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

Abstract

Epilepsy is a chronic encephalopathy and one of the most common neurological disorders. Deathassociated 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.

Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer’s Disease Mouse Models

“…Mouse hippocampal extracts were prepared by homogenizing the tissue in ice-cold RIPA lysis buffer supplemented with 1% (v/v) phenylmethanesulfonyl fluoride, as previously described ( Gan et al, 2021 ). Boiled protein samples were subjected to SDS-PAGE, followed by semi-dry film transfer of the proteins onto polyvinylidene fluoride membranes.…”

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy

“…TLE induced by KA is different from absence epilepsy triggered by pentylenetetrazol (PTZ), with different EEGs, epilepsy phenotypes, and neuronal damage patterns in specific brain regions. Based on the EEG characteristics and behavioral observation, approximately 40–70 min pass before the first GTCS is induced by a single convulsion-inducing dose of KA, but a convulsion-inducing dose of PTZ induces the first GTCS within several minutes [ 42 ]. Since DAPK1 expression is upregulated in epilepsy patients, we aimed to examine whether DAPK1 expression and activity are increased by KA before GTCSs.…”

“…DAPK1 has been shown to be involved in various neurodegenerative diseases, such as AD, ischemic stroke, PD and epilepsy [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 62 ]. DAPK1 expression or activity is upregulated, and DAPK1 KO leads to a protective effect against neurodegenerative diseases.…”

“…Mice were anesthetized and placed on a stereotaxic apparatus to implant epidural electroencephalogram (EEG) electrodes at the following positions (anteroposterior (AP), +2.0 mm, and mediolateral (ML), +1.5 mm) and a reference electrode (AP, −2.0 mm, and ML, +3.0) as described previously [ 42 , 65 ]. Video EEG recordings were taken of freely moving mice to trace seizure behaviors and obtain EEGs.…”

“…Levels of DAPK1 are significantly increased in brain samples from patients with epilepsy compared with those in control subject samples [ 40 , 41 ]. In animal models, DAPK1 has been shown to interact with GluN2B and regulate absence epilepsy [ 42 ]. Furthermore, the interaction between DAPK1 and tumor necrosis factor receptor 1 or p53 promotes brain cell death in glutamate analog kainic acid (KA)-treated animals, which are commonly used to model human TLE [ 43 , 44 ].…”