Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.
Neurotherapeutics. 2022 Apr;19(3):994-1006. doi: 10.1007/s13311-022-01216-9. Epub 2022 Mar 25.
Leigh syndrome (LS) is one of the most common mitochondrial encephalopathy diseases in infants. To date, there is still an absence of effective therapy. Bezafibrate (BEZ), a pan-peroxisome proliferator-activated receptor (PPAR) agonist, ameliorates the phenotype of the mouse model of mitochondrial disease via an unclear mechanism. Here, we applied it to Ndufs4 knockout (KO) mice, a widely used LS animal model, to observe the therapeutic effects and metabolic changes associated with BEZ treatment to explore the therapeutic strategies for mitochondrial diseases. Administration of BEZ significantly enhances survival and attenuates disease progression in Ndufs4 KO mice. Decreased oxidative stress and stunted growth were also observed. As a PPAR agonist, we did not find mitochondrial biogenesis or enhanced metabolism upon BEZ treatment. On the contrary, mice with dietary BEZ showed daily torpor bouts and lower metabolic rates. We speculate that activating energy-saving metabolism in mice may be associated with the therapeutic effects of BEZ, but the exact mechanism of action requires further study.
Leigh 综合征（LS）是婴儿期最常见的线粒体脑病之一。迄今为止，仍然缺乏有效的治疗方法。苯扎贝特（BEZ）是一种全过氧化物酶体增殖物激活受体（PPAR）激动剂，通过一种尚不清楚的机制改善了线粒体疾病的小鼠模型的表型。在这里，我们将其应用于 Ndufs4 敲除（KO）小鼠，这是一种广泛使用的 LS 动物模型，以观察 BEZ 治疗相关的治疗效果和代谢变化，探索线粒体疾病的治疗策略。BEZ 的给药显著提高了 Ndufs4 KO 小鼠的存活率并减轻了疾病进展。还观察到氧化应激减少和生长发育迟缓。作为一种 PPAR 激动剂，我们没有发现 BEZ 治疗后线粒体生物发生或代谢增强。相反，饮食中含有 BEZ 的小鼠表现出每日蛰伏发作和较低的代谢率。我们推测，激活小鼠的节能代谢可能与 BEZ 的治疗效果有关，但确切的作用机制需要进一步研究。
