Primary open-angle glaucoma (POAG) is a leading cause of irreversible and preventable blindness and ocular hypertension is the strongest known risk factor. With current classes of drugs, management of the disease focuses on lowering intraocular pressure (IOP). Despite of their use to modify the course of the disease, none of the current medications for POAG is able to reduce the IOP by more than 25%–30%. Also, some glaucoma patients show disease progression despite of the therapeutics. This paper examines the new described physiological targets for reducing the IOP. The main cause of elevated IOP in POAG is thought to be an increased outflow resistance via the pressure-dependent trabecular outflow system, so there is a crescent interest in increasing trabecular meshwork outflow by extracellular matrix remodeling and/or by modulation of contractility/TM cytoskeleton disruption. Modulation of new agents that act mainly on trabecular meshwork outflow may be the future hypotensive treatment for glaucoma patients. There are also other agents in which modulation may decrease aqueous humour production or increase uveoscleral outflow by different mechanisms from those drugs available for glaucoma treatment. Recently, a role for the ghrelin-GHSR system in the pathophysiology modulation of the anterior segment, particularly regarding glaucoma, has been proposed. 1. Introduction Glaucoma is a progressive optic neuropathy caused by death of the retinal ganglion cells (RGCs) and is the leading cause of irreversible blindness worldwide. The mechanism by which this progressive RGC death occurs is not fully understood. It is clear that multiple causes may give rise to the common effect of ganglion cell death. Clinically, it is well accepted that the major risk factor for glaucoma is elevated intraocular pressure (IOP) [1, 2]. In open angle glaucoma (OAG), elevated IOP occurs from an imbalance between production and outflow of aqueous humor (AH). The mechanical theory argues the importance of direct compression of the axonal fibers and support structures of the anterior optic nerve by elevated IOP resulting in the death of the RGCs. Lowering the IOP (baroprotection) remains the only current therapeutic approach for preserving visual function in glaucoma patients. The six classes of drugs available for glaucoma treatment (miotics, beta-blockers, alfa-agonists, epinephrine derivatives, carbonic anhydrase inhibitors, and prostaglandin analogues) act by decreasing aqueous humor production and/or by improving trabecular meshwork-Schlemm’s canal or uveoscleral outflow. Better
References
[1]
A. Sommer, J. M. Tielsch, J. Katz et al., “Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore eye survey,” Archives of Ophthalmology, vol. 109, no. 8, pp. 1090–1095, 1991.
[2]
M. A. Kass, D. K. Heuer, E. J. Higginbotham 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,” Archives of Ophthalmology, vol. 120, no. 6, pp. 701–713, 2002.
[3]
R. N. Weinreb, C. B. Toris, B. T. Gabelt, J. D. Lindsey, and P. L. Kaufman, “Effects of prostaglandins on the aqueous humor outflow pathways,” Survey of Ophthalmology, vol. 47, no. 4, supplement 1, pp. S53–S64, 2002.
[4]
R. N. Weinreb and J. D. Lindsey, “Metalloproteinase gene transcription in human ciliary muscle cells with latanoprost,” Investigative Ophthalmology & Visual Science, vol. 43, no. 3, pp. 716–722, 2002.
[5]
C. B. Camras, A. H. Friedman, M. M. Rodrigues, B. J. Tripathi, R. C. Tripathi, and S. M. Podos, “Multiple dosing of prostaglandin F(2α) or epinephrine on cynomolgus monkey eyes—III. Histopathology,” Investigative Ophthalmology & Visual Science, vol. 29, no. 9, pp. 1428–1436, 1988.
[6]
P. L. Kaufman, “Pharmacologic trabeculocanalotomy: facilitating aqueous outflow by assaulting the meshwork cytoskeleton, junctional complexes, and extracellular matrix,” Archives of Ophthalmology, vol. 110, no. 1, pp. 34–36, 1992.
[7]
Y. Fukata, M. Amano, and K. Kaibuchi, “Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells,” Trends in Pharmacological Sciences, vol. 22, no. 1, pp. 32–39, 2001.
[8]
M. Honjo, H. Tanihara, M. Inatani et al., “Effects of Rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility,” Investigative Ophthalmology & Visual Science, vol. 42, no. 1, pp. 137–144, 2001.
[9]
B. Tian, B. Geiger, D. L. Epstein, and P. L. Kaufman, “Cytoskeletal involvement in the regulation of aqueous humor outflow,” Investigative Ophthalmology & Visual Science, vol. 41, no. 3, pp. 619–623, 2000.
[10]
B. Tian, L. C. Brumback, and P. L. Kaufman, “ML-7, chelerythrine and phorbol ester increase outflow facility in the monkey eye,” Experimental Eye Research, vol. 71, no. 6, pp. 551–566, 2000.
[11]
P. V. Rao, P. Deng, Y. Sasaki, and D. L. Epstein, “Regulation of myosin light chain phosphorylation in the trabecular meshwork: role in aqueous humour outflow facility,” Experimental Eye Research, vol. 80, no. 2, pp. 197–206, 2005.
[12]
H. Thieme, M. Nuskovski, J. U. Nass, U. Pleyer, O. Strauss, and M. Wiederholt, “Mediation of calcium-independent contraction in trabecular meshwork through protein kinase C and rho-A,” Investigative Ophthalmology & Visual Science, vol. 41, no. 13, pp. 4240–4246, 2000.
