Research progress of β-adrenergic receptor antagonists in the treatment of ocular neovascular diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhao Ru , Luo Jinyuan , He Tao ,  Xing Yiqiao

Eye Center, Renmin Hospital of Wuhan University, Wuhan 430060, China;

Corresponding author：

Xing Yiqiao, Email: Yiqiao_xing57@whu.edu.cn

Keywords：

Adrenergic beta-antagonists; Corneal neovascularization; Retinal neovascularization; Choroidal neovascularization; Review

DOI：

10.3760/cma.j.cn511434-20210203-00063

Video：

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Ocular neovascularization is a pathological change in various ocular diseases such as diabetic retinopathy, retinopathy of prematurity, central retinal vein occlusion and age-related macular degeneration, which seriously affects patient's vision. β receptors are expressed in conjunctiva, corneal epithelial cells, corneal endothelial cells, extraocular muscles, trabecular meshwork, ciliary muscle, lens and retina. β adrenergic receptor antagonists bind to β receptors to exert anti-angiogenic effects by inhibiting the expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1, interleukin-6 and other angiogenic cytokines; reducing macrophage-related inflammatory response; increasing the expression of anti-angiogenic factors. In the treatment of corneal neovascularization, choroidal neovascularization, and retinopathy of prematurity, it can significantly reduce the area of neovascularization and delay disease progression. Co-administration of anti-VEGF drugs can reduce the frequency of administration of anti-VEGF drugs. At effective therapeutic concentrations, β-adrenergic receptor antagonists are well tolerated; they have broader targets than anti-VEGF drugs, which offers new treatment strategies for ocular neovascularization such as corneal, choroidal and retinal neovascularization.

Citation： Zhao Ru, Luo Jinyuan, He Tao, Xing Yiqiao. Research progress of β-adrenergic receptor antagonists in the treatment of ocular neovascular diseases. Chinese Journal of Ocular Fundus Diseases, 2022, 38(4): 330-333. doi: 10.3760/cma.j.cn511434-20210203-00063 Copy

