butylidenephthalide and Amyotrophic-Lateral-Sclerosis

To evaluate the therapeutic effects of n-butylidenephthalide (BP) in SOD1. Although BP treatment did not delay the disease onset, it prolonged the life span and thereafter extended the disease duration in SOD1. Our study suggests that BP may be a promising candidate for the treatment of ALS.

Topics: Administration, Oral; Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Autophagy; Cell Survival; Disease Models, Animal; Drug Evaluation, Preclinical; Hindlimb; Humans; Mice, Transgenic; Motor Activity; Motor Neurons; Muscle Strength; Muscle, Skeletal; Neuroimmunomodulation; Neuroprotective Agents; Phthalic Anhydrides; Random Allocation; Spinal Cord; Superoxide Dismutase-1

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.

Topics: Amyotrophic Lateral Sclerosis; Animals; Autophagy; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Female; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons; Phthalic Anhydrides; Random Allocation; Superoxide Dismutase-1; Survival Rate