Ocular Safety of Intravitreal Propranolol and Its Efficacy in Attenuation of Choroidal Neovascularization

Nourinia, Ramin; Kanavi, Mozhgan Rezaei; Kaharkaboudi, Amir; Taghavi, Seyed Iman; Aldavood, Seyed Javid; Darjatmoko, Soesiawati R.; Wang, Shoujian; Gurel, Zafer; Lavine, Jeremy A.; Safi, Sare; Ahmadieh, Hamid; Daftarian, Narsis; Sheibani, Nader

doi:10.1167/iovs.15-17169

Cited by 25 publications

(28 citation statements)

References 24 publications

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“…This dose was chosen because we have previously demonstrated that a single intravitreal dose of propranolol at 0.3 μg per eye (0.03 mg/mL) could inhibit CNV in mice and is nontoxic in rabbits. 25 In an initial pilot study, we performed a dose-escalation series by using 0.003 μg, 0.03 μg, and 0.3 μg ICI-118,551 per eye (not shown). We found that 0.03 μg per eye inhibited CNV formation.…”

Section: Resultsmentioning

confidence: 99%

β2–Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression

Lavine

Farnoodian

Wang

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeThe role of β–adrenergic receptor (AR) signaling in neovascular ocular diseases has recently emerged. We have previously reported that intraperitoneal propranolol inhibits choroidal neovascularization (CNV) in vivo and β2-AR blockade reduces vascular endothelial growth factor (VEGF) expression in mouse retinal pigment epithelium and choroidal endothelial cells in culture. Here we tested the hypothesis that the β2-AR regulates CNV through modulation of VEGF and inflammatory cytokine expression.MethodsMice were subjected to laser burns, inducing CNV, and were treated with an intravitreal β2-AR antagonist. After 3 and 5 days, total eye interleukin-6 (IL-6) and VEGF protein levels were measured, respectively. After 14 days, CNV was measured on choroidal–scleral flatmounts. The effects of β-AR signaling on VEGF and IL-6 expression were investigated in various mouse retinal and human RPE cells by using specific β-AR agonists and antagonists.Resultsβ2–Adrenergic receptor signaling increased Vegf mRNA expression by approximately 3- to 4-fold in mouse retinal microglia and pericytes in culture. β2–Adrenergic receptor signaling upregulated IL-6 mRNA expression between 10- and 60-fold in mouse retinal microglia, pericytes, RPE, and choroidal endothelial cells in culture. Intravitreal injection of β2-AR antagonist ICI 118,551 reduced CNV by 35% and decreased IL-6 protein levels by approximately 50%. In primary human RPE cells, β2-AR activation also stimulated VEGF and IL-6 mRNA expression by 2- and 10-fold, respectively.ConclusionsAnti-VEGF therapy for CNV is highly effective; however, some patients are resistant to therapy while others undergo repeated, frequent treatments. β2–Adrenergic receptor signaling is a potential therapeutic target because of its angiogenic and inflammatory properties.

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Section: Resultsmentioning

confidence: 99%

β2–Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression

Lavine

Farnoodian

Wang

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…These results provide us with the basis to explore higher doses of propranolol—up to 3 mg/kg body weight/day, adjusting dose by body weight—and even consider the use of a more selective β-blocker that could be more effective. It may be interesting as well to explore the effect of intravitreal injection of propranolol in clinical trials, as the case report recently published21 and based on the previous work by Nourinia et al , to determine the safe dose of intravitreal propranolol 22. Using intravitreal administration, the drug would achieve more easily the retina.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the safety and effectiveness of oral propranolol in patients with von Hippel-Lindau disease and retinal hemangioblastomas: phase III clinical trial

et al. 2019

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Backgroundvon Hippel-Lindau disease (VHL) is a multisystem cancer syndrome caused by mutations in the VHL gene. Retinal hemangioblastoma is one of the most common tumours, and when it appears near the optic nerve, its treatment is challenging and risky. To date, no treatment has proven effective in changing the course of the disease. This study was designed to evaluate the safety and effectiveness of propranolol in controlling these tumours.MethodsSeven patients were included. All patients took a daily dose of 120 mg of propranolol for 1 year. Clinical variables were assessed at baseline, and at 1, 3, 6, 9 and 12 months. The primary endpoint of the study was the number and size of retinal hemangioblastomas. On every visit, retinal outcomes and blood biomarkers (such as vascular endothelial growth factor (VEGF) and miR210) were analysed.ResultsNumber and size of retinal hemangioblastomas remained stable in all patients. All of them had initially increased levels of VEGF and miR210. There was a gradual reabsorption of retinal exudation in two patients, correlating with a progressive decrease of both biomarkers. The only adverse effect reported was hypotension in one patient.ConclusionsPropranolol could be used to treat retinal hemangioblastomas in VHL patients, although more studies are needed to determine the ideal dose and long-term effect. VEGF and miR210 should be explored as biomarkers of disease activity. As far as we know, these are the first biomarkers proposed to monitor the VHL disease activity.Trial registration number2014-003671-30

