Intranasal administration is emerging as a very promising route to deliver therapeutics to the brain. We have recently shown that the intranasal delivery of progesterone at 8 mg/kg is neuroprotective after stroke in male mice. To explore the translational potential of intranasal progesterone treatment, we performed a dose-response study and analyzed outcomes at 48 h after middle cerebral artery occlusion (MCAO). The effects on functional outcomes at long-term were examined by using the optimal dose. In the first experiment, male C57BL/6JRj mice were treated with progesterone at 8, 16 or 24 mg/kg, or with placebo at 1, 6 and 24 h post-MCAO. Our results show that the dose of 8 mg/kg was optimal in counteracting the early histopathological impairments as well as in improving functional recovery. Steroid profiling in plasma showed that the dose of 8 mg/kg is the one that leads to sustained high levels of progesterone and its neuroactive metabolites. In the second experiment, the dose of 8 mg/kg was used and analyzes were performed at 2, 7 and 21 days post-MCAO. Progesterone increased survival, glycemia and body weight. Furthermore, progesterone decreased neurological deficits and improved performances of mice on the rotarod and pole as early as 2 days and up to 21 days post-MCAO. These findings show that intranasal administration of progesterone has a significant translational potential as a cerebroprotective treatment after stroke that can be effective to reduce mortality, to limit tissue and cell damage at the acute phase; and to confer a long-term functional recovery.

中文翻译：

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雄性小鼠缺血性卒中后鼻内输送孕激素的剂量依赖性和长期脑保护作用。

鼻内给药正在成为将治疗剂输送至大脑的非常有希望的途径。我们最近显示，雄性小鼠中风后鼻内递送8 mg / kg的孕酮对神经有保护作用。为了探索鼻内孕酮治疗的翻译潜力，我们进行了剂量反应研究并分析了大脑中动脉闭塞（MCAO）后48小时的结果。通过使用最佳剂量来检查长期对功能结局的影响。在第一个实验中，雄性C57BL / 6JRj小鼠在MCAO后1、8、16或24 mg / kg用孕酮治疗，或在安慰剂治疗后1、6和24 h用安慰剂治疗。我们的结果表明8 mg / kg的剂量在抵消早期的组织病理学损害以及改善功能恢复方面是最佳的。血浆中的类固醇分析表明，剂量为8 mg / kg是导致持续高水平的孕酮及其神经活性代谢物的剂量。在第二个实验中，使用8 mg / kg的剂量，并在MCAO后第2、7和21天进行了分析。孕酮可提高生存率，血糖和体重。此外，早在MCAO后2天至21天，孕酮减少了神经系统缺陷并改善了小鼠在旋转杆和杆上的性能。这些发现表明，鼻内给予黄体酮具有显着的翻译潜力，可作为卒中后的脑保护治疗，可有效降低死亡率，限制急性期的组织和细胞损伤。并给予长期的功能恢复。