[13]
F. J. Munoz-Negrete, M. Pérez-López, H. R. Won Kim, and G. Rebolleda, “New developments in glaucoma medical treatment,” Archivos de la Sociedad Espa？ola de Oftalmología, vol. 84, no. 10, pp. 491–500, 2009.
[14]
M. Y. Avila, R. A. Stone, and M. M. Civan, “A1-, A2a- and A3-subtype adenosine receptors modulate intraocular pressure in the mouse,” British Journal of Pharmacology, vol. 134, no. 2, pp. 241–245, 2001.
[15]
G. Beidoe and S. A. Mousa, “Current primary open-angle glaucoma treatments and future directions,” Clinical Ophthalmology, vol. 6, pp. 1699–1707, 2012.
[16]
A. J. Lee and I. Goldberg, “Emerging drugs for ocular hypertension,” Expert Opinion on Emerging Drugs, vol. 16, no. 1, pp. 137–161, 2011.
[17]
M. D. Pinazo-Duran, V. Zanon-Moreno, J. J. Garcia-Medina, and R. Gallego-Pinazo, “Evaluation of presumptive biomarkers of oxidative stress, immune response and apoptosis in primary open-angle glaucoma,” Current Opinion in Pharmacology, vol. 13, no. 1, pp. 98–107, 2013.
[18]
J. Wierzbowska, J. Robaszkiewicz, M. Figurska, and A. Stankiewicz, “Future possibilities in glaucoma therapy,” Case Reports and Clinical Practice Review, vol. 16, no. 11, pp. RA252–RA259, 2010.
[19]
M. F. Armaly, D. E. Krueger, and L. Maunder, “Biostatistical analysis of the collaborative glaucoma study—I. Summary report of the risk factors for glaucomatous visual-field defects,” Archives of Ophthalmology, vol. 98, no. 12, pp. 2163–2171, 1980.
[20]
Y. Shiose, Y. Kitazawa, S. Tsukahara et al., “Epidemiology of glaucoma in Japan. A nationwide glaucoma survey,” Japanese Journal of Ophthalmology, vol. 35, no. 2, pp. 133–155, 1991.
[21]
M. Amano, M. Nakayama, and K. Kaibuchi, “Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity,” Cytoskeleton, vol. 67, no. 9, pp. 545–554, 2010.
[22]
C. Hahmann and T. Schroeter, “Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity,” Cellular and Molecular Life Sciences, vol. 67, no. 2, pp. 171–177, 2010.
[23]
B. Colligris, A. Crooke, F. Huete, and J. Pintor, “Potential role of Rho-associated protein kinase inhibitors for glaucoma treatment,” Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, vol. 6, no. 2, pp. 89–98, 2012.
[24]
E. Nakajima, T. Nakajima, Y. Minagawa, T. R. Shearer, and M. Azuma, “Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes,” Journal of Pharmaceutical Sciences, vol. 94, no. 4, pp. 701–708, 2005.
[25]
H. Tokushige, M. Inatani, S. Nemoto et al., “Effects of topical administration of Y-39983, a selective Rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys,” Investigative Ophthalmology & Visual Science, vol. 48, no. 7, pp. 3216–3222, 2007.
[26]
M. Zhang, R. Maddala, and P. V. Rao, “Novel molecular insights into RhoA GTPase-induced resistance to aqueous humor outflow through the trabecular meshwork,” American Journal of Physiology, vol. 295, no. 5, pp. C1057–C1070, 2008.
[27]
X. Fang, Y. T. Chen, E. H. Sessions, et al., “Synthesis and biological evaluation of 4-quinazolinones as Rho kinase inhibitors,” Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 6, pp. 1844–1848, 2011.
[28]
D. R. Anderson, S. M. Drance, and M. Schulzer, “Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures,” American Journal of Ophthalmology, vol. 126, no. 4, pp. 487–497, 1998.
[29]
K. Zhang, L. Zhang, and R. N. Weinreb, “Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma,” Nature Reviews Drug Discovery, vol. 11, no. 7, pp. 541–559, 2012.
[30]
V. P. Rao and D. L. Epstein, “Rho GTPase/Rho kinase inhibition as a novel target for the treatment of glaucoma,” BioDrugs, vol. 21, no. 3, pp. 167–177, 2007.
[31]
A. Lepple-Wienhues, F. Stahl, U. Willner, R. Schafer, and M. Wiederholt, “Endothelin-evoked contractions in bovine ciliary muscle and trabecular meshwork: interaction with calcium, nifedipine and nickel,” Current Eye Research, vol. 10, no. 10, pp. 983–989, 1991.
[32]
G. Renieri, L. Choritz, R. Rosenthal, S. Meissner, N. Pfeiffer, and H. Thieme, “Effects of endothelin-1 on calcium-independent contraction of bovine trabecular meshwork,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 8, pp. 1107–1115, 2008.
[33]
L. Choritz, M. Machert, and H. Thieme, “Correlation of endothelin-1 concentration in aqueous humor with intraocular pressure in primary open angle and pseudoexfoliation glaucoma,” Investigative Ophthalmology & Visual Science, vol. 53, no. 11, pp. 7336–7342, 2012.