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“…We thus justifiably focused on expression of major antiangiogenic TSP-1 and especially PEDF 37 as both have been found to be upregulated by propranolol. 10,38 TSP-1 was negligibly expressed in J774 CM and did not change in response to propranolol treatment; whereas PEDF protein expression was found to be markedly increased in propranolol-incubated J774 macrophages on dotblot, Western blot, ELISA assay, and immunohistochemistry (Figs. 4A-D); these changes in MPs were independent of VEGF, which was hardly affected by propranolol (Fig.…”

Section: Propranolol Induces Expression Of the Antiangiogenic Factor mentioning

confidence: 96%

“…These findings indicate that actions of propranolol on MPs depend on antagonism of more than one or two b-adrenoceptors, in contrast to other cell types. [8][9][10] To elucidate the antiangiogenic properties of propranolol via MPs, we measured inflammatory factors from incubated macrophages J774 cells, which were found to exert the most robust CNV reduction after 24 hours treatment with propranolol (10 lM; compared with other macrophages). Because the effects of propranolol were associated with caspase 3 activation (cleaved caspase 3) on endothelial cells (Fig.…”

Section: Propranolol Restricts Inflammation and Angiogenesis Through mentioning

confidence: 99%

“…More recently, the antiangiogenic properties of propranolol have been demonstrated in a model of CNV. [8][9][10] Although these studies pointed to an effect of propranolol in reducing VEGF, others have questioned this mechanism to fully explain the effects of propranolol, 11,12 while proposing concomitant respective activation of prodeath and suppression of prosurvival factors 5,13 in b-adrenoceptor-bearing vascular cells, 7 suggesting that antiangiogenic mechanisms for propranolol may differ depending on the type of environment and tissue/cell incurring vasoproliferation. In this context, CNV as observed in various clinical conditions as well as in the laser-induced photocoagulation model, is associated with an inflammatory component.…”

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Propranolol Attenuates Proangiogenic Activity of Mononuclear Phagocytes: Implication in Choroidal Neovascularization

Omri

Tahiri

Pierre

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Targeting b-adrenergic receptor signaling with propranolol has emerged as a potential candidate to counteract choroidal neovascularization (CNV). Little is known of its effect on macrophages, which play a critical role in CNV. We investigated the effect of propranolol on angiogenic response of mononuclear phagocytes (MPs). METHODS. The angiogenic effect of propranolol was evaluated in laser-induced CNV model. Mice received intraperitoneal injections of propranolol (6 mg/kg/d) or vehicle. CNV area and inflammatory cells were determined respectively by using lectin staining and an anti-IBA-1 antibody on RPE/choroid flat mounts. Inflammatory gene expression was evaluated by quantitative (q) PCR analysis. Mechanisms of propranolol was studied in MP cell lines J774 and RAW264.7 and in primary peritoneal macrophages. Expression of pro-and antiangiogenic mediators was studied. In addition, effects of propranolol treatment of MPs was assessed on choroidal explant. RESULTS. CNV was attenuated by propranolol and concomitantly associated with decreased inflammatory mediators IL-6 and TNFa, albeit with accumulation of (b-adrenoceptor harboring) MPs in the CNV area. Conditioned media from MPs preincubated with propranolol exerted antiangiogenic effects. Treatment of J774 confirmed the attenuation of inflammatory response to propranolol and increased cleaved caspase-3 on choroidal explant. We found that propranolol increased pigment epithelium-derived factor (PEDF) expression in MPs. Trapping of PEDF with an antibody abrogated antiangiogenic effects of propranolol. PEDF was also detected in CNV-associated MPs. CONCLUSIONS. We hereby show that propranolol confers on MPs antiangiogenic properties by increasing PEDF expression, which complements its effects on vascular tissue resulting in inhibition of choroidal vasoproliferation in inflammatory conditions. The study supports possible use of propranolol as a therapeutic modality for CNV.

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Ocular Safety of Intravitreal Propranolol and Its Efficacy in Attenuation of Choroidal Neovascularization

Cited by 25 publications

References 24 publications

β2–Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression

β2–Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression

Evaluation of the safety and effectiveness of oral propranolol in patients with von Hippel-Lindau disease and retinal hemangioblastomas: phase III clinical trial

Propranolol Attenuates Proangiogenic Activity of Mononuclear Phagocytes: Implication in Choroidal Neovascularization

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