Levosulpiride Increases the Levels of Prolactin and Antiangiogenic Vasoinhibin in the Vitreous of Patients with Proliferative Diabetic Retinopathy
Levosulpiride Increases the Levels of Prolactin and Antiangiogenic Vasoinhibin in the Vitreous of Patients with Proliferative Diabetic Retinopathy
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DOI：
10.1167/tvst.9.9.27
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发表时间：
2020-08-01
影响因子：
3
通讯作者：
Clapp, Carmen
中科院分区：
文献类型：
--
作者：
Nunez-Amaro, Carlos D.;Moreno-Vega, Aura Ileana;Clapp, Carmen
目的：高循环水平的激素催乳素（PRL）可以防止实验性糖尿病视网膜病变（DR），这是由于视网膜积累血管抑制素（一种抑制血管通透性和生长的PRL片段）。一项2期临床试验正在研究一种新的治疗DR的方法，该方法基于左旋舒匹利（一种促动力学多巴胺D2受体阻滞剂）提高血清PRL水平。在这里，我们测试了左旋舒必林诱导的高泌乳素血症是否会升高自愿接受选择性玻璃体部分切除术的增殖性DR （PDR）患者玻璃体中的PRL和血管抑制素。方法：患者在玻璃体切除术前7天随机接受安慰剂（乳糖丸，口服TID， n = 19）或左旋硫吡脲（口服TID， 25 mg, n = 18）。未治疗的非糖尿病患者（n = 10）和PDR患者（n = 17）的玻璃体样本也进行了研究。结果：左苏必利可提高体表PRL水平（101 +/- 13 [SEM] vs. 9.2 +/- 1.3 ng/mL, P < 0.0001）和玻璃体PRL水平（3.2 +/- 0.4 vs. 1.5 +/- 0.2 ng/mL, P < 0.0001），且两者水平直接相关（r = 0.58, P < 0.0002）。非糖尿病患者或接受左舒必利治疗的PDR患者的玻璃体，而不是安慰剂治疗的PDR患者的玻璃体，抑制了培养中碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）诱导的内皮细胞增殖。血管抑制素中和抗体降低玻璃体抗血管生成作用。基质金属蛋白酶（MMPs）在玻璃体劈裂PRL中对血管抑制素有抑制作用，其活性在非糖尿病患者中高于PDR患者。结论：左舒必利可提高PDR患者玻璃体PRL水平，促进其mmp介导的向血管抑制素的转化，从而抑制DR的血管生成。
Purpose: 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 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.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.