Female Sex Hormones and Spinal Injury

描述(由申请人提供)：我们建议确定内源性和外源性女性性激素对颈髓损伤(SCI)可能最关键的运动功能：呼吸的恢复的影响。虽然内源性雌激素和孕激素可以促进创伤性脑损伤后的恢复，但它们对脊髓损伤后运动恢复的影响尚不清楚。雌性啮齿动物发情周期中这些激素的波动表明，潜在的神经保护作用可能取决于受伤的时间。指导这一建议的第一个假设是，脊髓损伤时的发情周期阶段和相应的孕酮(孕激素)和17β-雌二醇(雌激素)水平将与运动恢复相关(目标1)。外源性黄体酮和17β-雌二醇的应用已被证明能促进脊髓损伤后的运动恢复。然而，这些激素也是强大的呼吸兴奋剂。P.I.和其他机构收集的数据表明，脊髓损伤后的呼吸刺激加强了现有的脊髓突触对膈运动神经元的输入。因此，针对呼吸功能不全的性激素治疗可能会将全身性神经保护作用与特定于膈运动系统的作用结合起来。因此，我们的第二个假设是，颈椎脊髓损伤后给予外源性孕酮和17β-雌二醇将促进呼吸运动恢复(目标2)。这些假说将在大鼠身上使用行为、神经生理学和免疫分析技术进行检验。在未麻醉的大鼠中，将通过气压体积描记仪评估其通气性。麻醉下的膈神经输出量将被量化，血浆激素水平将用酶联免疫吸附试验测定。这些数据将有助于确定1)内源性性激素是否可以影响临床前脊髓损伤的研究，以及2)孕酮和17P-雌二醇激素治疗是否是促进颈椎脊髓损伤后持续呼吸恢复的有效手段。

DESCRIPTION (provided by applicant): We propose to determine the effects of endogenous and exogenous female sex hormones on recovery of perhaps the most critical motor function impaired by cervical spinal cord injury (SCI): breathing. Although endogenous estrogens and progestins promote recovery following traumatic brain injury, their impact on motor recovery after SCI is unknown. Fluctuations in these hormones during the estrous cycle in female rodents suggest that potential "neuroprotective" effects may depend on the time of the injury. The first hypothesis guiding this proposal is that the estrous cycle stage and corresponding levels of progesterone (a progestin) and 17beta-estradiol (an estrogen) at the time of SCI will correlate with motor recovery (Aim 1). Administration of exogenous progesterone and 17beta-estradiol has been shown to improve locomotor recovery after SCI. However, these hormones are also powerful respiratory stimulants. Data collected by the P.I. and others indicates that respiratory stimulation after SCI strengthens existing spinal synaptic inputs to phrenic motoneurons. Thus, sex hormone therapy targeting respiratory insufficiency may combine generalized neuroprotective effects with effects specific to the phrenic motor system. Accordingly, our second hypothesis is that administration of exogenous progesterone and 17beta-estradiol after cervical SCI will improve respiratory motor recovery (Aim 2). These hypotheses will be tested using behavioral, neurophysiological, and immunoassay techniques in rats. Ventilation will be assessed in unanesthetized rats via barometric plethysmography. Phrenic output will be quantified under anesthesia, and plasma hormone levels will be measured with ELISA. These data will help establish 1) if endogenous gender hormones can influence preclinical SCI research, and 2) if progesterone and 17p-estradiol hormone therapy is an effective means of promoting persistent respiratory recovery following cervical SCI.