the ideal glaucoma medication should be well tolerated when taken orally, prevent destruction of retinal ganglion cells, and possess a low side effect profile.
Literatur
Anderson DR (1996) Glaucoma, capillaries and pericytes. 1. Blood flow regulation. Ophthalmologica 210:257–262
Anderson DR, Davis EB (1996) Glaucoma, capillaries and pericytes. 5. Preliminary evidence that carbon dioxide relaxes pericyte contractile tone. Ophthalmologica 210:280–284
Anderson DR, Davis EB (1996) Glaucoma, capillaries and pericytes. 2. Identification and characterization of retinal pericytes in culture. Ophthalmologica 210:263–268
Brown SM, Jampol LM (1996) New concepts of regulation of retinal vessel tone. Arch Ophthalmol 114:199–204
Chakravarthy U, Gardiner TA, Anderson P, Archer DB, Trimble ER (1992) The effect of endothelin 1 on the retinal microvascular pericyte. Microvasc Res 43:241–254
Chen Q, Anderson DR (1997) Effect of CO2 on intracellular pH and contraction of retinal capillary pericytes. Invest Ophthalmol Vis Sci 38:643–651
Chidlow G, Schmidt KG, Wood JPM, Osborne NN (2002) Lipoic acid protects the retina against ischaemia/reperfusion. Neuropharmacology 43:15–25
Crosson CE, Willis JA, Potter DE (1990) Effect of the calcium antagonist, nifedipine, on ischemic retinal dysfunction. J Ocul Pharmacol 6:293–299
Crosson CE, DeBenedetto R, Gidday JM (1994) Functional evidence for retinal adenosine receptors. J Ocul Pharmacol 10:499–507
Danser AH, Derkx FH, Admiraal PJ, Deinum J, de Jong PT, Schalekamp MA (1994) Angiotensin levels in the eye. Invest Ophthalmol Vis Sci 35:1008–1018
Dawson TM, Dawson VL (1996) Nitric oxide synthase: role as a transmitter/mediator in the brain and endocrine system. Annu Rev Med 47:219–227
Dodge AB, Hechtman HB, Shepro D (1991) Microvascular endothelial-derived autacoids regulate pericyte contractility. Cell Motil Cytoskeleton 8:18880–18915
Dreyer EB, Zurakowski D, Schumer RA, Podos SM, Lipton SA (1996) Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol 114:299–305
Funk R (1986) Studies on the functional morphology of rat ocular vessels with scanning electron microscopy. Acta Anat 125:252–257
Funk RH (1997) Blood supply of the retina. Ophthalmic Res 29:320–325
Funk R, Rohen JW (1985) Comparative morphological studies on blood vessels in eyes of normotensive and spontaneously hypertensive rats. Exp Eye Res 40:191–203
Funk RH, Nagel F, Wonka F, Krinke HE, Golfert F, Hofer A (1999) Effects of heat shock on the functional morphology of cell organelles observed by video-enhanced microscopy. Anat Rec 255:458–464
Gasser P, Flammer J (1990) Short- and long-term effect of nifedipine on the visual field in patients with presumed vasospasm. J Int Med Res 18:334–339
Giusti P, Franceschini D, Petrone M, Manev H, Floreani M (1996) In vitro and in vivo protection against kainate-induced excitotoxicity by melatonin. J Pineal Res 20:226–231
Gupta LY, Marmor MF (1993) Mannitol, dextromethorphan, and catalase minimize ischemic damage to retinal pigment epithelium and retina. Arch Ophthalmol 111:384–388
Haefliger IO, Meyer P, Flammer J, Luscher TF (1994) The vascular endothelium as a regulator of the ocular circulation: A new concept in ophthalmology? Surv Ophthalmol 39:123–132
Haefliger IO, Anderson DR (1997) Oxygen modulation of guanylate cyclase-mediated retinal pericyte relaxations with 3-morpholino-sydnonimine and atrial natriuretic peptide. Invest Ophthalmol Vis Sci 38:1563–1568
Haefliger IO, Chen Q, Anderson DR (1997) Effect of oxygen on relaxation of retinal pericytes by sodium nitroprusside. Graefes Arch Clin Exp Ophthalmol 235:388–392
Hayashi H, Miyata H, Noda N, Kobayashi A, Hirano M, Kawai T, Yamazaki N (1992) Intracellular Ca2+ concentration and pHi during metabolic inhibition. Am J Physiol 262:628–634
