International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
Department of Zoology, University of British Columbia, Vancouver, BC V6T 1Z1, Canada.
Cells. 2024 Oct 22;13(21):1746. doi: 10.3390/cells13211746.
Spinal cord injury (SCI) pathology and pathophysiology can be attributed to both primary physical injury and secondary injury cascades. Secondary injury cascades involve dysregulated metabolism and energetic deficits directly linked to compromised mitochondrial bioenergetics. Rescuing mitochondrial function and reducing oxidative stress are associated with neuroprotection. In this regard, ketosis after traumatic brain injury (TBI), or after SCI, improves secondary neuropathology by decreasing oxidative stress, increasing antioxidants, reducing inflammation, and improving mitochondrial bioenergetics. Here, we follow up on our previous study and have used an exogenous ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), as an alternative to a ketogenic diet, focusing on mitochondrial function between 1 and 14 days after injury. Starting 3 h following a cervical level 5 (C5) hemi-contusion injury, animals were fed either a standard control diet (SD) or a ketone ester diet (KED) combined with KE administered orally (OKE). We found that mitochondrial function was reduced after SCI at all times post-SCI, accompanied by reduced expression of most of the components of the electron transport chain (ETC). The KE rescued some of the bioenergetic parameters 1 day after SCI when D-β-Hydroxybutyrate (BHB) concentrations were ~2 mM. Still, most of the beneficial effects were observed 14 days after injury, with BHB concentrations reaching values of 4-6 mM. To our knowledge, this is the first report to show the beneficial effects of KE in rescuing mitochondrial function after SCI and demonstrates the suitability of KE in ameliorating the metabolic dysregulation that occurs after traumatic SCI without requiring a restrictive dietary regime.
脊髓损伤 (SCI) 的病理学和病理生理学既可以归因于原发性物理损伤，也可以归因于继发性损伤级联。继发性损伤级联涉及代谢失调和能量不足，这与受损的线粒体生物能直接相关。恢复线粒体功能和减少氧化应激与神经保护有关。在这方面，创伤性脑损伤 (TBI) 或 SCI 后的酮症通过降低氧化应激、增加抗氧化剂、减少炎症和改善线粒体生物能来改善继发性神经病理学。在这方面，我们跟进了之前的研究，并使用外源性酮单酯 (R)-3-羟基丁酸 (R)-3-羟基丁酸酯 (KE) 作为生酮饮食的替代品，重点研究损伤后 1 至 14 天的线粒体功能。在颈 5 水平 (C5) 半挫伤损伤后 3 小时，动物开始喂食标准对照饮食 (SD) 或酮酯饮食 (KED)，同时口服给予 KE (OKE)。我们发现，SCI 后所有时间点的线粒体功能都降低了，同时电子传递链 (ETC) 的大多数组件的表达也降低了。KE 在 SCI 后 1 天当 D-β-羟丁酸 (BHB) 浓度约为 2 mM 时，可挽救一些生物能量参数。尽管如此，大多数有益作用是在损伤后 14 天观察到的，BHB 浓度达到 4-6 mM。据我们所知，这是第一个报道显示 KE 在挽救 SCI 后线粒体功能方面有益作用的报告，并证明了 KE 适合改善创伤性 SCI 后发生的代谢失调，而无需限制饮食。
