Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study.
Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study.
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DOI：
10.1093/brain/awt319
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发表时间：
2014-02
期刊：
影响因子：
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通讯作者：
Bushra Wali;Tauheed Ishrat;Soonmi Won;D. Stein;I. Sayeed
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文献类型：
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作者：
Bushra Wali;Tauheed Ishrat;Soonmi Won;D. Stein;I. Sayeed
目前，唯一批准的治疗缺血性中风的方法是组织纤溶酶原激活剂，一种血栓克星。如果在中风后的前4小时内不给予这种治疗，可能会产生危险的后果。我们的研究小组和其他研究人员已经证明孕酮在中风的临床前研究中是有益的，但是缺乏孕酮剂量反应和时间窗研究。我们测试了永久性大脑中动脉闭塞或假手术的雄性Sprague-Dawley大鼠（12个月大）的感觉、运动和认知表现的多项指标。对于剂量-反应研究，动物在闭塞后1小时接受孕酮（8、16或32 mg/kg）的腹膜内注射，并在6小时皮下注射，然后每24小时一次，持续7天。对于时间窗研究，在卒中后3、6或24小时开始给予孕酮的最佳剂量。重复评价行为恢复。在中风后22天处死大鼠，并提取脑用于评估梗死体积。与安慰剂相比，8和16 mg/kg剂量的孕酮均能减少梗死体积，并改善卒中后3周的运动活动、握力、感觉忽略、步态障碍、运动协调和空间导航测试的功能结局。在时间窗研究中，孕酮组表现出实质性的神经保护作用，迟至6小时后中风发作。与安慰剂相比，孕激素在3小时和6小时的延迟中显示出梗死面积的显著减少。在我们的临床相关中风模型中，中等剂量（8和16 mg/kg）的孕酮可减少梗死面积并改善功能缺陷。8 mg/kg剂量在改善运动、感觉和记忆功能方面是最佳的，并且在较大的治疗时间窗内观察到这种效果。Progestine显示出作为潜在治疗药物的前景，应在缺血性卒中的临床试验中检查其安全性和有效性。
Currently, the only approved treatment for ischaemic stroke is tissue plasminogen activator, a clot-buster. This treatment can have dangerous consequences if not given within the first 4 h after stroke. Our group and others have shown progesterone to be beneficial in preclinical studies of stroke, but a progesterone dose-response and time-window study is lacking. We tested male Sprague-Dawley rats (12 months old) with permanent middle cerebral artery occlusion or sham operations on multiple measures of sensory, motor and cognitive performance. For the dose-response study, animals received intraperitoneal injections of progesterone (8, 16 or 32 mg/kg) at 1 h post-occlusion, and subcutaneous injections at 6 h and then once every 24 h for 7 days. For the time-window study, the optimal dose of progesterone was given starting at 3, 6 or 24 h post-stroke. Behavioural recovery was evaluated at repeated intervals. Rats were killed at 22 days post-stroke and brains extracted for evaluation of infarct volume. Both 8 and 16 mg/kg doses of progesterone produced attenuation of infarct volume compared with the placebo, and improved functional outcomes up to 3 weeks after stroke on locomotor activity, grip strength, sensory neglect, gait impairment, motor coordination and spatial navigation tests. In the time-window study, the progesterone group exhibited substantial neuroprotection as late as 6 h after stroke onset. Compared with placebo, progesterone showed a significant reduction in infarct size with 3- and 6-h delays. Moderate doses (8 and 16 mg/kg) of progesterone reduced infarct size and improved functional deficits in our clinically relevant model of stroke. The 8 mg/kg dose was optimal in improving motor, sensory and memory function, and this effect was observed over a large therapeutic time window. Progesterone shows promise as a potential therapeutic agent and should be examined for safety and efficacy in a clinical trial for ischaemic stroke.