[34]
M. Cellini, P. Versura, E. Zamparini, E. Bendo, and E. C. Campos, “Effects of endothelin-1 and flunarizine on human trabecular meshwork cell contraction,” Experimental Biology and Medicine, vol. 231, no. 6, pp. 1081–1084, 2006.
[35]
L. Choritz, R. Rosenthal, M. Fromm, M. H. Foerster, and H. Thieme, “Pharmacological and functional characterization of endothelin receptors in bovine trabecular meshwork and ciliary muscle,” Ophthalmic Research, vol. 37, no. 4, pp. 179–187, 2005.
[36]
M. Wiederholt, A. Sturm, and A. Lepple-Wienhues, “Relaxation of trabecular meshwork and ciliary muscle by release of nitric oxide,” Investigative Ophthalmology & Visual Science, vol. 35, no. 5, pp. 2515–2520, 1994.
[37]
M. De Caestecker, “The transforming growth factor-β superfamily of receptors,” Cytokine and Growth Factor Reviews, vol. 15, no. 1, pp. 1–11, 2004.
[38]
M. A. Prendes, “The role of transforming growth factor beta in glaucoma and the therapeutic implications,” British Journal of Ophthalmology, vol. 97, no. 6, pp. 680–686, 2013.
[39]
J. Gottanka, D. Chan, M. Eichhorn, E. Lütjen-Drecoll, and C. R. Ethier, “Effects of TGF-beta2 in perfused human eyes,” Investigative Ophthalmology & Visual Science, vol. 45, no. 1, pp. 153–158, 2004.
[40]
S. H. Min, T.-I. Lee, Y. S. Chung, and H. K. Kim, “Transforming growth factor-beta levels in human aqueous humor of glaucomatous, diabetic and uveitic eyes,” Korean Journal of Ophthalmology, vol. 20, no. 3, pp. 162–165, 2006.
[41]
R. C. Tripathi, J. Li, F. A. Chan, and B. J. Tripathi, “Aqueous humor in glaucomatous eyes contains an increased level of TGF-β2,” Experimental Eye Research, vol. 59, no. 6, pp. 723–728, 1994.
[42]
A. R. Shepard, J. Cameron Millar, I.-H. Pang, N. Jacobson, W.-H. Wang, and A. F. Clark, “Adenoviral gene transfer of active human transforming growth factor-β2 elevates intraocular pressure and reduces outflow facility in rodent eyes,” Investigative Ophthalmology & Visual Science, vol. 51, no. 4, pp. 2067–2076, 2010.
[43]
R. H. Trivedi, M. Nutaitis, D. Vroman, and C. E. Crosson, “Influence of race and age on aqueous humor levels of transforming growth factor-beta 2 in glaucomatous and nonglaucomatous eyes,” Journal of Ocular Pharmacology and Therapeutics, vol. 27, no. 5, pp. 477–480, 2011.
[44]
B. Da, Y. Cao, H. Wei, Z. Chen, Y. Shui, and Z. Li, “Antagonistic effects of tranilast on proliferation and collagen synthesis induced by TGF-β2 in cultured human trabecular meshwork cells,” Journal of Huazhong University of Science and Technology, vol. 24, no. 5, pp. 490–496, 2004.
[45]
R. J. Wordinger, D. L. Fleenor, P. E. Hellberg et al., “Effects of TGF-β2, BMP-4, and gremlin in the trabecular meshwork: implications for glaucoma,” Investigative Ophthalmology & Visual Science, vol. 48, no. 3, pp. 1191–1200, 2007.
[46]
R. Fuchshofer, U. Welge-Lussen, and E. Lütjen-Drecoll, “The effect of TGF-β2 on human trabecular meshwork extracellular proteolytic system,” Experimental Eye Research, vol. 77, no. 6, pp. 757–765, 2003.
[47]
P. B. Liton, X. Liu, P. Challa, D. L. Epstein, and P. Gonzalez, “Induction of TGF-β1 in the trabecular meshwork under cyclic mechanical stress,” Journal of Cellular Physiology, vol. 205, no. 3, pp. 364–371, 2005.
[48]
R. Fuchshofer and E. R. Tamm, “The role of TGF-β in the pathogenesis of primary open-angle glaucoma,” Cell and Tissue Research, vol. 347, no. 1, pp. 279–290, 2012.
[49]
U. Schl？tzer-Schrehardt, M. Zenkel, M. Küchle, L. Y. Sakai, and G. O. H. Naumann, “Role of transforming growth factor-β1 and its latent form binding protein in pseudoexfoliation syndrome,” Experimental Eye Research, vol. 73, no. 6, pp. 765–780, 2001.
[50]
Y. Nakamura, S. Hirano, K. Suzuki, K. Seki, T. Sagara, and T. Nishida, “Signaling mechanism of TGF-β1-induced collagen contraction mediated by bovine trabecular meshwork cells,” Investigative Ophthalmology & Visual Science, vol. 43, no. 11, pp. 3465–3472, 2002.
[51]
U. Welge-Lü？en, C. A. May, and E. Lütjen-Drecoll, “Induction of tissue transglutaminase in the trabecular meshwork by TGF- β1 and TGF-β2,” Investigative Ophthalmology & Visual Science, vol. 41, no. 8, pp. 2229–2238, 2000.
[52]
E. R. Tamm, P. Russell, D. L. Epstein, D. H. Johnson, and J. Piatigorsky, “Modulation of myocilin/TIGR expression in human trabecular meshwork,” Investigative Ophthalmology & Visual Science, vol. 40, no. 11, pp. 2577–2582, 1999.
