Levosulpiride Increases the Levels of Prolactin and Antiangiogenic Vasoinhibin in the Vitreous of Patients with Proliferative Diabetic Retinopathy

Abstract

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. Methods: 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. Results: 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 nondiabetic patients or from PDR patients treated with levosulpiride, but not from placebotreated 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. Conclusions: 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. Translational Relevance: These findings support the potential therapeutic benefit of levosulpiride against vision loss in diabetes.

The HGR motif is the antiangiogenic determinant of vasoinhibin: implications for a therapeutic orally active oligopeptide

“…Vasoinhibin is generated in the hypothalamus, the pituitary, and the target tissues defining the PRL/vasoinhibin axis [ 16 ]. Disruption of this axis can contribute to the progression of diabetic retinopathy [ 17 , 18 ], retinopathy of prematurity [ 19 ], peripartum cardiomyopathy [ 20 ], pre-eclampsia [ 21 ], and rheumatoid arthritis [ 22 ]. However, translation of vasoinhibin into the clinic has been tempered by difficulties in its recombinant production [ 23 ].…”

Sulpiride‐induced hyperprolactinaemia increases retinal vasoinhibin and protects against diabetic retinopathy in rats

“…IP‐Western blot, a semiquantitative method that may not be sensitive enough to detect vasoinhibin in the circulation, 21 was not able to show an elevation of systemic vasoinhibin. However, sulpiride did enhance the Western blot detection of a vasoinhibin‐like protein in the retina of diabetic rats.…”

“…The reason for this difference may relate to the integrity of the blood ocular barrier of the nondiabetic condition limiting access of systemic PRL into the eye. It may also be possible that the activity of PRL cleaving proteases is reduced under normal health conditions, albeit the opposite has been reported for the vitreous of nondiabetic patients compared to patients with proliferative DR. 21 Clarification of these possibilities warrants further research.…”

“…20 The ongoing clinical trial supported the potential beneficial outcome of levosulpiride by showing that this compound elevates PRL and vasoinhibin levels in the vitreous of patients with proliferative DR undergoing elective pars plana vitrectomy. 21 Here, we report that rats treated with either racemic sulpiride or exogenous PRL have increased levels of vasoinhibin in the retina and display reduced retinal hypervasopermeability in response to diabetes or vascular endothelial growth factor (VEGF) intravitreal administration.…”

Future Perspectives of Therapeutic, Diagnostic and Prognostic Aptamers in Eye Pathological Angiogenesis

“…Besides PEDF, there are other antiangiogenic factors in the retina that play an important role in maintaining the angiogenic homeostasis, such as the transforming growth factor beta (TFG-beta), endostatin [63], thrombospondin [64], somatostatin [65] and vasoinhibins [66]. Vasoinhibins maintain the quiescent state of retinal blood vessels and protect retinal cells against a dysregulated angiogenic environment in DR and ROP [67]. Vasoinhibins are antiangiogenic peptides synthetized from prolactin, growth hormone and placental lactogen in physiological conditions.…”