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

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.