[53]
D. D. Konz, C. Flügel-Koch, A. Ohlmann, and E. R. Tamm, “Myocilin in the trabecular meshwork of eyes with primary open-angle glaucoma,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 247, no. 12, pp. 1643–1649, 2009.
[54]
B. S. Weston, N. A. Wahab, and R. M. Mason, “CTGF mediates TGF-β-induced fibronectin matrix deposition by upregulating active α5β1 integrin in human mesangial cells,” Journal of the American Society of Nephrology, vol. 14, no. 3, pp. 601–610, 2003.
[55]
D. Kothapalli and G. R. Grotendorst, “CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts,” Journal of Cellular Physiology, vol. 182, no. 1, pp. 119–126, 2000.
[56]
M. Inatani, H. Tanihara, H. Katsuta, M. Honjo, N. Kido, and Y. Honda, “Transforming growth factor-β2 levels in aqueous humor of glaucomatous eyes,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 239, no. 2, pp. 109–113, 2001.
[57]
U. B. Kottler, A. G. M. Jünemann, T. Aigner, M. Zenkel, C. Rummelt, and U. Schl？tzer-Schrehardt, “Comparative effects of TGF-β1 and TGF-β2 on extracellular matrix production, proliferation, migration, and collagen contraction of human Tenon's capsule fibroblasts in pseudoexfoliation and primary open-angle glaucoma,” Experimental Eye Research, vol. 80, no. 1, pp. 121–134, 2005.
[58]
J. Gottanka, C. Flügel-Koch, P. Martus, D. H. Johnson, and E. Lütjen-Drecoll, “Correlation of pseudoexfoliative material and optic nerve damage in pseudoexfoliation syndrome,” Investigative Ophthalmology & Visual Science, vol. 38, no. 12, pp. 2435–2446, 1997.
[59]
J. K. G. Crean, D. Finlay, M. Murphy et al., “The role of p42/44 MAPK and protein kinase B in connective tissue growth factor induced extracellular matrix protein production, cell migration, and actin cytoskeletal rearrangement in human mesangial cells,” Journal of Biological Chemistry, vol. 277, no. 46, pp. 44187–44194, 2002.
[60]
J. K. Crean, F. Furlong, D. Finlay et al., “Connective tissue growth factor [CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization,” The FASEB Journal, vol. 18, no. 13, pp. 1541–1543, 2004.
[61]
J. K. Crean, F. Furlong, D. Mitchell, E. McArdle, C. Godson, and F. Martin, “Connective tissue growth factor/CCN2 stimulates actin disassembly through Akt/protein kinase B-mediated phosphorylation and cytoplasmic translocation of p27(Kip-1),” The FASEB Journal, vol. 20, no. 10, pp. 1712–1714, 2006.
[62]
F. Furlong, J. Crean, L. Thornton, R. O'Leary, M. Murphy, and F. Martin, “Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose,” American Journal of Physiology, vol. 292, no. 6, pp. F1691–F1700, 2007.
[63]
J. G. Browne, S. L. Ho, R. Kane, et al., “Connective tissue growth factor is increased in pseudoexfoliation glaucoma,” Investigative Ophthalmology & Visual Science, vol. 52, no. 6, pp. 3660–3666, 2011.
[64]
W. M. Grant, “Experimental aqueous perfusion in enucleated human eyes,” Archives of Ophthalmology, vol. 69, pp. 783–801, 1963.
[65]
M. Johnson, “What controls aqueous humour outflow resistance?” Experimental Eye Research, vol. 82, no. 4, pp. 545–557, 2006.
[66]
E. Lutjen-Drecoll, T. Shimizu, M. Rohrbach, and J. W. Rohen, “Quantitative analysis of “plaque material” between ciliary muscle tips in normal- and glaucomatous eyes,” Experimental Eye Research, vol. 42, no. 5, pp. 457–465, 1986.
[67]
J. W. Rohen, E. Lutjen-Drecoll, C. Flugel, M. Meyer, and I. Grierson, “Ultrastructure of the trabecular meshwork in untreated cases of primary open-angle glaucoma (POAG),” Experimental Eye Research, vol. 56, no. 6, pp. 683–692, 1993.
[68]
A. Leask and D. J. Abraham, “All in the CCN family: essential matricellular signaling modulators emerge from the bunker,” Journal of Cell Science, vol. 119, no. 23, pp. 4803–4810, 2006.
[69]
H. Yokoi, M. Mukoyama, A. Sugawara et al., “Role of connective tissue growth factor in fibronectin expression and tubulointerstitial fibrosis,” American Journal of Physiology, vol. 282, no. 5, pp. F933–F942, 2002.
[70]
U. Schl？tzer-Schrehardt, K. Von der Mark, L. Y. Sakai, and G. O. H. Naumann, “Increased extracellular deposition of fibrillin-containing fibrils in pseudoexfoliation syndrome,” Investigative Ophthalmology & Visual Science, vol. 38, no. 5, pp. 970–984, 1997.
[71]
R. Fuchshofer, M. Birke, U. Welge-Lussen, D. Kook, and E. Lütjen-Drecoll, “Transforming growth factor-β2 modulated extracellular matrix component expression in cultured human optic nerve head astrocytes,” Investigative Ophthalmology & Visual Science, vol. 46, no. 2, pp. 568–578, 2005.
