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

Jing Jing Zhang, Qin Ming Zhou, Sheng Chen, Wei Dong Le

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1163-1174
Number of pages12
JournalCNS Neuroscience and Therapeutics
Volume24
Issue number12
DOIs
StatePublished - Dec 2018

Keywords

  • SOD1-G93A mice
  • amyotrophic lateral sclerosis
  • autophagy
  • carbamazepine

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Physiology (medical)
  • Pharmacology (medical)

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