Pharmacological antagonism of EP2 receptor does not modify basal cardiovascular and respiratory function, blood cell counts, and bone morphology in animal models.
Pharmacological antagonism of EP2 receptor does not modify basal cardiovascular and respiratory function, blood cell counts, and bone morphology in animal models.
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DOI：
10.1016/j.biopha.2022.112646
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Ganesh T
中科院分区：
文献类型：
--
作者：
Rawat V;Banik A;Amaradhi R;Rojas A;Taval S;Nagy T;Dingledine R;Ganesh T
EP 2受体已成为多种外周和中枢神经系统疾病的治疗靶点，在疾病病理学中具有加重作用。我们和其他人最近已经证明了EP 2拮抗剂在神经炎症和外周炎症的临床前模型中的有益作用。然而，早期报道，具有全局EP 2敲除（KO）的小鼠显示出对生育力和血压不利的表型。其他研究表明，用激动剂激活EP 2在动物模型中具有愈合骨折的有益效果。这些结果阻碍了EP 2拮抗剂的开发，以及EP 2拮抗剂作为治疗策略的发展。为了确定用EP 2拮抗剂治疗是否模拟EP 2 global KO小鼠的不良表型，我们在小鼠和大鼠中测试了两种EP 2拮抗剂TG 11 -77.HCl和TG 6 -10-1，同时它们处于正常或高盐饮食，并且通过两种不同的施用方案（急性和慢性）。无论啮齿类动物是常规饮食还是高盐饮食，拮抗剂对小鼠和大鼠的收缩压和舒张压、心率、呼吸功能均无不良影响。此外，长期暴露于TG 11 -77.HCl对小鼠的血细胞计数、骨体积和骨矿物质密度无不良影响。我们的研究结果反对使用EP 2的小分子可逆拮抗剂对健康啮齿动物的心血管和呼吸系统，血细胞计数和骨结构的不良影响，与遗传消融模型相反。这项研究为推进EP 2拮抗剂对涉及EP 2功能障碍的疾病的治疗应用铺平了道路。
The EP2 receptor has emerged as a therapeutic target with exacerbating role in disease pathology for a variety of peripheral and central nervous system disorders. We and others have recently demonstrated beneficial effects of EP2 antagonists in preclinical models of neuroinflammation and peripheral inflammation. However, it was earlier reported that mice with global EP2 knockout (KO) display adverse phenotypes on fertility and blood pressure. Other studies indicated that EP2 activation with an agonist has a beneficial effect of healing fractured bone in animal models. These results impeded the development of EP2 antagonists, and EP2 antagonism as therapeutic strategy. To determine whether treatment with EP2 antagonists mimics the adverse phenotypes of the EP2 global KO mouse, we tested two EP2 antagonists TG11-77.HCl and TG6-10-1 in mice and rats while they are on normal or high-salt diet, and by two different administration protocols (acute and chronic). There were no adverse effects of the antagonists on systolic and diastolic blood pressure, heart rate, respiratory function in mice and rats regardless of rodents being on a regular or high salt diet. Furthermore, chronic exposure to TG11-77.HCl produced no adverse effects on blood cell counts, bone-volume and bone-mineral density in mice. Our findings argue against adverse effects on cardiovascular and respiratory systems, blood counts and bone structure in healthy rodents from the use of small molecule reversible antagonists for EP2, in contrast to the genetic ablation model. This study paves the way for advancing therapeutic applications of EP2 antagonists against diseases involving EP2 dysfunction.
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影响因子：
6.1
作者：
Jiang, Jianxiong;Yang, Myung-Soon;Quan, Yi;Gueorguieva, Paoula;Ganesh, Thota;Dingledine, Raymond
通讯作者：
Dingledine, Raymond
影响因子：
15.9
作者：
Johansson, Jenny U.;Woodling, Nathaniel S.;Andreasson, Katrin I.
通讯作者：
Andreasson, Katrin I.
影响因子：
4.8
作者：
Hoshino, Tatsuya;Nakaya, Tadashi;Mizushima, Tohru
通讯作者：
Mizushima, Tohru
影响因子：
4.8
作者：
Li, XD;Okada, Y;Raisz, LG
通讯作者：
Raisz, LG
影响因子：
6.1
作者：
Kay, L. J.;Gilbert, M.;Peachell, P. T.
通讯作者：
Peachell, P. T.