[72]
R. Fuchshofer, A. H. L. Yu, U. Welge-Lüssen, and E. R. Tamm, “Bone morphogenetic protein-7 is an antagonist of transforming growth factor-β2 in human trabecular meshwork cells,” Investigative Ophthalmology & Visual Science, vol. 48, no. 2, pp. 715–726, 2007.
[73]
B. Junglas, S. Kuespert, A. A. Seleem, et al., “Connective tissue growth factor causes glaucoma by modifying the actin cytoskeleton of the trabecular meshwork,” American Journal of Pathology, vol. 180, no. 6, pp. 2386–2403, 2012.
[74]
P. Iyer, R. Maddala, P. P. Pattabiraman, and P. V. Rao, “Connective tissue growth factor-mediated upregulation of neuromedin U expression in trabecular meshwork cells and its role in homeostasis of aqueous humor outflow,” Investigative Ophthalmology & Visual Science, vol. 53, no. 8, pp. 4952–4962, 2012.
[75]
A. Lepple-Wienhues, R. Rauch, A. F. Clark, A. Grassmann, S. Berweck, and M. Wiederholt, “Electrophysiological properties of cultured human trabecular meshwork cells,” Experimental Eye Research, vol. 59, no. 3, pp. 305–311, 1994.
[76]
F. Stumpff, O. Strauss, M. Boxberger, and M. Wiederholt, “Characterization of maxi-K-channels in bovine trabecular meshwork and their activation by cyclic guanosine monophosphate,” Investigative Ophthalmology & Visual Science, vol. 38, no. 9, pp. 1883–1892, 1997.
[77]
J. A. Nathanson and M. McKee, “Identification of an extensive system of nitric oxide-producing cells in the ciliary muscle and outflow pathway of the human eye,” Investigative Ophthalmology & Visual Science, vol. 36, no. 9, pp. 1765–1773, 1995.
[78]
S. Moncada, R. M. J. Palmer, and E. A. Higgs, “Nitric oxide: physiology, pathophysiology, and pharmacology,” Pharmacological Reviews, vol. 43, no. 2, pp. 109–142, 1991.
[79]
M. T. Nelson and J. M. Quayle, “Physiological roles and properties of potassium channels in arterial smooth muscle,” American Journal of Physiology, vol. 268, no. 4, pp. C799–C822, 1995.
[80]
P. P. Pattabiraman and P. V. Rao, “Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells,” American Journal of Physiology, vol. 298, no. 3, pp. C749–C763, 2010.
[81]
F. Stumpff and M. Wiederholt, “Regulation of trabecular meshwork contractility,” Ophthalmologica, vol. 214, no. 1, pp. 33–53, 2000.
[82]
Y. Oike and M. Tabata, “Angiopoietin-like proteins—potential therapeutic targets for metabolic syndrome and cardiovascular disease,” Circulation Journal, vol. 73, no. 12, pp. 2192–2197, 2009.
[83]
I. Kim, H.-G. Kim, H. Kim et al., “Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis,” Biochemical Journal, vol. 346, no. 3, pp. 603–610, 2000.
[84]
G. Camenisch, M. T. Pisabarro, D. Sherman et al., “ANGPTL3 stimulates endothelial cell adhesion and migration via integrin αvβ3 and induces blood vessel formation in vivo,” Journal of Biological Chemistry, vol. 277, no. 19, pp. 17281–17290, 2002.
[85]
Y. Katoh and M. Katoh, “Comparative integromics on Angiopoietin family members,” International Journal of Molecular Medicine, vol. 17, no. 6, pp. 1145–1149, 2006.
[86]
Y. Oike, Y. Ito, H. Maekawa et al., “Angiopoietin-related growth factor (AGF) promotes angiogenesis,” Blood, vol. 103, no. 10, pp. 3760–3765, 2004.
[87]
T. Hato, M. Tabata, and Y. Oike, “The role of angiopoietin-like proteins in angiogenesis and metabolism,” Trends in Cardiovascular Medicine, vol. 18, no. 1, pp. 6–14, 2008.
[88]
M. Ono, T. Shimizugawa, M. Shimamura et al., “Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo,” Journal of Biological Chemistry, vol. 278, no. 43, pp. 41804–41809, 2003.
[89]
Y. Oike, M. Akao, K. Yasunaga et al., “Angiopoietin-related growth factor antagonizes obesity and insulin resistance,” Nature Medicine, vol. 11, no. 4, pp. 400–408, 2005.
[90]
A. Xu, M. C. Lam, K. W. Chan et al., “Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 17, pp. 6086–6091, 2005.
[91]
R. Peek, B. Van Elske Gelderen, M. Bruinenberg, and A. Kijlstm, “Molecular cloning of a new angiopoietinlike factor from the human cornea,” Investigative Ophthalmology & Visual Science, vol. 39, no. 10, pp. 1782–1788, 1998.
[92]
P. Gonzalez, D. L. Epstein, and T. Borras, “Characterization of gene expression in human trabecular meshwork using single-pass sequencing of 1060 clones,” Investigative Ophthalmology & Visual Science, vol. 41, no. 12, pp. 3678–3693, 2000.
