Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, Barcelona, Spain.
Nat Commun. 2024 Sep 4;15(1):7730. doi: 10.1038/s41467-024-51884-8.
Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD's beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS.
线粒体能量产生基因的突变导致一组无法治疗的异质性疾病，称为原发性线粒体疾病（MD）。 Leigh 综合征（LS）是最常见的儿科 MD，其特征是进行性神经肌肉影响和过早死亡。在这里，我们表明，大麻二酚（CBD）的每日给药可显著延长两种 LS 小鼠模型的寿命并改善其病理学，并改善 LS 患者成纤维细胞的细胞功能。CBD 可延缓运动能力下降和神经退行性病变，改善社交缺陷和呼吸异常，减少热诱导性癫痫发作，并改善受影响大脑区域的神经病理学。从机制上讲，我们确定过氧化物酶体增殖物激活受体γ（PPARγ）为介导 CBD 有益作用的关键核受体，同时还提供了证据证明 LS 患者的神经元和成纤维细胞中普遍存在失调的 PPARγ 表达和活性。总之，我们的研究结果为 CBD 作为 LS 的潜在治疗方法提供了首个证据。