1.	Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review[J]. Surv Ophthalmol, 1998, 43(3): 245-269. DOI: 10.1016/s0039-6257(98)00035-6.
2.	Oliver E, Mayor FJ, D'Ocon P. Beta-blockers: historical perspective and mechanisms of action[J]. Rev Esp Cardiol (Engl Ed), 2019, 72(10): 853-862. DOI: 10.1016/j.rec.2019.04.006.
3.	Walkenbach RJ, Chao WT, Bylund DB, et al. Characterization of beta-adrenergic receptors in fresh and primary cultured bovine corneal endothelium[J]. Exp Eye Res, 1985, 40(1): 15-21. DOI: 10.1016/0014-4835(85)90104-6.
4.	Kahle G, Kaulen P, Wollensak J. Quantitative autoradiography of beta-adrenergic receptors in rabbit eyes[J]. Exp Eye Res, 1990, 51(5): 503-507. DOI: 10.1016/0014-4835(90)90080-e.
5.	Elena PP, Denis P, Kosina-Boix M, et al. Beta adrenergic binding sites in the human eye: an autoradiographic study[J]. J Ocul Pharmacol, 1990, 6(2): 143-149. DOI: 10.1089/jop.1990.6.143.
6.	Ferrari-Dileo G. Beta 1 and beta 2 adrenergic binding sites in bovine retina and retinal blood vessels[J]. Invest Ophthalmol Vis Sci, 1988, 29(5): 695-699.
7.	Martini D, Monte MD, Ristori C, et al. Antiangiogenic effects of beta2 -adrenergic receptor blockade in a mouse model of oxygen-induced retinopathy[J]. J Neurochem, 2011, 119(6): 1317-1329. DOI: 10.1111/j.1471-4159.2011.07530.x.
8.	Lusthaus J, Goldberg I. Current management of glaucoma[J]. Med J Aust, 2019, 210(4): 180-187. DOI: 10.5694/mja2.50020.
9.	Steinle JJ, Cappocia FJ, Jiang Y. Beta-adrenergic receptor regulation of growth factor protein levels in human choroidal endothelial cells[J]. Growth Factors, 2008, 26(6): 325-330. DOI: 10.1080/08977190802442070.
10.	Steinle JJ, Zamora DO, Rosenbaum JT, et al. Beta 3-adrenergic receptors mediate choroidal endothelial cell invasion, proliferation, and cell elongation[J]. Exp Eye Res, 2005, 80(1): 83-91. DOI: 10.1016/j.exer.2004.08.015.
11.	Steinle JJ, Booz GW, Meininger CJ, et al. Beta 3-adrenergic receptors regulate retinal endothelial cell migration and proliferation[J]. J Biol Chem, 2003, 278(23): 20681-20686. DOI: 10.1074/jbc.M300368200.
12.	Chan SW, Hu M, Tomlinson B. The pharmacogenetics of β-adrenergic receptor antagonists in the treatment of hypertension and heart failure[J]. Expert Opin Drug Metab Toxicol, 2012, 8(7): 767-790. DOI: 10.1517/17425255.2012.685157.
13.	Nocentini A, Supuran CT. Adrenergic agonists and antagonists as antiglaucoma agents: a literature and patent review (2013-2019)[J]. Expert Opin Ther Pat, 2019, 29(10): 805-815. DOI: 10.1080/13543776.2019.1665023.
14.	Wohleb ES, Hanke ML, Corona AW, et al. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat[J]. J Neurosci, 2011, 31(17): 6277-6288. DOI: 10.1523/JNEUROSCI.0450-11.2011.
15.	Lavine JA, Farnoodian M, Wang S, et al. Beta2-adrenergic receptor antagonism attenuates CNV through Inhibition of VEGF and IL-6 expression[J]. Invest Ophthalmol Vis Sci, 2017, 58(1): 299-308. DOI: 10.1167/iovs.16-20204.
16.	Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis[J]. Cell, 2011, 146(6): 873-887. DOI: 10.1016/j.cell.2011.08.039.
17.	Yeo NJY, Chan EJJ, Cheung C. Choroidal neovascularization: mechanisms of endothelial dysfunction[J/OL]. Front Pharmacol, 2019, 10: 1363[2019-11-29]. https://pubmed.ncbi.nlm.nih.gov/31849644/. DOI: 10.3389/fphar.2019.01363.
18.	Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease[J]. Retina, 2005, 25(2): 111-118. DOI: 10.1097/00006982-200502000-00001.
19.	Ristori C, Filippi L, Dal Monte M, et al. Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of beta-adrenoreceptor blockade[J]. Invest Ophthalmol Vis Sci, 2011, 52(1): 155-170. DOI: 10.1167/iovs.10-5536.
20.	Lavine JA, Sang Y, Wang S, et al. Attenuation of choroidal neovascularization by β(2)-adrenoreceptor antagonism[J]. JAMA Ophthalmol, 2013, 131(3): 376-382. DOI: 10.1001/jamaophthalmol.2013.1476.
21.	Kasiri A, Ghomi MR, Feghhi M, et al. Topical timolol inhibits corneal neovascularization in rabbits[J]. Med Hypothesis Discov Innov Ophthalmol, 2017, 6(2): 39-43.
