Department of Physical Medicine and Rehabilitation, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alhabama 35249, USA.
J Neurotrauma. 2010 Mar;27(3):611-26. doi: 10.1089/neu.2009.1069.
Several groups have recently shown that 17beta-estradiol is protective in spinal cord injury (SCI). Testosterone can be aromatized to 17beta-estradiol and may increase estrogen-mediated protection. Alternatively, testosterone has been shown to increase excitotoxicity in models of central nervous system (CNS) injury. These experiments test the hypothesis that endogenous testosterone in male rats alters 17beta-estradiol-mediated protection by evaluating a delayed administration over a clinically relevant dose range and manipulating testicular-derived testosterone. Adult male Sprague Dawley rats were either gonadectomized or left gonad-intact prior to SCI. SCI was produced by a midthoracic crush injury. At 30 min post SCI, animals received a subcutaneous pellet of 0.0, 0.05, 0.5, or 5.0 mg of 17beta-estradiol, released over 21 days. Hindlimb locomotion was analyzed weekly in the open field. Spinal cords were collected and analyzed for cell death, expression of Bcl-family proteins, and white-matter sparing. Post-SCI administration of the 0.5- or 5.0-mg pellet improved hindlimb locomotion, reduced urinary bladder size, increased neuronal survival, reduced apoptosis, improved the Bax/Bcl-xL protein ratio, and increased white-matter sparing. In the absence of endogenous testicular-derived androgens, SCI induced greater apoptosis, yet 17beta-estradiol administration reduced apoptosis to the same extent in gonadectomized and gonad-intact male rats. These data suggest that delayed post-SCI administration of a clinically relevant dose of 17beta-estradiol is protective in male rats, and endogenous androgens do not alter estrogen-mediated protection. These data suggest that 17beta-estradiol is an effective therapeutic intervention for reducing secondary damage after SCI in males, which could be readily translated to clinical trials.
最近有几个研究小组表明，17β-雌二醇对脊髓损伤（SCI）具有保护作用。睾酮可以被芳香化为 17β-雌二醇，并可能增加雌激素介导的保护作用。另一方面，睾酮已被证明会增加中枢神经系统（CNS）损伤模型中的兴奋性毒性。这些实验通过评估临床相关剂量范围内的延迟给药和操纵睾丸源性睾酮，来检验内源性睾酮会改变雄性大鼠中 17β-雌二醇介导的保护作用这一假说。成年雄性 Sprague Dawley 大鼠在 SCI 前接受睾丸切除术或保留睾丸。SCI 通过胸段挤压伤产生。在 SCI 后 30 分钟，动物接受了皮下 0.0、0.05、0.5 或 5.0mg 的 17β-雌二醇植入物，该植入物可在 21 天内释放。每周在开放场中分析后肢运动。收集脊髓并分析细胞死亡、Bcl 家族蛋白表达和白质保留情况。SCI 后给予 0.5 或 5.0mg 植入物可改善后肢运动，减少膀胱大小，增加神经元存活，减少细胞凋亡，改善 Bax/Bcl-xL 蛋白比值，并增加白质保留。在缺乏内源性睾丸源性雄激素的情况下，SCI 诱导更多的细胞凋亡，但在去势和保留睾丸的雄性大鼠中，17β-雌二醇的给药同样减少了细胞凋亡。这些数据表明，延迟给予临床相关剂量的 17β-雌二醇对雄性大鼠具有保护作用，而内源性雄激素不会改变雌激素介导的保护作用。这些数据表明，17β-雌二醇是一种有效的治疗干预措施，可减少男性 SCI 后的继发性损伤，这可以很容易地转化为临床试验。
