The Rho kinase inhibitor fasudil attenuates Aβ1–42-induced apoptosis via the ASK1/JNK signal pathway in primary cultures of hippocampal neurons

Gao, Ye; Yan, Yuqing; Fang, Qingli; Zhang, Nianping; Kumar, Gajendra; Zhang, Jihong; Song, Li-Juan; Yu, Jiezhong; Zhao, Linhu; Zhang, Han-Ting; Ma, Cun-Gen

doi:10.1007/s11011-019-00487-0

Original Article
Published: 03 September 2019

The Rho kinase inhibitor fasudil attenuates Aβ_1–42-induced apoptosis via the ASK1/JNK signal pathway in primary cultures of hippocampal neurons

Ye Gao¹^na1,
Yuqing Yan¹^na1,
Qingli Fang¹,
Nianping Zhang¹,
Gajendra Kumar^3,4,
Jihong Zhang¹,
Li-Juan Song²,
Jiezhong Yu^1,5,
Linhu Zhao¹,
Han-Ting Zhang⁶ &
Cun-Gen Ma^1,2

Metabolic Brain Disease volume 34, pages 1787–1801 (2019)Cite this article

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Abstract

Alzheimer’s disease (AD), a chronic, progressive, neurodegenerative disorder, is the most common type of dementia. Beta amyloid (Aβ) peptide aggregation and phosphorylated tau protein accumulation are considered as one of the causes for AD. Our previous studies have demonstrated the neuroprotective effect of the Rho kinase inhibitor fasudil, but the mechanism remains elucidated. In the present study, we examined the effects of fasudil on Aβ_1–42 aggregation and apoptosis and identified the intracellular signaling pathways involved in these actions in primary cultures of mouse hippocampal neurons. The results showed that fasudil increased neurite outgrowth (52.84%), decreased Aβ burden (46.65%), Tau phosphorylation (96.84%), and ROCK-II expression. In addition, fasudil reversed Aβ_1–42-induced decreased expression of Bcl-2 and increases in caspase-3, cleaved-PARP, phospho-JNK(Thr183/Tyr185), and phospho-ASK1(Ser966). Further, fasudil decreased mitochondrial membrane potential and intracellular calcium overload in the neurons treated with Aβ_1–42. These results suggest that inhibition of Rho kinase by fasudil reverses Aβ_1–42-induced neuronal apoptosis via the ASK1/JNK signal pathway, calcium ions, and mitochondrial membrane potential. Fasudil could be a drug of choice for treatment of Alzheimer’s disease.

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Funding

This work was supported by research grants from the National Natural Science Foundation of China (No. 81272163 and 81,371,414 to C-GM), the Department of Science and Technology, Shanxi Province of China (201803D421073 to YY, 201803D31079 to NPZ, 201805D111009 to CGM, 201805D131005 to JZY), Datong Municipal Science and Technology Bureau (2,017,134 to YY, 2019152 to NPZ, 2019072 to YG, 2019198 to C-GM), PhD Initiation Grant of Datong University (2016-B-01 to YY, 2018-B-01 to YG), Key Discipline of Internal Medicine Grant of Datong University (100,201 to NPZ)and the Open Project of State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China (2018-MDB-KF-07 to YY).

Author information

Ye Gao and Yuqing Yan contributed equally to this work.

Affiliations

Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China
Ye Gao, Yuqing Yan, Qingli Fang, Nianping Zhang, Jihong Zhang, Jiezhong Yu, Linhu Zhao & Cun-Gen Ma
The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Taiyuan, China
Li-Juan Song & Cun-Gen Ma
Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Hong Kong
Gajendra Kumar
Bio-Signal technologies (HK) Limited, 9th Floor, Amtel Building,148 Des Voeux Road Central, Central, Hong Kong
Gajendra Kumar
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
Jiezhong Yu
Departments of Neuroscience and Behavioral Medicine & Psychiatry, the Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA
Han-Ting Zhang

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Ye Gao
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Yuqing Yan
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Qingli Fang
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Nianping Zhang
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Gajendra Kumar
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Jihong Zhang
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Li-Juan Song
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Jiezhong Yu
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Linhu Zhao
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Han-Ting Zhang
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Cun-Gen Ma
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Contributions

YG, YY, QLF designed the study, carried out the primary neuron cell tests, immunoassays and western blotting. CGM, HTZ and YY conceived the study, participated in its design and coordination and helped draft the manuscript. NZ, GK participated in its design and revised the manuscript. HTZ revised and finalized the manuscript. JHZ and LHZ participated in the statistical analysis. LJS and JZY participated in figures revision, statistics and text revision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yuqing Yan, Han-Ting Zhang or Cun-Gen Ma.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Gao, Y., Yan, Y., Fang, Q. et al. The Rho kinase inhibitor fasudil attenuates Aβ_1–42-induced apoptosis via the ASK1/JNK signal pathway in primary cultures of hippocampal neurons. Metab Brain Dis 34, 1787–1801 (2019). https://doi.org/10.1007/s11011-019-00487-0

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Received: 01 July 2019
Accepted: 27 August 2019
Published: 03 September 2019
Issue Date: December 2019
DOI: https://doi.org/10.1007/s11011-019-00487-0

Keywords

Fasudil
Rho kinase
Aβ_1–42
Apoptosis
JNK
Neurons
Alzheimer’s disease