Hernandez MR, Pena JD, Selvidge JA, Salvador-Silva M, Yang P (2000) Hydrostatic pressure stimulates synthesis of elastin in cultured optic nerve head astrocytes. Glia 32:122–136
Hessemer V, Schmidt KG (1997) Influence of the vasodilator drug isosorbide dinitrate on ocular circulation. Arch Ophthalmol 115:324–327
Hofer A, Nagel F, Wonka F, Krinke H, Gölfert F, Funk R (1999) A new perfusable microchamber system for determination of cellular stress effects using video-enhanced microscopy during and after heat shock. Med Biol Eng Comput 37:667–669
Jacobson MD (1996) Reactive oxygen species and programmed cell death. Trends Biochem Sci 21:83–86
Kitazawa Y, Shirai H, Go FJ (1989) The effect of Ca2(+)-antagonist on visual field in low-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 227:408–412
Klingmüller V, Schmidt KG, v Rückmann A, Gumbrecht S, Stein A, Koch B (2000) Farb- und Spektral-Doppler-sonographische Perfusionsmessungen in den kurzen hinteren Ziliararterien bei gesunden Probanden. In: Schmidt KG, Pillunat LE (Hrsg) Fortbildung Glaukom, Bd 3. Enke, Stuttgart, S 29–38
Koch T, Funk RH (2001) Cellular dysfunction in the pathogenesis of organ failure. New insights from molecular and cell biology. Anaesthesist 50:742–749
Kornhuber J, Weller M (1997) Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 41:135–144
Kumagai N, Yuda K, Kadota T, Goris RC, Kishida R (1988) Substance P-like immunoreactivity in the central retinal artery of the rabbit. Exp Eye Res 46:591–596
Lam TT, Siew E, Chu R, Tso MO (1997) Ameliorative effect of MK-801 on retinal ischemia. J Ocul Pharmacol Ther 13:129–137
Levin LA, Clark JA, Johns LK (1996) Effect of lipid peroxidation inhibition on retinal ganglion cell death. Invest Ophthalmol Vis Sci 37:2744–2749
Lieberman MF, Maumenee AE, Green WR (1976) Histologic studies of the vasculature of the anterior optic nerve. Am J Ophthalmol 82:405–423
Luksch A, Polak K, Beier C et al. (2000) Effects of systemic NO synthase inhibition on choroidal and optic nerve head blood flow in healthy subjects. Invest Ophthalmol Vis Sci 41:3080–3084
Manev H, Uz T, Kharlamov A, Joo JY (1996) Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats. FASEB J 10:1546–1551
Matsugi T, Chen Q, Anderson DR (1997) Adenosine-induced relaxation of cultured bovine retinal pericytes. Invest Ophthalmol Vis Sci 38:2695–2701
Menke T, Gille G, Reber F, Janetzky B, Andler W, Funk RH, Reichmann H (2003) Coenzyme Q10 reduces the toxicity of rotenone in neuronal cultures by preserving the mitochondrial membrane potential. Biofactors 18:65–72
Mori H, Mishina M (1995) Structure and function of the NMDA receptor channel. Neuropharmacology 34:1219–1237
Morrison JC, Johnson EC, Cepurna WO, Funk RH (1999) Microvasculature of the rat optic nerve head. Invest Ophthalmol Vis Sci 40:1702–1709
Müller A, Pietri S, Villain M, Frejaville C, Bonne C, Culcas M (1997) Free radicals in rabbit retina under ocular hyperpressure and functional consequences. Exp Eye Res 64:637–643
Müller M, Albrecht S, Gölfert F et al. (1999) Localization of tissue factor in actin-filament-rich membrane areas of epithelial cells. Exp Cell Res 248:136–147
Neufeld AH, Liu B (2003) Glaucomatous optic neuropathy: when glia misbehave. Neuroscientist 9:485–495
Ophir A, Berenshtein E, Kitrossky N, Averbukh E (1994) Protection of the transiently ischemic cat retina by zinc-desferrioxamine. Invest Ophthalmol Vis Sci 35:1212–1222
Osborne NN (1999) Memantine reduces alterations to the mammalian retina, in situ, induced by ischaemia. Vis Neurosci 16:45–52
Osborne NN, DeSantis L, Bae JH et al. (1999) Topically applied betaxolol attenuates NMDA-induced toxicity to ganglion cells and the effects of ischaemia to the retina. Exp Eye Res 69:331–342
Osborne NN, Ugarte M, Chao M et al. (1999) Neuroprotection in relation to retinal ischaemia and relevance to glaucoma. Surv Ophthalmol 43 [suppl]:S102-S129
