Influence of aromatase on neuromuscular plasticity resulting from testosterone plus locomotor training after spinal cord injury

芳香酶对睾酮联合运动训练脊髓损伤后神经肌肉可塑性的影响

• 批准号: 10382225
• 负责人: Dana M Otzel
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382225
• 关键词: Address; Adjuvant; Anatomy; Animals; Area; Aromatase; Aromatase Inhibitors; Award; Body Weight; Chest; Clinical; Clinical Trials; Combined Modality Therapy; Data; Distal; Dose; Estradiol; Exhibits; Fiber; Future; Growth; Health system; Hemoglobin; Heptanoates; Hindlimb; Histologic; Hormonal; Impairment; In Situ; Individual; Injury; K-Series Research Career Programs; Lesion; Locomotor Recovery; Locomotor training; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Morphology; Motor Neurons; Muscle; Muscle Fibers; Muscle function; Neuraxis; Neuronal Plasticity; Output; Paralysed; Pharmacotherapy; Physical Rehabilitation; Prostate; Rattus; Recovery; Rodent; Severities; Site; Soleus Muscle; Spinal; Spinal Cord Contusions; Spinal Cord Lesions; Spinal cord injury; Testosterone; Testosterone Enanthate; Translations; Treatment Efficacy; Veterans; Walking; anastrozole; androgenic; base; comparative efficacy; efficacy study; experimental study; functional adaptation; functional gain; improved; male; men; motor disorder; neuromuscular; neuromuscular function; neuromuscular plasticity; neuroprotection; novel; novel strategies; novel therapeutics; pre-clinical; preservation; prevent; primary outcome; prostate enlargement; relating to nervous system; response; secondary outcome; sham surgery; side effect; success; treadmill training; white matter

The motor dysfunction resulting from spinal cord injury (SCI) is precipitated by the neural insult and is exacerbated by other factors that hinder motoneuron survival and muscle recovery, including disuse and low testosterone (T). The success of bodyweight-supported treadmill training (BWSTT) diminishes as the SCI severity worsens. We have developed a novel strategy involving BWSTT with adjuvant T-enanthate (TE) drug treatment that promotes use-dependent neuroplasticity, in-part, by preserving white matter at the spinal lesion and by supporting motoneuron survival, which stimulates neuromuscular recovery. However, the supraphysiologic TE dose we used produced prostate enlargement in our rodent severe contusion SCI model, which limits translation. The purpose of this proposal is to improve the translational applicability of BWSTT+TE by identifying the lowest TE dose that enhances BWSTT-mediated neuromotor improvement, in an effort to limit prostate growth and other androgenic side-effects. Secondly, we will determine the influence of estradiol (E2) on BWSTT-mediated locomotor recovery and neuromuscular plasticity. The latter remains important from translational and mechanistic perspectives because (1) T is converted to E2, via aromatase, within the central nervous system and (2) E2 treatment produces potent neuroprotection in rats after SCI. To provide comprehensive evidence of neuroplasticity, we will evaluate functional adaptations in our rodent SCI model in response to the proposed treatments and assess anatomical changes that occur at the spinal cord lesion and distal to the lesion, and in spinal motoneurons and muscle. To support this proposal, we have established a male rodent severe mid-thoracic contusion SCI model that exhibits persistent hindlimb paralysis and progressive muscle decline and 50% lower circulating T than non-SCI animals, similar to the T deficiency present in nearly all men after SCI. Our data indicate that BWSTT+TE restored hindlimb overground walking after severe SCI more so than BWSTT (alone) or TE (alone). Moreover, BWSTT+TE improved recovery of muscle fiber cross-sectional area (fCSA), muscle force output, and prevented the deleterious slow (oxidative) to fast (glycolytic) fiber-type transition in muscle. In Aim 1, we will perform a dose-optimization experiment to identify the lowest effective TE dose and we will build upon our original data by comprehensively evaluating locomotor recovery and neuromuscular plasticity in response to BWSTT+TE. The primary outcomes are open- field locomotor recovery, soleus muscle function, soleus fCSA and fiber type distribution. In Experiment 1a, SCI animals will remain untreated (vehicle) or will receive BWSTT with low, moderate, or high-dose TE, with the lowest effective dose advancing. In Experiment 1b, SCI animals will receive vehicle, BWSTT, TE, or BWSTT+TE. Aim 2 will then determine the influence of estradiol (E2) on BWSTT-mediated locomotor recovery and neuromuscular plasticity. In Experiment 2a, SCI rats will receive vehicle, BWSTT, BWSTT+AN (aromatase inhibitor that blocks conversion of T to E2), BWSTT+TE, or BWSTT+TE+AN. Experiment 2b will be a dose- optimization study to identify the lowest E2 dose that enhances BWSTT-mediated neuromotor improvement. SCI animals will receive vehicle or BWSTT with low-, moderate-, or high-dose E2. Experiment 2c will be a comparative efficacy study in which SCI animals will receive vehicle, BWSTT or E2 (alone and in combination), or BWSTT+TE. We hypothesize that the functional and anatomical measures of neuromuscular plasticity will be most evident in SCI animals receiving BWSTT+TE, that E2 partially mediates neuromuscular plasticity resulting from BWSTT+TE, and that more robust neuromotor improvement will occur in response to BWSTT+TE versus BSWTT+E2. We anticipate that these experiments will provide the necessary data to establish preclinical proof-of-principle for our multimodal therapy. If successful, this will set the stage for translation of our preclinical findings to future clinical trials intended to hasten locomotor recovery and improve neuromuscular function in Veterans with SCI.

