Inhibition of Death-associated Protein Kinase 1 protects against Epileptic Seizures in mice.
Animals
Death-Associated Protein Kinases
/ antagonists & inhibitors
Disease Models, Animal
Epilepsy
/ drug therapy
Hippocampus
/ metabolism
Kindling, Neurologic
/ drug effects
Male
Mice
Mice, Inbred C57BL
Pentylenetetrazole
/ pharmacology
Receptors, N-Methyl-D-Aspartate
/ metabolism
Seizures
/ chemically induced
Death-associated protein kinase 1
epilepsy
kindling
pentylenetetrazol
phosphorylation
seizure
Journal
International journal of biological sciences
ISSN: 1449-2288
Titre abrégé: Int J Biol Sci
Pays: Australia
ID NLM: 101235568
Informations de publication
Date de publication:
2021
2021
Historique:
received:
28
02
2021
accepted:
28
05
2021
entrez:
9
7
2021
pubmed:
10
7
2021
medline:
26
3
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34239362
doi: 10.7150/ijbs.59922
pii: ijbsv17p2356
pmc: PMC8241737
doi:
Substances chimiques
Receptors, N-Methyl-D-Aspartate
0
Dapk1 protein, mouse
EC 2.7.11.1
Death-Associated Protein Kinases
EC 2.7.11.1
Pentylenetetrazole
WM5Z385K7T
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2356-2366Informations de copyright
© The author(s).
Déclaration de conflit d'intérêts
Competing Interests: The authors have declared that no competing interest exists.
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