Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1‐G93A mouse model

摘要

Aims To investigate the effect and mechanisms of carbamazepine (CBZ) on the onset and progression of amyotrophic lateral sclerosis (ALS) in SOD1‐G93A mouse model. Methods Starting from 64?days of age, SOD1‐G93A mice were orally administered with CBZ at 200?mg/kg once daily until death. The disease onset and life span of SOD1‐G93A mice were recorded. Motor neurons (MNs) in anterior horn of spinal cord were quantified by Nissl staining and SMI‐32 immunostaining. Hematoxylin and eosin (H&E), nicotinamide adenine dinucleotide hydrogen (NADH), modified Gomori trichrome (MGT), and α‐bungarotoxin‐ATTO‐488 staining were also performed to evaluate muscle and neuromuscular junction (NMJ) damage. Expressions of aggregated SOD1 protein and autophagy‐related proteins were further detected by Western blot and immunofluorescent staining. Results Carbamazepine treatment could delay the disease onset and extend life span of SOD1‐G93A mice by about 14.5% and 13.9%, respectively. Furthermore, CBZ treatment reduced MNs loss by about 46.6% and ameliorated the altered muscle morphology and NMJ. Much more interestingly, mechanism study revealed that CBZ treatment activated autophagy via AMPK‐ULK1 pathway and promoted the clearance of mutant SOD1 aggregation. Conclusion Our findings uncovered the therapeutic effects of CBZ against disease pathogenesis in SOD1‐G93A mice, indicating a promising clinical utilization of CBZ in ALS therapy.