Yang Shao-Hua, Liu Ran, Wu Samuel S, Simpkins James W
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
Ann N Y Acad Sci. 2003 Dec;1007:101-7. doi: 10.1196/annals.1286.010.
There are 750,000 new cases of stroke each year in the United States, and brain damage from stroke leads to high health care costs and disabilities. Needed, but currently not available, are therapies that can be administered prior to, during, or after cerebral ischemia that reduce or eliminate neuronal damage from stroke. To address this issue, we began to assess the neuroprotective effects of estrogens and related compounds in stroke neuroprotection to determine whether these compounds had potential for clinical application. First, we demonstrated that 17 beta-estradiol (E2) pretreatment exerted potent neuroprotection of the cerebral cortex over a wide dose range and pretreatment interval. Thereafter, we assessed the ability of a variety of non-feminizing estrogens to protect brain tissue from stroke. We observed that pretreatment with 17 alpha-estradiol, the complete enantiomer of E2 (ENT-E2), 2-adamantylestrone, and the enantiomer of 17-desoxyestradiol, were as effective as E2 in pretreatment protection from stroke damage. These data suggest that non-estrogen receptor mechanisms are involved in brain neuroprotection under our treatment conditions. We then determined whether the observed E2 protection could be extended to times after the onset of the cerebral ischemic event. Using a formulation of E2 that rapidly delivers the steroid, a necessary condition for acute therapy of an ongoing stroke, we demonstrated that 100 mg E2/kg could protect brain tissue for up to 3 h after the onset of the stroke. To determine whether this therapeutic window could be extended with higher doses of the steroid, we conducted a dose-response assessment of E2 when administered at 6 h after the onset of the ischemic event. While the effectiveness of the 100 micro g E2/kg was reduced at this time interval, higher doses of E2 were effective. E2, at doses of 500 and 1000 micro g/kg, reduced infarct volume by more than 50%, even with this 6-h delay in treatment. Collectively, these data indicate that estrogens could prove to be useful therapies in preventing brain damage from strokes.
在美国，每年有75万例新发中风病例，中风导致的脑损伤会带来高昂的医疗成本和残疾问题。目前迫切需要但尚未有可用的疗法，即在脑缺血发生之前、期间或之后给予能够减少或消除中风所致神经元损伤的治疗方法。为了解决这个问题，我们开始评估雌激素及相关化合物在中风神经保护中的神经保护作用，以确定这些化合物是否具有临床应用潜力。首先，我们证明17β-雌二醇（E2）预处理在很宽的剂量范围和预处理间隔内对大脑皮层具有强大的神经保护作用。此后，我们评估了多种非女性化雌激素保护脑组织免受中风损伤的能力。我们观察到，用17α-雌二醇（E2的完全对映体，ENT-E2）、2-金刚烷雌酮和17-脱氧雌二醇的对映体进行预处理，在预防中风损伤方面与E2同样有效。这些数据表明，在我们的治疗条件下，非雌激素受体机制参与了脑保护作用。然后，我们确定观察到的E2保护作用是否可以扩展到脑缺血事件发生后的时间段。使用一种能快速递送该类固醇的E2制剂（这是正在发生的中风急性治疗的必要条件），我们证明100mg E2/kg在中风发作后长达3小时内可保护脑组织。为了确定更高剂量的类固醇是否可以延长这个治疗窗口，我们在缺血事件发作6小时后进行了E2的剂量反应评估。虽然在这个时间间隔内100μg E2/kg的有效性有所降低，但更高剂量的E2是有效的。即使治疗延迟6小时，500和1000μg/kg剂量的E2仍能使梗死体积减少超过50%。总体而言，这些数据表明雌激素可能被证明是预防中风脑损伤的有效疗法。
