Neuroprotection selective Estrogen or Genistein in Spinal Cord Injury

描述（由申请人提供）：随着甲基强的松龙在脊髓损伤（SCI）后的临床疗效和使用的持续争议，发现新的神经保护治疗靶点的兴趣重新燃起。最近，17¿-雌二醇被发现对脊髓损伤有益，这表明雌激素受体（er）可能是治疗的靶点。雌激素以相同的亲和力结合两种ER亚型，经典ERa和最近发现的ERa。然而，哪种亚型是神经保护作用所必需的仍然存在争议，尚未在脊髓损伤中进行研究。此外，没有亚型选择性拮抗剂可用于分离特异性作用。选择性ERp激活可能对脊髓损伤具有保护作用的线索来自植物源性雌激素的研究。染料木黄酮，一种来自大豆的植物雌激素和一种优先的ERp激动剂，剂量依赖性地赋予神经元损伤和心脏缺血模型保护作用。我们假设染料木素选择性激活ER¿会对脊髓损伤产生显著的保护作用。

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.