RSS-Feed abonnieren
DOI: 10.1055/a-1079-5778
Aktuelle Forschungsbemühungen zur Neuroprotektion, Verlauf und Behandlung eines Glaukoms
Recent Research Efforts to Achieve Neuroprotection, Progression and Treatment of GlaucomaPublikationsverlauf
eingereicht 27. September 2019
akzeptiert 11. November 2019
Publikationsdatum:
10. Februar 2020 (online)
![](https://www.thieme-connect.de/media/klimo/202002/lookinside/thumbnails/10-1055-a-1079-5778_kl2109-1.jpg)
Zusammenfassung
Das Glaukom ist eine neurodegenerative Erkrankung, die mit der Zeit zu irreversibler Erblindung führt. Als bestimmendes Merkmal hier gilt der Verlust von retinalen Ganglienzellen (RGZ) im Auge und ihrer Axone im Sehnerv. Ein erhöhter Augeninnendruck (intraokularer Druck, IOD) gilt als Hauptrisikofaktor für die Entstehung eines Glaukoms, jedoch zeigt sich, dass dieser weder notwendig noch ausreichend für die Entstehung und das Fortschreiten der Erkrankung ist. Dies hat die Forschung und Entwicklung neuer Strategien zur Erkennung und Behandlung von Glaukomen mit dem Schwerpunkt auf Neuroprotektion – dem Schutz von RGZs vor dem Sterben – motiviert. Zusätzlich ist es im Bereich der Diagnose und Behandlung durch eine Reduktion des IOD in den letzten Jahren zur Entwicklung neuer Herangehensweisen gekommen. Dieser Artikel gibt einen Überblick über die zurzeit gängigen Theorien der pathophysiologischen Mechanismen, die einer Entstehung eines Glaukoms zugrunde liegen, sowie neuester Forschungsbemühungen mit Fokus auf Neuroprotektion und aktueller präklinischer und klinischer Studien, um eine Diagnose und Therapie des Glaukoms zu verbessern.
Abstract
Glaucoma is a neurodegenerative disease that leads to irreversible blindness over time. Its defining feature is the loss of retinal ganglion cells (RGCs) in the eye and their axons in the optic nerve. Increased intraocular pressure (IOP) is a major risk factor for the development of glaucoma, but is neither necessary nor sufficient for the disease and its progression; this motivates research and development of new strategies for the detection and treatment of glaucoma that focus on neuroprotection – protection of RGCs from dying. In addition, for diagnosis and treatment by reducing IOP, new approaches have been developed in recent years. This article reviews current theories of pathophysiological mechanisms underlying glaucoma and recent research – with a focus on neuroprotection and current preclinical and clinical studies to improve the diagnosis and treatment of glaucoma.
-
Literatur
- 1 Tham YC, Li X, Wong TY. et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 2014; 121: 2081-2090
- 2 Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006; 90: 262-267
- 3 Kapetanakis VV, Chan MP, Foster PJ. et al. Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Br J Ophthalmol 2016; 100: 86-93
- 4 Sommer A, Tielsch JM, Katz J. et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 1991; 109: 1090-1095
- 5 Tamm ER, Braunger BM, Fuchshofer R. Intraocular Pressure and the Mechanisms Involved in Resistance of the Aqueous Humor Flow in the Trabecular Meshwork Outflow Pathways. Prog Mol Biol Transl Sci 2015; 134: 301-314
- 6 Kass MA, Heuer DK, Higginbotham EJ. 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
- 7 Tezel G, Hernandez MR, Wax MB. In vitro evaluation of reactive astrocyte migration, a component of tissue remodeling in glaucomatous optic nerve head. Glia 2001; 34: 178-189
- 8 Quigley HA, Addicks EM. Regional differences in the structure of the lamina cribrosa and their relation to glaucomatous optic nerve damage. Arch Ophthalmol 1981; 99: 137-143
- 9 Salinas-Navarro M, Alarcon-Martınez L, Valiente-Soriano FJ. et al. Ocular hypertension impairs optic nerve axonal transport leading to progressive retinal ganglion cell degeneration. Exp Eye Res 2010; 90: 168-183
- 10 Hernandez MR. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res 2000; 19: 297-321
- 11 Dai C, Khaw PT, Yin ZQ. et al. Structural basis of glaucoma: the fortified astrocytes of the optic nerve head are the target of raised intraocular pressure. Glia 2012; 60: 13-28
- 12 Li Y, Li D, Ying X. et al. An energy theory of glaucoma. Glia 2015; 63: 1537-1552
- 13 Lakk M, Young D, Baumann JM. et al. Polymodal TRPV1 and TRPV4 sensors colocalize but do not functionally interact in a subpopulation of mouse retinal ganglion cells. Front Cell Neurosci 2018; 12: 353
- 14 Križaj D, Ryskamp DA, Tian N. et al. From mechanosensitivity to inflammatory responses: new players in the pathology of glaucoma. Curr Eye Res 2014; 39: 105-119
- 15 Ryskamp DA, Witkovsky P, Barabas P. et al. The polymodal ion channel transient receptor potential vanilloid 4 modulates calcium flux, spiking rate, and apoptosis of mouse retinal ganglion cells. J Neurosci 2011; 31: 7089-7101
