Neuroprotection selective Estrogen or Genistein in Spinal Cord Injury

脊髓损伤中选择性雌激素或金雀异黄酮的神经保护作用

基本信息

批准号：
7209450
负责人：
CANDACE L. FLOYD
金额：
$ 19.03万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-08 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7209450
关键词：
17p Acute Adverse effects Affinity Agonist Apoptosis Apoptotic Astrocytes BCL2 gene Binding Bladder Brain Cardiac Cell Count Cell Death Chest Clinical Clip Cultured Cells Cyclic AMP Dorsal Dose Estradiol Estrogen Receptors Estrogens Female Genistein Glial Fibrillary Acidic Protein Gonadal structure Horns ICI 182780 Impairment In Situ Nick-End Labeling Injury Intervention Ischemia Lead Lesion Lower urinary tract Measures Mediating Methylprednisolone Modeling Multiple Trauma Nerve Degeneration Neuroglia Neuronal Injury Neurons Oligodendroglia Phytoestrogens Plants Proteins Rattus Reperfusion Injury Reporting Research Personnel Residual state Role Serum Spinal Cord Spinal cord injury Testing Thoracic spinal cord structure Tissues Weight Western Blotting caspase-3 clinically relevant day fluoro jade functional improvement gray matter in vivo interest male neuron loss neuroprotection neurotrophic factor neurotropic novel therapeutics programs protective effect receptor expression research study soy spinal cord compression therapeutic target white matter

项目摘要

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.

描述（由应用提供）：随着脊髓损伤（SCI）后的临床效率和使用的持续争议（SCI）的使用，兴趣的兴趣正在发现神经保护的新治疗靶标。最近，发现17？雌二醇在SCI中是有益的，这表明雌激素受体（ERS）可能是治疗靶标。雌激素与ER的两个亚型，经典时代和最近发现的时代具有同等亲和力。但是，哪种亚型对于神经保护作用是必要的，仍然存在争议，尚未在SCI中进行研究。此外，没有亚型选择性拮抗剂可以教授特定效果。选择性ERP激活可能提供保护的线索是SCI来自对植物衍生的雌激素或植物雌激素的研究。 Genastein是一种来自大豆的植物雌激素，剂量依赖性地依赖于神经元损伤和心脏缺血模型的保护。我们假设通过染料木黄酮对ER？的选择性激活将在SCI中产生重大保护。我们将在AIM 1中通过在大鼠中度胸部脊髓损伤后30分钟施用低剂量的染料木黄酮来检验这一假设。另外一组将接收染料木黄酮和ER拮抗剂ICI 182,780的共同给药。 SCI后7天，我们将评估急性损伤标志物，包括：细胞死亡，ER表达和凋亡相关蛋白质的蛋白质Bcl-2，Bax和活化的caspase-3。在AIM 2中，我们将有或没有ER拮抗剂ICI 182,780进行染料木黄酮，并评估继发性损伤的亚急性标记物，包括运动障碍，白质避免，病变体积和较低的尿路功能。该提案中的实验探讨了更优选地靶向非举足轻重的ER¿的临床相关可能性是通过评估天然植物衍生雌激素的神经保护潜力，在SCI中具有神经保护作用。