Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
CNS Neurosci Ther. 2018 Dec;24(12):1163-1174. doi: 10.1111/cns.12855. Epub 2018 Apr 14.
To investigate the effect and mechanisms of carbamazepine (CBZ) on the onset and progression of amyotrophic lateral sclerosis (ALS) in SOD1-G93A mouse model.
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.
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.
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.
研究卡马西平（CBZ）对 SOD1-G93A 小鼠模型中肌萎缩侧索硬化（ALS）发病和进展的影响及机制。
从 64 天龄开始，SOD1-G93A 小鼠每天口服 CBZ 200mg/kg，直至死亡。记录 SOD1-G93A 小鼠的发病和生存期。通过尼氏染色和 SMI-32 免疫染色定量脊髓前角运动神经元（MNs）。还进行了苏木精和伊红（H&E）、烟酰胺腺嘌呤二核苷酸氢（NADH）、改良 Gomori 三色（MGT）和α-银环蛇毒素-ATTO-488 染色，以评估肌肉和神经肌肉接头（NMJ）损伤。进一步通过 Western blot 和免疫荧光染色检测聚集 SOD1 蛋白和自噬相关蛋白的表达。
卡马西平治疗可使 SOD1-G93A 小鼠的发病时间分别延迟约 14.5%和生存期分别延长约 13.9%。此外，CBZ 治疗减少了约 46.6%的 MNs 丢失，并改善了改变的肌肉形态和 NMJ。更有趣的是，机制研究表明 CBZ 通过 AMPK-ULK1 通路激活自噬，促进突变 SOD1 聚集物的清除。
我们的研究结果揭示了 CBZ 对 SOD1-G93A 小鼠疾病发病机制的治疗作用，表明 CBZ 在 ALS 治疗中有潜在的临床应用前景。