脊髓损伤（SCI）导致的运动功能障碍是由神经损伤引起的，并且是 阻碍运动神经元存活和肌肉恢复的其他因素（包括废用和低水平）会加剧这种情况 睾酮（T）。随着 SCI 的出现，自重跑步机训练 (BWSTT) 的成功率会降低 严重程度恶化。我们开发了一种新策略，涉及 BWSTT 和辅助 T-庚酸 (TE) 药物 部分通过保留脊髓病变处的白质来促进使用依赖性神经可塑性的治疗 并支持运动神经元的存活，从而刺激神经肌肉的恢复。然而， 我们使用的超生理学 TE 剂量在我们的啮齿动物严重挫伤 SCI 模型中产生了前列腺增大， 这限制了翻译。该提案的目的是提高 BWSTT+TE 的翻译适用性 通过确定增强 BWSTT 介导的神经运动改善的最低 TE 剂量， 限制前列腺生长和其他雄激素副作用。其次，我们将确定雌二醇的影响 (E2) BWSTT 介导的运动恢复和神经肌肉可塑性。后者仍然很重要 翻译和机械观点，因为 (1) T 通过芳香酶在中枢内转化为 E2 (2) E2 治疗对 SCI 后的大鼠产生有效的神经保护作用。提供 神经可塑性的综合证据，我们将评估我们的啮齿动物 SCI 模型的功能适应 对所提议的治疗的反应并评估脊髓病变处发生的解剖学变化，以及 病变远端以及脊髓运动神经元和肌肉中。为了支持这项提议，我们设立了一个 雄性啮齿动物严重胸中部挫伤 SCI 模型，表现出持续性后肢麻痹和 与非 SCI 动物相比，进行性肌肉衰退，循环 T 值降低 50%，类似于 T 缺乏 几乎所有 SCI 后的男性都存在这种情况。我们的数据表明 BWSTT+TE 恢复了后肢地上行走 严重 SCI 后比 BWSTT（单独）或 TE（单独）更有效。此外，BWSTT+TE 改善了恢复 肌纤维横截面积（fCSA），肌肉力量输出，并防止有害的缓慢（氧化） 肌肉中的快速（糖酵解）纤维类型转变。在目标 1 中，我们将进行剂量优化实验 确定最低有效 TE 剂量，我们将在原始数据的基础上综合评估 BWSTT+TE 的运动恢复和神经肌肉可塑性。主要结果是开放的 场运动恢复、比目鱼肌功能、比目鱼肌 fCSA 和纤维类型分布。在实验1a中， SCI 动物将保持不治疗（车辆）或接受低、中或高剂量 TE 的 BWSTT， 最低有效剂量提前。在实验 1b 中，SCI 动物将接受载体、BWSTT、TE 或 BWSTT+TE。目标 2 将确定雌二醇 (E2) 对 BWSTT 介导的运动恢复的影响 和神经肌肉可塑性。在实验2a中，SCI大鼠将接受媒介物、BWSTT、BWSTT+AN（芳香酶 阻断 T 转化为 E2 的抑制剂)、BWSTT+TE 或 BWSTT+TE+AN。实验 2b 将是一个剂量- 优化研究以确定增强 BWSTT 介导的神经运动改善的最低 E2 剂量。 SCI 动物将接受低、中或高剂量 E2 的载体或 BWSTT。实验 2c 将是 比较功效研究，其中 SCI 动物将接受媒介物、BWSTT 或 E2（单独或组合）， 或 BWSTT+TE。我们假设神经肌肉可塑性的功能和解剖学测量将 在接受 BWSTT+TE 的 SCI 动物中最为明显，E2 部分介导神经肌肉可塑性 BWSTT+TE 产生的结果，并且会因响应而发生更强大的神经运动改善 BWSTT+TE 与 BSWTT+E2。我们预计这些实验将提供必要的数据 为我们的多模式治疗建立临床前原理验证。如果成功，这将为 将我们的临床前研究结果转化为未来的临床试验，旨在加速运动恢复并改善 患有 SCI 的退伍军人的神经肌肉功能。