[93]
S. I. Tomarev, G. Wistow, V. Raymond, S. Dubois, and I. Malyukova, “Gene expression profile of the human trabecular meshwork: NEIBank sequence tag analysis,” Investigative Ophthalmology & Visual Science, vol. 44, no. 6, pp. 2588–2596, 2003.
[94]
F. W. Rozsa, D. M. Reed, K. M. Scott et al., “Gene expression profile of human trabecular meshwork cells in response to long-term dexamethasone exposure,” Molecular Vision, vol. 12, pp. 125–141, 2006.
[95]
X. Zhao, K. E. Ramsey, D. A. Stephan, and P. Russell, “Gene and protein expression changes in human trabecular meshwork cells treated with transforming growth factor-β,” Investigative Ophthalmology & Visual Science, vol. 45, no. 11, pp. 4023–4034, 2004.
[96]
K. M. Cadigan, “Wnt-β-catenin signaling,” Current Biology, vol. 18, no. 20, pp. R943–R947, 2008.
[97]
W.-H. Wang, L. G. McNatt, I.-H. Pang et al., “Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure,” Journal of Clinical Investigation, vol. 118, no. 3, pp. 1056–1064, 2008.
[98]
N. Comes and T. Borrás, “Individual molecular response to elevated intraocular pressure in perfused postmortem human eyes,” Physiological Genomics, vol. 38, no. 2, pp. 205–225, 2009.
[99]
R. Peek, R. A. Kammerer, S. Frank, I. Otte-H？ller, and J. R. Westphal, “The angiopoietin-like factor cornea-derived transcript 6 is a putative morphogen for human cornea,” Journal of Biological Chemistry, vol. 277, no. 1, pp. 686–693, 2002.
[100]
B. T. Gabelt and P. L. Kaufman, “Changes in aqueous humor dynamics with age and glaucoma,” Progress in Retinal and Eye Research, vol. 24, no. 5, pp. 612–637, 2005.
[101]
J. Kuchtey, M. E. K？llberg, K. N. Gelatt, T. Rinkoski, A. M. Komàromy, and R. W. Kuchtey, “Angiopoietin-like 7 secretion is induced by glaucoma stimuli and its concentration is elevated in glaucomatous aqueous humor,” Investigative Ophthalmology & Visual Science, vol. 49, no. 8, pp. 3438–3448, 2008.
[102]
F. Mabuchi, J. D. Lindsey, M. Aihara, M. R. Mackey, and R. N. Weinreb, “Optic nerve damage in mice with a targeted type I collagen mutation,” Investigative Ophthalmology & Visual Science, vol. 45, no. 6, pp. 1841–1845, 2004.
[103]
M. Aihara, J. D. Lindsey, and R. N. Weinreb, “Ocular hypertension in mice with a targeted type I collagen mutation,” Investigative Ophthalmology & Visual Science, vol. 44, no. 4, pp. 1581–1585, 2003.
[104]
N. Comes, L. K. Buie, and T. Borrás, “Evidence for a role of angiopoietin-like 7 (ANGPTL7) in extracellular matrix formation of the human trabecular meshwork: implications for glaucoma,” Genes to Cells, vol. 16, no. 2, pp. 243–259, 2011.
[105]
J. A. Faralli, M. K. Schwinn, J. M. Gonzalez Jr., M. S. Filla, and D. M. Peters, “Functional properties of fibronectin in the trabecular meshwork,” Experimental Eye Research, vol. 88, no. 4, pp. 689–693, 2009.
[106]
J. M. Bradley, J. Vranka, C. M. Colvis, et al., “Effect of matrix metalloproteinases activity on outflow in perfused human organ culture,” Investigative Ophthalmology & Visual Science, vol. 39, no. 13, pp. 2649–2658, 1998.
[107]
J. Chen, S. A. Runyan, and M. R. Robinson, “Novel ocular antihypertensive compounds in clinical trials,” Clinical Ophthalmology, vol. 5, no. 1, pp. 667–677, 2011.
[108]
B. Tian, B. T. Gabelt, C. E. Crosson, and P. L. Kaufman, “Effects of adenosine agonists on intraocular pressure and aqueous humor dynamics in cynomolgus monkeys,” Experimental Eye Research, vol. 64, no. 6, pp. 979–989, 1997.
[109]
C. E. Crosson, “Adenosine receptor activation modulates intraocular pressure in rabbits,” Journal of Pharmacology and Experimental Therapeutics, vol. 273, no. 1, pp. 320–326, 1995.
[110]
I. Avni, H. J. Garzozi, I. S. Barequet et al., “Treatment of dry eye syndrome with orally administered CF101: data from a phase 2 clinical trial,” Ophthalmology, vol. 117, no. 7, pp. 1287–1293, 2010.
[111]
M. M. Civan and A. D. C. Macknight, “The ins and outs of aqueous humour secretion,” Experimental Eye Research, vol. 78, no. 3, pp. 625–631, 2004.
[112]
J. A. Peterson, B. Tian, J. W. McLaren, W. C. Hubbard, B. Geiger, and P. L. Kaufman, “Latrunculins' effects on intraocular pressure, aqueous humor flow, and corneal endothelium,” Investigative Ophthalmology & Visual Science, vol. 41, no. 7, pp. 1749–1758, 2000.
