Inhibition of Death-associated Protein Kinase 1 protects against Epileptic Seizures in mice

Gan, Chen-Ling; Zou, Yulian; Xia, Yongfang; Zhang, Tao; Chen, Dongmei; Lan, Guihua; Mei, Yingxue; Wang, Long; Shui, Xindong; Hu, Li; Liu, Hekun; Lee, Tae Ho

doi:10.7150/ijbs.59922

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Int J Biol Sci 2021; 17(9):2356-2366. doi:10.7150/ijbs.59922 This issue Cite

Research Paper

Inhibition of Death-associated Protein Kinase 1 protects against Epileptic Seizures in mice

Chen-Ling Gan^1,2, Yulian Zou³, Yongfang Xia¹, Tao Zhang¹, Dongmei Chen¹, Guihua Lan¹, Yingxue Mei¹, Long Wang¹, Xindong Shui¹, Li Hu¹, Hekun Liu¹, Tae Ho Lee^1✉

1. Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, China.
2. Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Institute of Materia Medical, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China.
3. Immunotherapy Institute, Fujian Medical University, Fuzhou, Fujian 350122, China.

Citation:

Gan CL, Zou Y, Xia Y, Zhang T, Chen D, Lan G, Mei Y, Wang L, Shui X, Hu L, Liu H, Lee TH. Inhibition of Death-associated Protein Kinase 1 protects against Epileptic Seizures in mice. Int J Biol Sci 2021; 17(9):2356-2366. doi:10.7150/ijbs.59922. https://www.ijbs.com/v17p2356.htm

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Abstract

Epilepsy is a chronic encephalopathy and one of the most common neurological disorders. Death-associated protein kinase 1 (DAPK1) expression has been shown to be upregulated in the brains of human epilepsy patients compared with those of normal subjects. However, little is known about the impact of DAPK1 on epileptic seizure conditions. In this study, we aim to clarify whether and how DAPK1 is regulated in epilepsy and whether targeting DAPK1 expression or activity has a protective effect against epilepsy using seizure animal models. Here, we found that cortical and hippocampal DAPK1 activity but not DAPK1 expression was increased immediately after convulsive pentylenetetrazol (PTZ) exposure in mice. However, DAPK1 overexpression was found after chronic low-dose PTZ insults during the kindling paradigm. The suppression of DAPK1 expression by genetic knockout significantly reduced PTZ-induced seizure phenotypes and the development of kindled seizures. Moreover, pharmacological inhibition of DAPK1 activity exerted rapid antiepileptic effects in both acute and chronic epilepsy mouse models. Mechanistically, PTZ stimulated the phosphorylation of NR2B through DAPK1 activation. Combined together, these results suggest that DAPK1 regulation is a novel mechanism for the control of both acute and chronic epilepsy and provide new therapeutic strategies for the treatment of human epilepsy.

Keywords: Death-associated protein kinase 1, epilepsy, kindling, pentylenetetrazol, phosphorylation, seizure

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APA

Gan, C.L., Zou, Y., Xia, Y., Zhang, T., Chen, D., Lan, G., Mei, Y., Wang, L., Shui, X., Hu, L., Liu, H., Lee, T.H. (2021). Inhibition of Death-associated Protein Kinase 1 protects against Epileptic Seizures in mice. International Journal of Biological Sciences, 17(9), 2356-2366. https://doi.org/10.7150/ijbs.59922.

ACS

Gan, C.L.; Zou, Y.; Xia, Y.; Zhang, T.; Chen, D.; Lan, G.; Mei, Y.; Wang, L.; Shui, X.; Hu, L.; Liu, H.; Lee, T.H. Inhibition of Death-associated Protein Kinase 1 protects against Epileptic Seizures in mice. Int. J. Biol. Sci. 2021, 17 (9), 2356-2366. DOI: 10.7150/ijbs.59922.

NLM

CSE

Gan CL, Zou Y, Xia Y, Zhang T, Chen D, Lan G, Mei Y, Wang L, Shui X, Hu L, Liu H, Lee TH. 2021. Inhibition of Death-associated Protein Kinase 1 protects against Epileptic Seizures in mice. Int J Biol Sci. 17(9):2356-2366.

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