The role of EP(2) receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.
The role of EP(2) receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.
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DOI：
10.1136/bjophthalmol-2020-317762
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Overby DR
中科院分区：
文献类型：
--
作者：
Bertrand JA;Woodward DF;Sherwood JM;Wang JW;Overby DR
JV-GL 1的单次应用显著降低非人灵长类动物眼内压（IOP）约一周，与剂量无关。这种高度持久的作用与其眼部生物分布无关，也与其他前列腺素类EP 2受体（如曲拉帕格或奥美拉帕格）的每日一次给药方案无关。JV-GL 1多日延长活性的潜在药理机制非常有趣。本研究旨在通过使用EP 2受体遗传缺陷的小鼠来确定EP 2受体参与介导JV-GL 1的长期眼部扩张活性。在C57 BL/6 J和EP 2受体敲除小鼠（B6.129-Ptger 2 tm 1Brey/J; EP 2KO）中研究了JV-GL 1产生的持久眼内压降低。研究了眼压正常和类固醇诱导的高眼压（SI-OHT）小鼠。在全身麻醉下通过眼压计测量眼内压（IOP）。使用iPerfusion在灌注100 nM去酯JV-GL 1的血压正常的C57 BL/6 J小鼠眼中以及在3天前接受局部JV-GL 1（0.01%）的SI-OHT C57 BL/6 J小鼠眼中离体测量房水流出能力。JV-GL 1在类固醇诱导的青光眼高眼压模型中的初始一天和延长的多日效应都通过缺失编码EP 2受体的基因而消除。因此，JV-GL 1在SI-OHT EP 2KO小鼠中不降低IOP，但在同窝SI-OHT EP 2 WT对照小鼠中，JV-GL 1统计学显著地降低IOP 4-6天。JV-GL 1对IOP的一天和长期作用均完全依赖于EP 2受体。
A single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose. This highly protracted effect does not correlate with its ocular bio-disposition, or correlate with the once-daily dosing regimen for other prostanoid EP2 receptor such as trapenepag or omidenepag. The underlying pharmacological mechanism for the multi-day extended activity of JV-GL1 is highly intriguing. The present studies were intended to determine EP2 receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP2 receptors. The protracted intraocular pressure reduction produced by JV-GL1 was investigated in C57BL/6J and EP2 receptor knock-out mice (B6.129-Ptger2tm1Brey/J; EP2KO). Both ocular normotensive and steroid induced ocular hypertensive (SI-OHT) mice were studied. Intraocular pressure (IOP) was measured tonometrically under general anesthesia. Aqueous humor outflow facility was measured ex vivo using iPerfusion in normotensive C57BL/6J mouse eyes perfused with 100 nM de-esterified JV-GL1 and in SI-OHT C57BL/6J mouse eyes that had received topical JV-GL1 (0.01%) 3 days previously. Both the initial one day and protracted multi-day effects of JV-GL1 in the steroid induced ocular hypertension model for glaucoma, were abolished by deletion of the gene encoding the EP2 receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP2KO mice, but in littermate SI-OHT EP2WT control mice JV-GL1 statistically significantly lowered IOP for 4–6 days. Both the one-day and long-term effect of JV-GL1 on IOP are entirely EP2 receptor dependent.
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