- 16 Osuagwu UL, Alanazi SA. Eye rubbing-induced changes in intraocular pressure and corneal thickness measured at five locations, in subjects with ocular allergy. Int J Ophthalmol 2015; 8: 81-88
- 17 Turner DC, Girkin CA, Downs JC. The Magnitude of Intraocular Pressure Elevation Associated with Eye Rubbing. Ophthalmology 2019; 126: 171-172
- 18 Anderson DR. Collaborative normal tension glaucoma study. Curr Opin Ophthalmol 2003; 14: 86-90
- 19 Almasieh M, Wilson AM, Morquette B. et al. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 2012; 31: 152-181
- 20 Yu S, Tanabe T, Yoshimura N. A rat model of glaucoma induced by episcleral vein ligation. Exp Eye Res 2006; 83: 758-770
- 21 Pease ME, Zack DJ, Berlinicke CA. et al. Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci 2009; 50: 2194-2200
- 22 Shpak AA, Guekht AB, Druzhkova TA. et al. Ciliary neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract. Mol Vis 2017; 23: 799-809
- 23 Hashimoto K, Parker A, Malone P. et al. Long-term activation of c-Fos and c-Jun in optic nerve head astrocytes in experimental ocular hypertension in monkeys and after exposure to elevated pressure in vitro. Brain Res 2005; 1054: 103-115
- 24 Levkovitch-Verbin H, Quigley HA, Martin KR. et al. The transcription factor c-jun is activated in retinal ganglion cells in experimental rat glaucoma. Exp Eye Res 2005; 80: 663-670
- 25 Sun H, Wang Y, Pang IH. et al. Protective effect of a JNK inhibitor against retinal ganglion cell loss induced by acute moderate ocular hypertension. Mol Vis 2011; 17: 864-875
- 26 Fernandes KA, Harder JM, John SW. et al. DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury. Neurobiol Dis 2014; 69: 108-116
- 27 Shekhar K, Lapan SW, Whitney IE. et al. Comprehensive Classification of Retinal Bipolar Neurons by Single-Cell Transcriptomics. Cell 2016; 166: 1308-1323
- 28 Peng YR, Shekhar K, Yan W. et al. Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina. Cell 2019; 176: 1222-1237
- 29 Lukowski SW, Lo CY, Sharov A. et al. Generation of human neural retina transcriptome atlas by single cell RNA sequencing. Im Internet: https://www.biorxiv.org/content/10.1101/425223v1 Stand: 02.01.2020
- 30 Tran NM, Shekhar K, Whitney IE. et al. Single-cell profiles of retinal ganglion cells differing in resilience to injury reveal neuroprotective genes. Neuron 2019; 104: 1039-1055.e12
- 31 Bill A, Phillips CI. Uveoscleral drainage of aqueous humour in human eyes. Exp Eye Res 1971; 12: 275-281
- 32 Overby DR, Zhou EH, Vargas-Pinto R. et al. Altered mechanobiology of Schlemmʼs canal endothelial cells in glaucoma. Proc Natl Acad Sci U S A 2014; 111: 13876-13881
- 33 Overby DR, Gong H, Qui G. et al. The mechanism of increasing outflow facility during washout in the bovine eye. Invest Ophthalmol Vis Sci 2002; 43: 3455-3464
- 34 Tanna AP, Rademaker AW, Stewart WC. et al. Meta-analysis of the efficacy and safety of alpha2-adrenergic agonists, beta-adrenergic antagonists, and topical carbonic anhydrase inhibitors with prostaglandin analogs. Arch Ophthalmol 2010; 128: 825-833
- 35 Lewis RA, Levy B, Ramirez N. et al. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br J Ophthalmol 2016; 100: 339-344
- 36 Rao PV, Deng PF, Kumar J. et al. Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest Ophthalmol Vis Sci 2001; 42: 1029-1037
- 37 Tanna AP, Johnson M. Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension. Ophthalmology 2018; 125: 1741-1756
- 38 Amano M, Nakayama M, Kaibuchi K. Rho-Kinase/ROCK: A Key Regulator of the Cytoskeleton and Cell Polarity. Cytoskeleton (Hoboken) 2010; 67: 545-554
- 39 Mueller BK, Mack H, Teusch N. Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 2005; 4: 387-398
- 40 Aliancy J, Stamer WD, Wirostko B. A Review of Nitric Oxide for the Treatment of Glaucomatous Disease. Ophthalmol Ther 2017; 6: 221-232
- 41 Chang J, Stamer WD, Bertrand J. et al. Role of nitric oxide in murine conventional outflow physiology. Am J Physiol Cell Physiol 2015; 309: C205-C214
- 42 Doganay S, Evereklioglu C, Turkoz Y. et al. Decreased nitric oxide production in primary open-angle glaucoma. Eur J Ophthalmol 2002; 12: 44-48
- 43 Medeiros F, Martin KR, Peace J. et al. Comparison of latanoprostene bunod 0.024 % and timolol maleate 0.5 % in open-angle glaucoma or ocular hypertension: the LUNAR study. Am J Ophthalmol 2016; 168: 250-259
- 44 Cong L, Ran FA, Cox D. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013; 339: 819-823
- 45 Tamm ER. Myocilin and glaucoma: facts and ideas. Prog Retin Eye Res 2002; 21: 395-428
- 46 Jain A, Zode G, Kasetti RB. et al. CRISPR-Cas9-based treatment of myocilin-associated glaucoma. Proc Natl Acad Sci U S A 2017; 114: 11199-11204