22.	Simavli H, Erdurmus M, Terzi EH, et al. The effect of beta receptor blockade through propranolol on corneal neovascularization[J]. J Ocul Pharmacol Ther, 2014, 30(8): 650-656. DOI: 10.1089/jop.2013.0238.
23.	Droho S, Cuda CM, Perlman H, et al. Monocyte-derived macrophages are necessary for beta-adrenergic receptor-driven choroidal neovascularization inhibition[J]. Invest Ophthalmol Vis Sci, 2019, 60(15): 5059-5069. DOI: 10.1167/iovs.19-28165.
24.	Omri S, Tahiri H, Pierre WC, et al. Propranolol attenuates proangiogenic activity of mononuclear phagocytes: implication in choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2019, 60(14): 4632-4642. DOI: 10.1167/iovs.18-25502.
25.	Madrigal JL, Leza JC, Polak P, et al. Astrocyte-derived MCP-1 mediates neuroprotective effects of noradrenaline[J]. J Neurosci, 2009, 29(1): 263-267. DOI: 10.1523/JNEUROSCI.4926-08.2009.
26.	Madrigal JL, Kalinin S, Richardson JC, et al. Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta[J]. J Neurochem, 2007, 103(5): 2092-2101. DOI: 10.1111/j.1471-4159.2007.04888.x.
27.	Casini G, Dal Monte M, Fornaciari I, et al. The beta-adrenergic system as a possible new target for pharmacologic treatment of neovascular retinal diseases[J]. Prog Retin Eye Res, 2014, 42: 103-129. DOI: 10.1016/j.preteyeres.2014.06.001.
28.	Nourinia R, Rezaei Kanavi M, Kaharkaboudi A, et al. Ocular safety of intravitreal propranolol and its efficacy in attenuation of choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2015, 56(13): 8228-8235. DOI: 10.1167/iovs.15-17169.
29.	Filippi L, Cavallaro G, Bagnoli P, et al. Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives[J]. J Pediatr, 2013, 163(6): 1570-1577. DOI: 10.1016/j.jpeds.2013.07.049.
30.	Eghrari AO, Riazuddin SA, Gottsch JD. Overview of the cornea: structure, function, and development[J]. Prog Mol Biol Transl Sci, 2015, 134: 7-23. DOI: 10.1016/bs.pmbts.2015.04.001.
31.	Sharif Z, Sharif W. Corneal neovascularization: updates on pathophysiology, investigations & management[J]. Rom J Ophthalmol, 2019, 63(1): 15-22. DOI: 10.22336/rjo.2019.4.
32.	Kasiri A, Mirdehghan MS, Farrahi F, et al. Prevention of corneal neovascularization; a preliminary experimental study in rabbits[J]. Med Hypothesis Discov Innov Ophthalmol, 2020, 9(1): 47-55.
33.	Cho YK, Shin EY, Uehara H, et al. The effect of 0.5% timolol maleate on corneal (lymph) angiogenesis in a murine suture model[J]. J Ocul Pharmacol Ther, 2018, 34(5): 403-409. DOI: 10.1089/jop.2017.0119.
34.	Filippi L, de Libero C, Zamma GB, et al. Propranolol eye drops in patients with corneal neovascularization[J/OL]. Medicine (Baltimore), 2018, 97(45): e13002[2018-11-09]. https://pubmed.ncbi.nlm.nih.gov/30407290/. DOI: 10.1097/MD.0000000000013002.
35.	Montero JA, Ruiz-Moreno JM, Sanchis-Merino E, et al. Systemic beta-blockers may reduce the need for repeated intravitreal injections in patients with wet age-related macular degeneration treated by bevacizumab[J]. Retina, 2013, 33(3): 508-512. DOI: 10.1097/IAE.0b013e3182695ba0.
36.	Dal Monte M, Martini D, Latina V, et al. Beta-adrenoreceptor agonism influences retinal responses to hypoxia in a model of retinopathy of prematurity[J]. Invest Ophthalmol Vis Sci, 2012, 53(4): 2181-2192. DOI: 10.1167/iovs.11-9408.
37.	Dal Monte M, Cammalleri M, Mattei E, et al. Protective effects of beta1/2 adrenergic receptor deletion in a model of oxygen-induced retinopathy[J]. Invest Ophthalmol Vis Sci, 2014, 56(1): 59-73. DOI: 10.1167/iovs.14-15263.
38.	Filippi L, Cavallaro G, Berti E, et al. Propranolol 0.2% eye micro-drops for retinopathy of prematurity: a prospective phase ⅡB study[J]. Front Pediatr, 2019, 7: 180. DOI: 10.3389/fped.2019.00180.
39.	Filippi L, Cavallaro G, Perciasepe L, et al. Refractive outcome in pretermnewborns with ROP after propranolol treatment. A retrospective observational cohort study[J]. Front Pediatr, 2019, 7: 479. DOI: 10.3389/fped.2019.00479.

1. Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review[J]. Surv Ophthalmol, 1998, 43(3): 245-269. DOI: 10.1016/s0039-6257(98)00035-6.
2. Oliver E, Mayor FJ, D'Ocon P. Beta-blockers: historical perspective and mechanisms of action[J]. Rev Esp Cardiol (Engl Ed), 2019, 72(10): 853-862. DOI: 10.1016/j.rec.2019.04.006.
3. Walkenbach RJ, Chao WT, Bylund DB, et al. Characterization of beta-adrenergic receptors in fresh and primary cultured bovine corneal endothelium[J]. Exp Eye Res, 1985, 40(1): 15-21. DOI: 10.1016/0014-4835(85)90104-6.
4. Kahle G, Kaulen P, Wollensak J. Quantitative autoradiography of beta-adrenergic receptors in rabbit eyes[J]. Exp Eye Res, 1990, 51(5): 503-507. DOI: 10.1016/0014-4835(90)90080-e.
5. Elena PP, Denis P, Kosina-Boix M, et al. Beta adrenergic binding sites in the human eye: an autoradiographic study[J]. J Ocul Pharmacol, 1990, 6(2): 143-149. DOI: 10.1089/jop.1990.6.143.
6. Ferrari-Dileo G. Beta 1 and beta 2 adrenergic binding sites in bovine retina and retinal blood vessels[J]. Invest Ophthalmol Vis Sci, 1988, 29(5): 695-699.
7. Martini D, Monte MD, Ristori C, et al. Antiangiogenic effects of beta2 -adrenergic receptor blockade in a mouse model of oxygen-induced retinopathy[J]. J Neurochem, 2011, 119(6): 1317-1329. DOI: 10.1111/j.1471-4159.2011.07530.x.
8. Lusthaus J, Goldberg I. Current management of glaucoma[J]. Med J Aust, 2019, 210(4): 180-187. DOI: 10.5694/mja2.50020.
9. Steinle JJ, Cappocia FJ, Jiang Y. Beta-adrenergic receptor regulation of growth factor protein levels in human choroidal endothelial cells[J]. Growth Factors, 2008, 26(6): 325-330. DOI: 10.1080/08977190802442070.
10. Steinle JJ, Zamora DO, Rosenbaum JT, et al. Beta 3-adrenergic receptors mediate choroidal endothelial cell invasion, proliferation, and cell elongation[J]. Exp Eye Res, 2005, 80(1): 83-91. DOI: 10.1016/j.exer.2004.08.015.
11. Steinle JJ, Booz GW, Meininger CJ, et al. Beta 3-adrenergic receptors regulate retinal endothelial cell migration and proliferation[J]. J Biol Chem, 2003, 278(23): 20681-20686. DOI: 10.1074/jbc.M300368200.
12. Chan SW, Hu M, Tomlinson B. The pharmacogenetics of β-adrenergic receptor antagonists in the treatment of hypertension and heart failure[J]. Expert Opin Drug Metab Toxicol, 2012, 8(7): 767-790. DOI: 10.1517/17425255.2012.685157.
13. Nocentini A, Supuran CT. Adrenergic agonists and antagonists as antiglaucoma agents: a literature and patent review (2013-2019)[J]. Expert Opin Ther Pat, 2019, 29(10): 805-815. DOI: 10.1080/13543776.2019.1665023.
14. Wohleb ES, Hanke ML, Corona AW, et al. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat[J]. J Neurosci, 2011, 31(17): 6277-6288. DOI: 10.1523/JNEUROSCI.0450-11.2011.
15. Lavine JA, Farnoodian M, Wang S, et al. Beta2-adrenergic receptor antagonism attenuates CNV through Inhibition of VEGF and IL-6 expression[J]. Invest Ophthalmol Vis Sci, 2017, 58(1): 299-308. DOI: 10.1167/iovs.16-20204.
16. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis[J]. Cell, 2011, 146(6): 873-887. DOI: 10.1016/j.cell.2011.08.039.
17. Yeo NJY, Chan EJJ, Cheung C. Choroidal neovascularization: mechanisms of endothelial dysfunction[J/OL]. Front Pharmacol, 2019, 10: 1363[2019-11-29]. https://pubmed.ncbi.nlm.nih.gov/31849644/. DOI: 10.3389/fphar.2019.01363.
18. Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease[J]. Retina, 2005, 25(2): 111-118. DOI: 10.1097/00006982-200502000-00001.
19. Ristori C, Filippi L, Dal Monte M, et al. Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of beta-adrenoreceptor blockade[J]. Invest Ophthalmol Vis Sci, 2011, 52(1): 155-170. DOI: 10.1167/iovs.10-5536.
20. Lavine JA, Sang Y, Wang S, et al. Attenuation of choroidal neovascularization by β(2)-adrenoreceptor antagonism[J]. JAMA Ophthalmol, 2013, 131(3): 376-382. DOI: 10.1001/jamaophthalmol.2013.1476.
21. Kasiri A, Ghomi MR, Feghhi M, et al. Topical timolol inhibits corneal neovascularization in rabbits[J]. Med Hypothesis Discov Innov Ophthalmol, 2017, 6(2): 39-43.
