Open AccessVerapamil Ameliorates Motor Neuron Degeneration and Improves Lifespan in the SOD1G93A Mouse Model of ALS by Enhancing Autophagic Flux
Author(s) -
Xiaojie Zhang,
Sheng Chen,
Kaili Lu,
Feng Wang,
Jiangshan Deng,
Zhouwei Xu,
Xiuzhe Wang,
Qinming Zhou,
Weidong Le,
Yuwu Zhao
Publication year - 2019
Publication title -
aging and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.808
H-Index - 54
ISSN - 2152-5250
DOI - 10.14336/ad.2019.0228
Subject(s) - verapamil , endoplasmic reticulum , autophagy , neuroprotection , motor neuron , amyotrophic lateral sclerosis , medicine , sod1 , pharmacology , chemistry , endocrinology , neuroscience , calcium , biology , microbiology and biotechnology , biochemistry , disease , apoptosis
Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder caused by selective degeneration of motor neurons in the brain and spinal cord. Our previous studies indicated that abnormal protein aggregation and dysfunctional autophagic flux might contribute to the disease pathogenesis. In this study, we have detected the role of the Ca 2+ dependent autophagic pathway in ALS by using the L-type channel Ca 2+ blocker, verapamil. We have found that verapamil significantly delayed disease onset, prolonged the lifespan and extended disease duration in SOD1 G93A mice. Furthermore, verapamil administration rescued motor neuron survival and ameliorated skeletal muscle denervation in SOD1 G93A mice. More interestingly, verapamil significantly reduced SOD1 aggregation and improved autophagic flux, which might be mediated the inhibition of calpain 1 activation in the spinal cord of SOD1 G93A mice. Furthermore, we have demonstrated that verapamil reduced endoplasmic reticulum stress and suppressed glia activation in SOD1 G93A mice. Collectively, our study indicated that verapamil is neuroprotective in the ALS mouse model and the Ca 2+ -dependent autophagic pathway is a possible therapeutic target for the treatment of ALS.