[113]
R. Ritch, M. Schiewe, R. C. Zink, et al., “Latrunculin B (INS115644) reduces intraocular pressure (IOP) in ocular hypertension (OHT) and primary open angle glaucoma (POAG),” Investigative Ophthalmology & Visual Science, vol. 51, 2010, ARVO E-Abstract and Poster 6432.
[114]
S. K. Bhattacharya, E. J. Rockwood, S. D. Smith et al., “Proteomics reveal cochlin deposits associated with glaucomatous trabecular meshwork,” Journal of Biological Chemistry, vol. 280, no. 7, pp. 6080–6084, 2005.
[115]
C. Kung, “A possible unifying principle for mechanosensation,” Nature, vol. 436, no. 7051, pp. 647–654, 2005.
[116]
A. J. Patel, M. Lazdunski, and E. Honoré, “Lipid and mechano-gated 2P domain K+ channels,” Current Opinion in Cell Biology, vol. 13, no. 4, pp. 422–427, 2001.
[117]
M. Goel, A. E. Sienkiewicz, R. Picciani, J. Wang, R. K. Lee, and S. K. Bhattacharya, “Cochlin, intraocular pressure regulation and mechanosensing,” PLoS ONE, vol. 7, no. 4, Article ID e34309, 2012.
[118]
S. K. Bhattacharya, S. P. Annangudi, R. G. Salomon, R. W. Kuchtey, N. S. Peachey, and J. W. Crabb, “Cochlin deposits in the trabecular meshwork of the glaucomatous DBA/2J mouse,” Experimental Eye Research, vol. 80, no. 5, pp. 741–744, 2005.
[119]
M. Goel, A. E. Sienkiewicz, R. Picciani, R. K. Lee, and S. K. Bhattacharya, “Cochlin induced TREK-1 co-expression and annexin A2 secretion: role in trabecular meshwork cell elongation and motility,” PLoS ONE, vol. 6, no. 8, Article ID e23070, 2011.
[120]
A. J. Straiker, G. Maguire, K. Mackie, and J. Lindsey, “Localization of cannabinoid CB1 receptors in the human anterior eye and retina,” Investigative Ophthalmology & Visual Science, vol. 40, no. 10, pp. 2442–2448, 1999.
[121]
S. Yazulla, K. M. Studholme, H. H. McIntosh, and D. G. Deutsch, “Immunocytochemical localization of cannabinoid CB1 receptor and fatty acid amide hydrolase in rat retina,” Journal of Comparative Neurology, vol. 415, no. 1, pp. 80–90, 1999.
[122]
S. Pinar-Sueiro, R. Rodríguez-Puertas, and E. Vecino, “Cannabinoid applications in glaucoma,” Archivos de la Sociedad Espanola de Oftalmologia, vol. 86, no. 1, pp. 16–23, 2011.
[123]
F. Y. Chien, R.-F. Wang, T. W. Mittag, and S. M. Podos, “Effect of WIN 55212-2, a cannabinoid receptor agonist, on aqueous humor dynamics in monkeys,” Archives of Ophthalmology, vol. 121, no. 1, pp. 87–90, 2003.
[124]
A. Porcella, C. Maxia, G. L. Gessa, and L. Pani, “The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies,” European Journal of Neuroscience, vol. 13, no. 2, pp. 409–412, 2001.
[125]
Y. F. Njie, A. Kumar, Z. Qiao, L. Zhong, and Z.-H. Song, “Noladin ether acts on trabecular meshwork cannabinoid (CB1) receptors to enhance aqueous humor outflow facility,” Investigative Ophthalmology & Visual Science, vol. 47, no. 5, pp. 1999–2005, 2006.
[126]
B. D. Hudson, M. Beazley, A.-M. Szczesniak, A. Straiker, and M. E. M. Kelly, “Indirect sympatholytic actions at β-adrenoceptors account for the ocular hypotensive actions of cannabinoid receptor agonists,” Journal of Pharmacology and Experimental Therapeutics, vol. 339, no. 3, pp. 757–767, 2011.
[127]
S. R？sch, R. Ramer, K. Brune, and B. Hinz, “R+-methanandamide and other cannabinoids induce the expression of cyclooxygenase-2 and matrix metalloproteinases in human nonpigmented ciliary epithelial cells,” Journal of Pharmacology and Experimental Therapeutics, vol. 316, no. 3, pp. 1219–1228, 2006.
[128]
A. Crooke, B. Colligris, and J. Pintor, “Update in glaucoma medicinal chemistry: emerging evidence for the importance of melatonin analogues,” Current Medicinal Chemistry, vol. 19, no. 21, pp. 3508–3522, 2012.
[129]
J. Pintor, T. Peláez, C. H. V. Hoyle, and A. Peral, “Ocular hypotensive effects of melatonin receptor agonists in the rabbit: further evidence for an MT3 receptor,” British Journal of Pharmacology, vol. 138, no. 5, pp. 831–836, 2003.
[130]
S. Alcantara-Contreras, K. Baba, and G. Tosini, “Removal of melatonin receptor type 1 increases intraocular pressure and retinal ganglion cells death in the mouse,” Neuroscience Letters, vol. 494, no. 1, pp. 61–64, 2011.
[131]
M. A. Babizhayev and A. Bunin Ya., “Lipid peroxidation in open-angle glaucoma,” Acta Ophthalmologica, vol. 67, no. 4, pp. 371–377, 1989.
