Intranasal delivery of progesterone after transient ischemic stroke decreases mortality and provides neuroprotection
Intranasal delivery of progesterone after transient ischemic stroke decreases mortality and provides neuroprotection
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DOI：
10.1016/j.neuropharm.2015.06.002
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发表时间：
2015-10-01
影响因子：
4.7
通讯作者：
Guennoun, Rachida
中科院分区：
文献类型：
--
作者：
Frechou, Magalie;Zhang, Shaodong;Guennoun, Rachida
Progesterone是一种潜在的脑卒中神经保护剂。STAIR的建议之一是测试治疗剂的不同递送途径。在这里，我们研究了鼻内递送孕酮油凝胶的神经保护功效。雄性小鼠进行短暂性大脑中动脉闭塞（MCAO）1小时。在MCAO后1、6和24 h，小鼠接受孕酮（8 mg/kg）的鼻内或腹腔内给药。血浆和脑中的类固醇水平，通过气相色谱-质谱法测定2和24小时后，最后一次给药的孕酮。在MCAO后48 h进行行为学和组织病理学分析。对于血脑屏障（BBB）渗透性分析，小鼠在再灌注时接受一次孕酮或安慰剂的鼻内给药，并在MCAO后4小时评估伊文思蓝和荧光素钠外渗。经鼻给药后两小时，孕酮在脑和血浆中达到升高的水平，并被生物转化为5 α-还原代谢物和20 α-二氢孕酮。然而，脑水平的孕酮及其代谢物的一半左右，腹腔注射后测量，而11-脱氧皮质酮和皮质酮的水平低5倍。相比之下，24小时后，较高水平的孕酮测定在脑和血浆后鼻内比后腹腔内交付。鼻内注射孕酮可降低死亡率，改善运动功能，减少梗死，减轻神经元丢失，并减少早期血脑屏障破坏。本研究证明了孕酮鼻内给药的良好生物利用度、延长的吸收和良好的神经保护功效，从而潜在地为中风患者提供了一种有效、安全、无压力和非常简单的给药模式。(C)2015爱思唯尔有限公司版权所有。
Progesterone is a potential neuroprotective agent for cerebral stroke. One of the STAIR's recommendations is to test different routes of delivery of therapeutic agents. Here, we investigated the neuroprotective efficacy of intranasal delivery of progesterone in oleogel. Male mice were subjected to transient middle cerebral occlusion (MCAO) for 1 h. Mice received intranasal or intraperitoneal administrations of progesterone (8 mg/kg) at 1, 6, and 24 h post-MCAO. Plasma and brain levels of steroids were measured by gas chromatography-mass spectrometry 2 and 24 h after the last administration of progesterone. Behavioral and histopathological analyzes were performed at 48 h post-MCAO. For blood-brain barrier (BBB) permeability analysis, mice received one intranasal administration of progesterone or placebo at reperfusion and Evans Blue and sodium fluorescein extravasations were assessed at 4 h post-MCAO. Two hours after its nasal administration, progesterone reached elevated levels in brain and plasma and was bioconverted to its 5 alpha-reduced metabolites and to 20 alpha-dihydroprogesterone. However, brain levels of progesterone and its metabolites were about half those measured after intraperitoneal injections, whereas levels of 11-deoxycorticosterone and corticosterone were 5-times lower. In contrast, after 24 h, higher levels of progesterone were measured in brain and plasma after intranasal than after intraperitoneal delivery. Intranasal progesterone decreased the mortality rate, improved motor functions, reduced infarct, attenuated neuronal loss, and decreased the early BBB disruption. This study demonstrates a good bioavailability, a prolonged absorption and a good neuroprotective efficacy of intranasal delivery of progesterone, thus potentially offering an efficient, safe, non-stressful and very easy mode of administration in stroke patients. (C) 2015 Elsevier Ltd. All rights reserved.