中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (10): 1912-1919.doi: 10.4103/1673-5374.280327

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

生酮饮食联合外源性酮盐对急性脊髓损伤有神经保护作用

  

  • 出版日期:2020-10-15 发布日期:2020-08-19
  • 基金资助:

    尼尔森基金会和加拿大卫生研究所的支持,中国国家留学基金委基金项目,Blusson访问学者,Rick Hansen基金会

Neuroprotective effects of a ketogenic diet in combination with exogenous ketone salts following acute spinal cord injury

Bo-Tao Tan1, 2, Hui Jiang2, 4, Aaron J. Moulson2, 3, Xiao-Liang Wu4, Wen-Chun Wang5, Jie Liu2, 3, Ward T. Plunet2, Wolfram Tetzlaff2, 3   

  1. 1 Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
    2 International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Center, Vancouver, British Columbia, Canada
    3 Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
    4 Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
    5 Department of Rehabilitation Medicine, The General Hospital of Western Theater Command PLA, Chengdu, Sichuan Province, China
  • Online:2020-10-15 Published:2020-08-19
  • Contact: Bo-Tao Tan, MD, PhD,tanbotao@hospital.cqmu.edu.cn.
  • Supported by:
    This study was supported by the Craig Neilsen Foundation (to WT), and the Canadian Institutes for Health Research (to WT). BTT was supported by the China Scholarship Council (No. 201508500102) and a visiting trainee stipend from the Blusson Integrated Cure Partnership. WT holds the John and Penny Ryan British Columbia Leadership Chair in Spinal Cord Research funded in part by the Rick Hansen Foundation.

摘要:

作者既往研究显示,生酮饮食可对脊髓损伤啮齿动物模型产生神经保护作用,但是在急性损伤期应用生酮饮食时,体内酮体水平升高需要一定时间,这限制了生酮饮食的临床应用。因此,作者希望通过外源酮补充剂联合生酮饮食作为脊髓损伤后快速诱导酮症代谢状态的手段。实验首先在正常大鼠中验证了生酮饮食基础上的酮盐灌胃能有效且快速的升高血酮体(主要是β-羟丁酸)水平。紧接着制备了大鼠C5半挫裂损伤模型,在损伤后3h接受生酮饮食,并补充了1000-1500 mg酮盐(钙/钠-βHB无机盐),每隔12h一次,连续4d。结果发现,生酮饮食+酮盐的联合干预在24h左右就能明显提升血液中酮体水平。使用圆筒测试和梯式食物抓取测试来评价大鼠的上肢随意运动能力,证实生酮饮食+酮盐联合干预可促进脊髓损伤大鼠行为功能的恢复,且这种恢复最早出现在损伤后4周;且组织学分析进一步发现,其还能增加损伤中心头侧的前角神经元和背侧皮质脊髓束的数量。结果表明对急性脊髓挫裂伤大鼠行生酮饮食及早期酮盐灌胃,可快速提高大鼠血液中酮体水平,促进运动功能的恢复。实验于2015年8月31日经加拿大不列颠哥伦比亚大学动物伦理委员会批准,批准号:A14-350。

orcid: 0000-0001-8513-3416 (Bo-Tao Tan)

关键词: 脊髓损伤, 酮补充剂, 神经保护, 生酮饮食, 轴突, 髓磷脂, 行为, 皮质脊髓束

Abstract: We have previously shown that induction of ketosis by ketogenic diet (KD) conveyed neuroprotection following spinal cord injury in rodent models, however, clinical translation may be limited by the slow raise of ketone levels when applying KD in the acute post-injury period. Thus we investigated the use of exogenous ketone supplementation (ketone sodium, KS) combined with ketogenic diet as a means rapidly inducing a metabolic state of ketosis following spinal cord injury in adult rats. In uninjured rats, ketone levels increased more rapidly than those in rats with KD alone and peaked at higher levels than we previously demonstrated for the KD in models of spinal cord injury. However, ketone levels in KD + KS treated rats with SCI did not exceed the previously observed levels in rats treated with KD alone. We still demonstrated neuroprotective effects of KD + KS treatment that extend our previous neuroprotective observations with KD only. The results showed increased neuronal and axonal sparing in the dorsal corticospinal tract. Also, better performance of forelimb motor abilities were observed on the Montoya staircase (for testing food pellets reaching) at 4 and 6 weeks post-injury and rearing in a cylinder (for testing forelimb usage) at 6 and 8 weeks post-injury. Taken together, the findings of this study add to the growing body of work demonstrating the potential benefits of inducing ketosis following neurotrauma. Ketone salt combined with a ketogenic diet gavage in rats with acute spinal cord injury can rapidly increase ketone body levels in the blood and promote motor function recovery. This study was approved by the Animal Care Committee of the University of British Columbia (protocol No. A14-350) on August 31, 2015.

Key words: axon, behavior, corticospinal tract, ketogenic diet, ketone supplementation, myelin, neuroprotection, spinal cord injury