Neuroprotection selective Estrogen or Genistein in Spinal Cord Injury

描述（由申请人提供）：随着对脊髓损伤（SCI）后甲基强的松龙的临床疗效和使用的持续争议，人们重新对发现新的神经保护治疗靶点产生了兴趣。最近，发现17 <$-雌二醇对SCI有益，这表明雌激素受体（ER）可能是治疗靶点。雌激素以相等的亲和力结合ER的两种亚型，经典的ER α和最近发现的ER α。然而，哪种亚型是神经保护作用所必需的仍然存在争议，并且尚未在SCI中进行研究。此外，没有亚型选择性拮抗剂可用于梳理除了具体的影响。选择性ERp激活可能提供保护的线索是SCI来自植物源性雌激素或植物雌激素的研究。染料木黄酮是一种来自大豆的植物雌激素，也是一种优先的ER β激动剂，在神经元损伤和心肌缺血模型中具有剂量依赖性的保护作用。我们推测，选择性激活雌激素受体将产生显着的保护SCI。 我们将测试这一假设，在目标1中，通过在大鼠中度胸脊髓损伤后30分钟给予低、中或高剂量的染料木黄酮。另一组将接受染料木黄酮和ER拮抗剂ICI 182，780的联合给药。在SCI后7天，我们将评估急性损伤标志物，包括：细胞死亡，ER表达，凋亡相关蛋白bcl-2，bax和活化的caspase-3的表达。在目标2中，我们将给予染料木黄酮与或不与ER拮抗剂ICI 182，780，并评估继发性损伤的亚急性标志物，包括运动障碍，白色物质保留，病变体积和下尿路功能。 本提案中的实验通过评估天然植物来源的雌激素染料木黄酮的神经保护潜力，探索了优先靶向非女性化ER在SCI中具有神经保护作用的临床相关可能性。

DESCRIPTION (provided by applicant): With the continuing controversy over the clinical efficiency and use of methylprednisolone after spinal cord injury (SCI), interest is renewed is discovering new therapeutic targets for neuroprotection. Recently, 17¿-estradiol was found to be beneficial in SCI which suggests that estrogen receptors (ERs) could be therapeutic targets. Estrogen binds with equal affinity to two subtypes of the ER, the classical ERa and the more recently discovered ERa. However, which subtype is necessary for neuroprotective effects remains controversial and has not been investigated in SCI. Also, no subtype selective antagonists are available to tease apart specific effects. A clue that selective ERp activation may confer protection is SCI comes from studies of plant-derived estrogens, or phytoestrogens. Genistein, a phytoestrogen from soy and a preferential ERp agonist, dose-dependently confers protection in models of neuronal injury and cardiac ischemia. We hypothesize that selective activation of the ER¿ by genistein will produce significant protection in SCI. We will test this hypothesis, in aim 1, by administering either a low, medium or high dose of genistein 30 minutes after a moderate thoracic spinal cord injury in rats. An additional group will receive co-administration of genistein and the ER antagonist ICI 182,780. At seven days post-SCI, we will evaluate acute injury markers including: cell death, ER expression, and expression of apoptosis related proteins bcl-2, bax, and activated caspase-3. In aim 2, we will administer genistein with and without the ER antagonist ICI 182,780 and evaluate sub-acute markers of secondary injury including locomotor impairment, white matter sparing, lesion volume, and lower urinary tract function. The experiments in this proposal explore the clinically relevant possibility that preferentially targeting the non-feminizing ER¿ is neuroprotective in SCI by evaluating the neuroprotective potential of a natural, plant- derived estrogen, genistein.