22. Simavli H, Erdurmus M, Terzi EH, et al. The effect of beta receptor blockade through propranolol on corneal neovascularization[J]. J Ocul Pharmacol Ther, 2014, 30(8): 650-656. DOI: 10.1089/jop.2013.0238.
23. Droho S, Cuda CM, Perlman H, et al. Monocyte-derived macrophages are necessary for beta-adrenergic receptor-driven choroidal neovascularization inhibition[J]. Invest Ophthalmol Vis Sci, 2019, 60(15): 5059-5069. DOI: 10.1167/iovs.19-28165.
24. Omri S, Tahiri H, Pierre WC, et al. Propranolol attenuates proangiogenic activity of mononuclear phagocytes: implication in choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2019, 60(14): 4632-4642. DOI: 10.1167/iovs.18-25502.
25. Madrigal JL, Leza JC, Polak P, et al. Astrocyte-derived MCP-1 mediates neuroprotective effects of noradrenaline[J]. J Neurosci, 2009, 29(1): 263-267. DOI: 10.1523/JNEUROSCI.4926-08.2009.
26. Madrigal JL, Kalinin S, Richardson JC, et al. Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta[J]. J Neurochem, 2007, 103(5): 2092-2101. DOI: 10.1111/j.1471-4159.2007.04888.x.
27. Casini G, Dal Monte M, Fornaciari I, et al. The beta-adrenergic system as a possible new target for pharmacologic treatment of neovascular retinal diseases[J]. Prog Retin Eye Res, 2014, 42: 103-129. DOI: 10.1016/j.preteyeres.2014.06.001.
28. Nourinia R, Rezaei Kanavi M, Kaharkaboudi A, et al. Ocular safety of intravitreal propranolol and its efficacy in attenuation of choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2015, 56(13): 8228-8235. DOI: 10.1167/iovs.15-17169.
29. Filippi L, Cavallaro G, Bagnoli P, et al. Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives[J]. J Pediatr, 2013, 163(6): 1570-1577. DOI: 10.1016/j.jpeds.2013.07.049.
30. Eghrari AO, Riazuddin SA, Gottsch JD. Overview of the cornea: structure, function, and development[J]. Prog Mol Biol Transl Sci, 2015, 134: 7-23. DOI: 10.1016/bs.pmbts.2015.04.001.
31. Sharif Z, Sharif W. Corneal neovascularization: updates on pathophysiology, investigations & management[J]. Rom J Ophthalmol, 2019, 63(1): 15-22. DOI: 10.22336/rjo.2019.4.
32. Kasiri A, Mirdehghan MS, Farrahi F, et al. Prevention of corneal neovascularization; a preliminary experimental study in rabbits[J]. Med Hypothesis Discov Innov Ophthalmol, 2020, 9(1): 47-55.
33. Cho YK, Shin EY, Uehara H, et al. The effect of 0.5% timolol maleate on corneal (lymph) angiogenesis in a murine suture model[J]. J Ocul Pharmacol Ther, 2018, 34(5): 403-409. DOI: 10.1089/jop.2017.0119.
34. Filippi L, de Libero C, Zamma GB, et al. Propranolol eye drops in patients with corneal neovascularization[J/OL]. Medicine (Baltimore), 2018, 97(45): e13002[2018-11-09]. https://pubmed.ncbi.nlm.nih.gov/30407290/. DOI: 10.1097/MD.0000000000013002.
35. Montero JA, Ruiz-Moreno JM, Sanchis-Merino E, et al. Systemic beta-blockers may reduce the need for repeated intravitreal injections in patients with wet age-related macular degeneration treated by bevacizumab[J]. Retina, 2013, 33(3): 508-512. DOI: 10.1097/IAE.0b013e3182695ba0.
36. Dal Monte M, Martini D, Latina V, et al. Beta-adrenoreceptor agonism influences retinal responses to hypoxia in a model of retinopathy of prematurity[J]. Invest Ophthalmol Vis Sci, 2012, 53(4): 2181-2192. DOI: 10.1167/iovs.11-9408.
37. Dal Monte M, Cammalleri M, Mattei E, et al. Protective effects of beta1/2 adrenergic receptor deletion in a model of oxygen-induced retinopathy[J]. Invest Ophthalmol Vis Sci, 2014, 56(1): 59-73. DOI: 10.1167/iovs.14-15263.
38. Filippi L, Cavallaro G, Berti E, et al. Propranolol 0.2% eye micro-drops for retinopathy of prematurity: a prospective phase ⅡB study[J]. Front Pediatr, 2019, 7: 180. DOI: 10.3389/fped.2019.00180.
39. Filippi L, Cavallaro G, Perciasepe L, et al. Refractive outcome in pretermnewborns with ROP after propranolol treatment. A retrospective observational cohort study[J]. Front Pediatr, 2019, 7: 479. DOI: 10.3389/fped.2019.00479.

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