Centre for Neuroscience, Surgery and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel, London, E1 2AT, UK.
University of Roehampton, Department of Life Sciences, Grove House, Roehampton Lane, London, SW15 5PJ, UK.
Theranostics. 2021 Jan 1;11(1):346-360. doi: 10.7150/thno.48995. eCollection 2021.
Traumatic brain injury (TBI) leads to neurological impairment, with no satisfactory treatments available. Classical ketogenic diets (KD), which reduce reliance on carbohydrates and provide ketones as fuel, have neuroprotective potential, but their high fat content reduces compliance, and experimental evidence suggests they protect juvenile brain against TBI, but not adult brain, which would strongly limit their applicability in TBI. We designed a new-KD with a fat to carbohydrate plus protein ratio of 2:1, containing medium chain triglycerides (MCT), docosahexaenoic acid (DHA), low glycaemic index carbohydrates, fibres and the ketogenic amino acid leucine, and evaluated its neuroprotective potential in adult TBI. Adult male C57BL6 mice were injured by controlled cortical impact (CCI) and assessed for 70 days, during which they received a control diet or the new-KD. The new-KD, that markedly increased plasma Beta-hydroxybutyrate (β-HB), significantly attenuated sensorimotor deficits and corrected spatial memory deficit. The lesion size, perilesional inflammation and oxidation were markedly reduced. Oligodendrocyte loss appeared to be significantly reduced. TBI activated the mTOR pathway and the new-KD enhanced this increase and increased histone acetylation and methylation. The behavioural improvement and tissue protection provide proof of principle that this new formulation has therapeutic potential in adult TBI.
创伤性脑损伤（TBI）导致神经功能障碍，目前尚无满意的治疗方法。经典的生酮饮食（KD）可以减少对碳水化合物的依赖，并提供酮体作为燃料，具有神经保护作用，但高脂肪含量会降低依从性，实验证据表明，它们可以保护青少年大脑免受 TBI 的影响，但不能保护成年大脑，这将极大地限制它们在 TBI 中的应用。我们设计了一种新的 KD，其脂肪与碳水化合物加蛋白质的比例为 2:1，含有中链甘油三酯（MCT）、二十二碳六烯酸（DHA）、低血糖指数碳水化合物、纤维和 ketogenic 氨基酸亮氨酸，并评估了它在成年 TBI 中的神经保护潜力。成年雄性 C57BL6 小鼠通过皮质控制冲击（CCI）受伤，并在 70 天内进行评估，在此期间它们接受对照饮食或新 KD。新 KD 显著增加了血浆 β-羟基丁酸（β-HB），明显减轻了感觉运动障碍，并纠正了空间记忆障碍。损伤大小、损伤周围炎症和氧化明显减少。少突胶质细胞的损失似乎明显减少。TBI 激活了 mTOR 通路，而新 KD 增强了这种增加，并增加了组蛋白乙酰化和甲基化。行为改善和组织保护提供了原理证明，这种新配方在成年 TBI 中有治疗潜力。