Osborne NN, Wood JPM, Chidlow G et al. (1999) Ganglion cell death in glaucoma: what do we really know? Brit J Ophthalmol 83:980–986
Osborne NN, Chidlow G, Wood JPM, Schmidt KG, Casson R, Melena J (2001) Expectations in the treatment of retinal diseases: neuroprotection. Curr Eye Res 22:321–232
Parsons CG, Gruner R, Rozental J, Millar J, Lodge D (1993) Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan). Neuropharmacology 32:1337–1350
Pillunat LE, Stodtmeister R, Willmanns I (1987) Pressure compliance of the optic nerve head in low tension glaucoma. Brit J Ophthalmol 71:181–187
Pillunat LE, Stodtmeister R, Marquardt R, Mattern A (1989) Ocular perfusion pressures in different types of glaucoma. Int Ophthalmol 13:37–42
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
Quigley HA, Sanchez RM, Dunkelberger GR, Baginski TA (1987) Chronic glaucoma selectively damages large optic nerve fibers. Invest Ophthalmol Vis Sci 28:913–920
Quigley HA, Nickells RW, Kerigan LA et al. (1995) Retinal cell ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 36:774–786
Reber F, Kasper M, Siegner A, Kniep E, Seigel G, Funk RH (2002) Alteration of the intracellular pH and apoptosis induction in a retinal cell line by the AGE-inducing agent glyoxal. Graefes Arch Clin Exp Ophthalmol 240:1022–1032
Reber F, Geffarth R, Kasper M, Reichenbach A, Schleicher ED, Siegner A, Funk RH (2003) Graded sensitiveness of the various retinal neuron populations on the glyoxal-mediated formation of advanced glycation end products and ways of protection. Graefes Arch Clin Exp Ophthalmol 241:213–225
Reber F, Gersch U, Funk RW (2003) Blockers of carbonic anhydrase can cause increase of retinal capillary diameter, decrease of extracellular and increase of intracellular pH in rat retinal organ culture. Graefes Arch Clin Exp Ophthalmol 241:140–148
Reber F, Reber U, Funk RH (2003) Intracellular changes in astrocytes and NG 108–15 neuroblastoma X glioma cells induced by advanced glycation end products. J Neural Transm 110:1103–1118
Reiter RJ (1997) Antioxidant actions of melatonin. Adv Pharmacol 38:103–117
Reiter RJ, Melchiorri D, Sewerynek E et al. (1995) A review of the evidence supporting melatonin’s role as an antioxidant. J Pineal Res 18:1–11
Sakagami K, Wu DM, Puro DG (1999) Physiology of rat retinal pericytes: modulation of ion channel activity by serum-derived molecules. J Physiol 521:637–650
Schmidt KG (1999) Antiglaukomatosa und choroidale Perfusion bei primärem und experimentell induziertem Offenwinkelglaukom. In: Schmidt KG, Pillunat LE (Hrsg) Fortbildung Glaukom, Bd 1, Perfusion und Pharmakologie. Enke, Stuttgart, S 39–50
Schmidt KG (1999) Einfluß antiglaukomatöser Substanzen auf die okuläre Perfusion. In: Pillunat LE, Böhm A, Schmidt KG (Hrsg) Fortbildung Glaukom, Bd 2. Enke, Stuttgart, S 79–99
Schmidt KG, Stegmann DY, Serle JB, Garrett DT, Camras CB, Mittag TW, Podos SM (1991) Ocular pulse amplitude (OPA) in primary open angle glaucoma, low tension glaucoma, and in ocular hypertensive patients before and after topical drug treatment. Invest Ophthalmol Vis Sci 32:943
Schmidt KG, Mittag TW, Pavlovic S, Hessemer V (1996) Influence of physical exercise and nifedipine on ocular pulse amplitude. Graefes Arch Clin Exp Ophthalmol 234:527–532
Schmidt KG, v Rückmann A, Geyer O, Mittag TW (1997) Einfluß des Nifedipins auf die okuläre Pulsamplitude bei Normaldruckglaukom. Klin Monatsbl Augenheilkd 210:355–359
Schmidt KG, v Rückmann A, Mittag TW, Hessemer V, Pillunat LE (1997) Reduced ocular pulse amplitude in low-tension glaucoma is independent of vasospasm. Eye 11:485–488
Schmidt KG, v Rückmann A, Pillunat LE (1998) Dorzolamide increases ocular pulse amplitude in high tension primary open angle glaucoma. Br J Ophthalmol 82:758–762
