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Carlos D. Nuñez-Amaro, Aura Ileana Moreno-Vega, Elva Adan-Castro, Magdalena Zamora, Renata Garcia-Franco, Paulina Ramirez-Neria, Marlon Garcia-Roa, Yolanda Villalpando, Juan Pablo Robles, Gabriela Ramirez-Hernandez, Mariana Lopez, Jorge Sanchez, Ellery Lopez-Star, Thomas Bertsch, Gonzalo Martinez de la Escalera, Ma. Ludivina Robles-Osorio, Jakob Triebel, Carmen Clapp; Levosulpiride Increases the Levels of Prolactin and Antiangiogenic Vasoinhibin in the Vitreous of Patients with Proliferative Diabetic Retinopathy. Trans. Vis. Sci. Tech. 2020;9(9):27. doi: https://doi.org/10.1167/tvst.9.9.27.
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High circulating levels of the hormone prolactin (PRL) protect against experimental diabetic retinopathy (DR) due to the retinal accumulation of vasoinhibin, a PRL fragment that inhibits blood vessel permeability and growth. A phase 2 clinical trial is investigating a new therapy for DR based on elevating serum PRL levels with levosulpiride, a prokinetic dopamine D2 receptor blocker. Here, we tested whether levosulpiride-induced hyperprolactinemia elevates PRL and vasoinhibin in the vitreous of volunteer patients with proliferative DR (PDR) undergoing elective pars plana vitrectomy.
Patients were randomized to receive placebo (lactose pill, orally TID; n = 19) or levosulpiride (25 mg orally TID; n = 18) for the 7 days before vitrectomy. Vitreous samples from untreated non-diabetic (n = 10) and PDR (n = 17) patients were also studied.
Levosulpiride elevated the systemic (101 ± 13 [SEM] vs. 9.2 ± 1.3 ng/mL, P < 0.0001) and vitreous (3.2 ± 0.4 vs. 1.5 ± 0.2 ng/mL, P < 0.0001) levels of PRL, and both levels were directly correlated (r = 0.58, P < 0.0002). The vitreous from non-diabetic patients or from PDR patients treated with levosulpiride, but not from placebo-treated PDR patients, inhibited the basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-induced proliferation of endothelial cells in culture. Vasoinhibin-neutralizing antibodies reduced the vitreous antiangiogenic effect. Matrix metalloproteases (MMPs) in the vitreous cleaved PRL to vasoinhibin, and their activity was higher in non-diabetic than in PDR patients.
Levosulpiride increases the levels of PRL in the vitreous of PDR patients and promotes its MMP-mediated conversion to vasoinhibin, which can inhibit angiogenesis in DR.
These findings support the potential therapeutic benefit of levosulpiride against vision loss in diabetes.
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