Jing-Jing Zhang1,2,3, Qin-Ming Zhou4, Sheng Chen5, Wei-Dong Le1,2,6. 1. Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, China. 2. Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, China. 3. Chifeng Municipal Hospital, Chifeng, China. 4. Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 5. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 6. Collaborative Innovation Center for Brain Science, the First Affiliated Hospital, Dalian Medical University, Dalian, China.
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.
AIMS: To investigate the effect and mechanisms of carbamazepine (CBZ) on the onset and progression of amyotrophic lateral sclerosis (ALS) in SOD1-G93Amouse model. METHODS: Starting from 64 days of age, SOD1-G93Amice were orally administered with CBZ at 200 mg/kg once daily until death. The disease onset and life span of SOD1-G93Amice 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-G93Amice 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-G93Amice, indicating a promising clinical utilization of CBZ in ALS therapy.
Authors: Katarzyna Switon; Katarzyna Kotulska; Aleksandra Janusz-Kaminska; Justyna Zmorzynska; Jacek Jaworski Journal: Neuroscience Date: 2016-11-23 Impact factor: 3.590
Authors: Nehal M Elsherbiny; Yousra Abdel-Mottaleb; Amany Y Elkazaz; Hoda Atef; Rehab M Lashine; Amal M Youssef; Wessam Ezzat; Sabah H El-Ghaiesh; Rabie E Elshaer; Mohamed El-Shafey; Sawsan A Zaitone Journal: Front Neurosci Date: 2019-11-01 Impact factor: 4.677