Schmidt KG, Klingmüller V, v Rückmann A, Koch B (2000) Retrobulbäre und chorioidale Hämodynamik bei Hochdruck- und Normaldruckglaukom. In: Schmidt KG, Pillunat LE (Hrsg) Fortbildung Glaukom, Bd 3. Enke, Stuttgart, S 103–114
Schmidt KG, Klingmüller V, Gouveia SM, Osborne NN, Pillunat LE (2003) Short posterior ciliary artery, central retinal artery, and choroidal hemodynamics in brimonidine-treated primary open-angle glaucoma patients. Am J Ophthalmol 136:1038–1048
Schmidt KG, Geyer O, Mittag TW (2004) Adenylyl and guanylyl cyclase activity in the choroid. Exp Eye Res 78:901–907
Schönfelder U, Hofer A, Paul M, Funk RH (1998) In situ observation of living pericytes in rat retinal capillaries. Microvasc Res 56:22–29
Sims DE (1991) Recent advances in pericyte biology—implications for health and disease. Can J Cardiol 7:431–443
Stitt AW, Li YM, Gardiner TA, Bucala R, Archer DB, Vlassara H (1997) Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol 150:523–531
Szabo ME, Droy Lefaix MT, Doly M, Braquet P (1992) Ischaemia- and reperfusion-induced Na+, K+, Ca2+ and Mg2+ shifts in rat retina: effects of two free radical scavengers, SOD and EGB 761. Exp Eye Res 55:39–45
Szabo ME, Droy Lefaix MT, Doly M, Braquet P (1993) Modification of ischemia/reperfusion-induced ion shifts (Na+, K+, Ca2+ and Mg2+) by free radical scavengers in the rat retina. Ophthalmic Res 25:1–9
Takahashi K, Lam TT, Edward DP, Buchi ER, Tso MO (1992) Protective effects of flunarizine on ischemic injury in the rat retina. Arch Ophthalmol 110:862–870
Toda N, Kitamura Y, Okamura T (1995) Functional role of nerve-derived nitric oxide in isolated dog ophthalmic arteries. Invest Ophthalmol Vis Sci 36:563–570
Urena J, Fernandez-Chacon R, Benot AR, Alvarez de Toledo GA, Lopez-Barneo J (1994) Hypoxia induces voltage-dependent Ca2+ entry and quantal dopamine secretion in carotid body glomus cells. Proc Natl Acad Sci U S A 91:10208–10211
Uz T, Giusti P, Franceschini D, Kharlamov A, Manev H (1996) Protective effect of melatonin against hippocampal DNA damage induced by intraperitoneal administration of kainate to rats. Neuroscience 73:631–636
Veriac S, Tissie G, Bonne C (1993) Oxygen free radicals adversely affect the regulation of vascular tone by nitric oxide in the rabbit retina under high intraocular pressure. Exp Eye Res 56:85–88
Wang L, Dong J, Cull G, Fortune B, Cioffi GA (2003) Varicosities of intraretinal ganglion cell axons in human and nonhuman primates. Invest Ophthalmol Vis Sci 44:2–9
Winter M, Eberhardt W, Scholz C, Reichenbach A (2000) Failure of potassium siphoning by Müller cells: a new hypothesis of perfluorocarbon liquid-induced retinopathy. Invest Ophthalmol Vis Sci 41:256–261
Wood JPM, Schmidt KG, Melena J, Chidlow G, Allmeier H, Osborne NN (2003) The β-adrenoceptor antagonists metipranolol and timolol are retinal neuroprotectants: comparison with betaxolol. Exp Eye Res 76:505–516
Yamamoto T, Kitazawa Y (1998) Vascular pathogenesis of normal-tension glaucoma: a possible pathogenic factor, other than intraocular pressure, of glaucomatous optic neuropathy. Prog Ret Eye Res 17:127–143
Ye XD, Laties AM, Stone RA (1990) Peptidergic innervation of the retinal vasculature and optic nerve head. Invest Ophthalmol Vis Sci 31:1731–1737
Yoon YH, Marmor MF (1989) Dextromethorphan protects retina against ischemic injury in vivo. Arch Ophthalmol 107:409–411
Interessenkonflikt:
Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Funk, R.H.W., Schmidt, KG. Besonderheiten der Optikusganglienzellen und Ansätze zur Neuroprotektion. Ophthalmologe 101, 1062–1070 (2004). https://doi.org/10.1007/s00347-004-1116-z
Issue Date:
DOI: https://doi.org/10.1007/s00347-004-1116-z
Schlüsselwörter
- Primär chronisches Offenwinkelglaukom
- Optikusganglienzellen
- Advanced glycation endproducts
- Ganglienzelluntergang
- NMDA-Rezeptor
- Kalziumkanalblocker