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.

由脊髓损伤（SCI）引起的运动功能障碍是由神经损伤引起的， 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 睾酮（T）。体重支持跑步机训练（BWSTT）的成功率随着SCI的发生而降低。 严重程度我们已经开发了一种新的策略，涉及BWSTT与辅助T-庚酸（TE）药物 通过保留脊柱病变处的白色物质，部分促进使用依赖性神经可塑性的治疗 并通过支持运动神经元存活，刺激神经肌肉恢复。但 我们使用的超生理TE剂量在我们的啮齿动物严重挫伤SCI模型中产生前列腺增大， 这限制了翻译。本文旨在提高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， 翻译和机制的观点，因为（1）T转化为E2，通过芳香化酶，在中央 （2）E2对大鼠脊髓损伤后神经系统有明显的保护作用。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， 对建议治疗的反应，并评估脊髓病变处发生的解剖学变化， 病变远端，脊髓运动神经元和肌肉。为了支持这项建议，我们设立了一个 雄性啮齿动物严重胸中部挫伤SCI模型，其表现出持续的后肢麻痹， 进行性肌肉衰退，循环T比非SCI动物低50%，类似于T缺乏症 几乎所有的人在SCI后都会出现这种情况。我们的数据表明，BWSTT+TE恢复后肢地上行走 在严重的SCI后，比BWSTT（单独）或TE（单独）更严重。此外，BWSTT+TE提高了 肌纤维横截面积（fCSA），肌肉力量输出，并防止有害的缓慢（氧化） 快速（糖酵解）肌肉纤维型转变。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， 运动恢复和神经肌肉可塑性。主要结果是开放的- 场地运动恢复、比目鱼肌功能、比目鱼肌fCSA和纤维类型分布。在实验1a中， SCI动物将保持未处理（媒介物）或将接受BWSTT与低、中或高剂量TE， 最低有效剂量推进。在实验1b中，SCI动物将接受溶媒、BWSTT、TE或 BWSTT+TE。目的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大鼠将接受载体、BWSTT、BWSTT+AN（芳香化酶 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动物将接受具有低、中或高剂量E2的媒介物或BWSTT。实验2C将是一个 比较功效研究，其中SCI动物将接受溶剂、BWSTT或E2（单独和组合）， 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的结果，并且响应于BWSTT+ TE，将发生更稳健的神经运动改善。 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 脊髓损伤退伍军人的神经肌肉功能