Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice

作者：Hsueh Kuo Wei; Chiou Tzyy Wen; Chiang Shu Fen; Yamashita Toru; Abe Koji; Borlongan Cesar V; Sanberg Paul R; Huang Angela; Lin Shinn Zong^*; Ham Horng Jyh^*

来源：Neuropharmacology, 2016, 108: 152-160.

DOI：10.1016/j.neuropharm.2016.03.035

Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1(G93A)). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 +/- 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 +/- 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1(G93A):LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases.

• 出版日期2016-9
• 单位中国医科大学; 东华大学