[132]
M. Kojima, H. Hosoda, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, “Ghrelin is a growth-hormone-releasing acylated peptide from stomach,” Nature, vol. 402, no. 6762, pp. 656–660, 1999.
[133]
H. Hosoda, M. Kojima, H. Matsuo, and K. Kangawa, “Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue,” Biochemical and Biophysical Research Communications, vol. 279, no. 3, pp. 909–913, 2000.
[134]
A. Rocha-Sousa, J. Saraiva, T. Henriques-Coelho, F. Falc？o-Reis, J. Correia-Pinto, and A. F. Leite-Moreira, “Ghrelin as a novel locally produced relaxing peptide of the iris sphincter and dilator muscles,” Experimental Eye Research, vol. 83, no. 5, pp. 1179–1187, 2006.
[135]
A. Rocha-Sousa, P. Alves-Faria, I. Falc？o-Pires, F. Falc？o-Reis, and A. F. Leite-Moreira, “Analyses of aqueous humour ghrelin levels of eyes with and without glaucoma,” British Journal of Ophthalmology, vol. 93, no. 1, pp. 131–132, 2009.
[136]
A. Katsanos, A. Dastiridou, P. Georgoulias, P. Cholevas, M. Kotoula, and E. E. Tsironi, “Plasma and aqueous humour levels of ghrelin in open-angle glaucoma patients,” Clinical and Experimental Ophthalmology, vol. 39, no. 4, pp. 324–329, 2011.
[137]
A. Rocha-Sousa, M. Tavares-Silva, P. Pereira-Silva, et al., “Ghrelin is expressed in the ciliary body and presents a significant and sustained hypotensive effect in acute glaucoma models,” ARVO Meeting Abstracts, vol. 53, 2012.
[138]
A. H. Danser, F. H. Derkx, P. J. Admiraal, J. Deinum, P. T. de Jong, and M. A. Schalekamp, “Angiotensin levels in the eye,” Investigative Ophthalmology & Visual Science, vol. 35, no. 3, pp. 1008–1018, 1994.
[139]
A. Vaajanen and H. Vapaatalo, “Local ocular renin-angiotensin system—a target for glaucoma therapy?” Basic and Clinical Pharmacology and Toxicology, vol. 109, no. 4, pp. 217–224, 2011.
[140]
M. Ramirez, E. A. Davidson, L. Luttenauer, et al., “The renin-angiotensin system in the rabbit eye,” Journal of Ocular Pharmacology and Therapeutics, vol. 12, no. 3, pp. 299–312, 1996.
[141]
R.-F. Wang, S. M. Podos, T. W. Mittag, and T. Yokoyoma, “Effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure in glaucomatous monkey eyes,” Experimental Eye Research, vol. 80, no. 5, pp. 629–632, 2005.
[142]
C. Tikellis, S. Bernardi, and W. C. Burns, “Angiotensin-converting enzyme 2 is a key modulator of the renin-angiotensin system in cardiovascular and renal disease,” Current Opinion in Nephrology and Hypertension, vol. 20, no. 1, pp. 62–68, 2011.
[143]
A. Vaajanen, H. Vapaatalo, H. Kautiainen, and O. Oksala, “Angiotensin (1–7) reduces intraocular pressure in the normotensive rabbit eye,” Investigative Ophthalmology & Visual Science, vol. 49, no. 6, pp. 2557–2562, 2008.
[144]
H. A. Reitsamer and J. W. Kiel, “Relationship between ciliary blood flow and aqueous production in rabbits,” Investigative Ophthalmology & Visual Science, vol. 44, no. 9, pp. 3967–3971, 2003.
[145]
C. Costagliola, F. Parmeggiani, F. Semeraro, and A. Sebastiani, “Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure,” Current Neuropharmacology, vol. 6, no. 4, pp. 293–310, 2008.
[146]
B. T. Gabelt, M. Okka, T. R. Dean, and P. L. Kaufman, “Aqueous humor dynamics in monkeys after topical R-DOI,” Investigative Ophthalmology & Visual Science, vol. 46, no. 12, pp. 4691–4696, 2005.
[147]
N. A. Sharif, M. A. McLaughlin, and C. R. Kelly, “AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist,” Journal of Ocular Pharmacology and Therapeutics, vol. 23, no. 1, pp. 1–13, 2007.
[148]
T. J. Bunch, J. L. Seeman, B. T. Gabelt, et al., “BVT.28949 as a potential ocular hypotensive agent in monkeys,” Investigative Ophthalmology & Visual Science, vol. 45, 2004, ARVO E-Abstract 5040.
[149]
V. D. Wagh, P. N. Patil, S. J. Surana, and K. V. Wagh, “Forskolin: upcoming antiglaucoma molecule,” Journal of Postgraduate Medicine, vol. 58, no. 3, pp. 199–202, 2012.
[150]
H. Metzger and E. Lindner, “The positive inotropic-acting forskolin, a potent adenylatecyclase activator,” Arzneimittel-Forschung, vol. 31, no. 8, pp. 1248–1250, 1981.
[151]
N. Pescosolido and A. Librando, “Oral administration of an association of forskolin, rutin and vitamins B1 and B2 potentiates the hypotonising effects of pharmacological treatments in POAG patients,” La Clinica terapeutica, vol. 161, no. 3, pp. e81–e85, 2010.
