Evaluation of a Ketogenic Diet for Improvement of Neurological Recovery in Individuals with Acute Spinal Cord Injury

摘要 尽管有广泛的研究、临床进步和改进的康复策略， 脊髓损伤（SCI）仍然是世界范围内残疾和死亡的重要原因， 药物治疗已经证明在神经系统或 SCI患者的功能恢复。因此，迫切需要创新 改善SCI后神经恢复的疗法。这个项目的科学前提是 越来越多的证据表明，基于饮食的治疗，如生酮饮食（KD），提供有效的 对大鼠继发性损伤级联反应的神经保护和改善前肢运动功能 SCI模型KD是一种高脂肪，低碳水化合物的饮食，旨在模拟代谢和 在热量限制期间发生的生化变化，特别是酮症。酮体具有 已经显示出通过减轻神经炎症和抑制 脊髓中的细胞凋亡。因为神经炎症和诱导凋亡途径 导致脊髓在损伤后不久进行性变性，抑制这些 通过酮体的代谢过程可以促进SCI后的神经恢复。事实上，我们最近 一项初步研究首次表明，与标准医院饮食（SD）相比， KD改善急性SCI患者的上肢运动功能。此外，a 神经炎性血液蛋白，纤维蛋白原，在KD血清样品中低于SD 血清样品，表明KD可能部分通过减少 纤维蛋白原。SCI后的急性期也以高血糖为特征，高血糖是严重的。 与出院时功能结果不佳相关。在我们的初步研究中，空腹血糖 在KD组中水平降低了24 mg/dl，但在SD组中增加了0.7 mg/dl。这些 一个具有挑战性的发现使我们得出了我们的中心假设，即服用KD的SCI患者 在受伤后的前5周（平均住院时间）内将有更好的神经恢复， 功能独立性和血糖控制比SCI患者谁消耗SD期间 此期间我们将在一项随机对照试验中检验这一假设，该试验有两个具体目标：1） 确定5周KD与SD相比是否显著改善了运动和感觉功能， 急性SCI患者的独立性和血糖控制，以及2）定量血清生物标志物 负责神经恢复和功能独立性的改善。我们 研究结果将揭示有针对性的营养策略的分子机制， 促进脊髓损伤后不久的神经恢复，并可能导致安全，有效，简单，经济 改善SCI后的健康状况。

ABSTRACT Despite extensive research, clinical advancements, and improved rehabilitation strategies, spinal cord injury (SCI) continues to be a significant cause of disability and mortality worldwide, and no pharmacologic therapy has demonstrated significant improvement effects in the neurological or functional recovery of individuals with SCI. Therefore, there is an urgent need for innovative therapies for improving neurorecovery after SCI. The scientific premise of this project builds upon accumulating evidence that diet-based therapies, such as the ketogenic diet (KD), offer effective neuroprotection against secondary injury cascades and improve forelimb motor function in a rat model of SCI. The KD is a high-fat, low-carbohydrate diet designed to mimic the metabolic and biochemical changes that occur during calorie restriction, specifically ketosis. Ketone bodies have been shown to exert neuroprotective effects by attenuating neuroinflammation and inhibiting apoptosis in the spinal cord. Because neuroinflammation and induction of apoptotic pathways lead to progressive degeneration in the spinal cord shortly after the injury, inhibition of these processes by ketone bodies may enhance neurological recovery after an SCI. Indeed, our recent pilot study showed for the first time that, compared with a standard hospital diet (SD), 5 weeks of KD improved upper extremity motor function in patients with acute SCI. In addition, levels of a neuroinflammatory blood protein, fibrinogen, were lower in the KD serum samples than in the SD serum samples, suggesting a KD may induce anti-inflammatory effects in part by reducing fibrinogen. The acute stage after SCI is also characterized by hyperglycemia, which is strongly associated with poor functional outcomes at discharge. In our pilot study, fasting serum glucose levels decreased by 24 mg/dl in the KD group but increased by 0.7 mg/dl in the SD group. These provocative findings have led us to our central hypothesis that SCI patients who consume a KD over the first 5 weeks (average hospital stay) after injury will have better neurological recovery, functional independence, and glycemic control than the SCI patients who consume an SD during this period. We will test this hypothesis in a randomized, controlled trial with two specific aims: 1) Determine if 5 weeks of KD vs. SD significantly improves motor and sensory function, functional independence, and glycemic control in patients with acute SCI, and 2) Quantify serum biomarkers that are responsible for improvements in neurological recovery and functional independence. Our findings will uncover the molecular mechanisms by which targeted nutritional strategies can promote neurorecovery shortly after SCI and may lead to a safe, effective, simple, and economical intervention that improves health outcomes after SCI.