Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy

Abstract

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy.

Ablation of Death-Associated Protein Kinase 1 Changes the Transcriptomic Profile and Alters Neural-Related Pathways in the Brain

“…Consistently, DAPK1 has also been demonstrated to regulate neuronal cell death [ 13 , 17 , 25 , 47 , 48 ]. Activation of DAPK1 by extracellular signal-regulated kinase (ERK) increases neuronal apoptosis in an epilepsy mouse model, while DAPK1 gene depletion alleviates neuronal cell death [ 11 ]. In addition to ribosome-related pathways, age-associated (including NAFLD pathways, oxidative phosphorylation pathways, as well as many neurodegenerative disease-related pathways) were also the significantly enriched KEGG pathways.…”

“…Substantial evidence indicates that DAPK1 is involved in apoptosis, autophagy, necrosis, and anoikis-like cell death [ 4 , 6 , 7 , 8 ]. Both DAPK1 knockout (DAPK1-KO) and the inhibition of DAPK1 function protects neurons against neuronal damage, whereas DAPK1 overexpression induces cell death [ 9 , 10 , 11 , 12 ]. In addition, DAPK1 may be involved in neurogenesis and other neuronal functions, such as synaptic transmission and plasticity, as well as cognition [ 5 , 6 , 13 , 14 , 15 , 16 ].…”

“…A large number of studies have proven that DAPK1 plays an Important role in mediating the pathological process of acute and chronic neurological disorders, such as Alzheimer’s disease (AD) [ 9 , 17 , 18 , 19 , 20 ], Parkinson’s disease (PD) [ 21 , 22 ], Huntington’s disease (HD) [ 23 ], traumatic brain injury (TBI) [ 24 , 25 ], stroke [ 15 , 26 , 27 , 28 ], and epilepsy [ 10 , 11 ]. We discovered that levels of DAPK1 are significantly increased in the hippocampi of 75% of AD patients compared to those in control subject samples [ 17 , 19 , 20 ].…”

“…Previous reports have shown that DAPK1 promotes neuronal apoptosis in seizures by interacting with tumor necrosis factor receptor 1 (TNFR1) or p53 [ 40 , 41 ]. We have recently reported that depletion of DAPK1 expression and inhibition of DAPK1 activity dramatically reduces epileptic seizures in mice after convulsive pentylenetetrazol or glutamate analog kainic acid exposure [ 10 , 11 ]. In summary, DAPK1 upregulation promotes neuronal damage, whereas downregulation of DAPK1 is beneficial for neuronal functions, which suggests that DAPK1 inhibition might exert therapeutic effects on many neurological diseases.…”

Network Pharmacology and Experimental Verification to Unveil the Mechanism of N-Methyl-D-Aspartic Acid Rescue Humantenirine-Induced Excitotoxicity

“…NMDAR is involved in excitotoxicity and neuronal death under many pathological conditions [ 32 , 33 ]. Treatment with a specific ERK inhibitor can dramatically reduce neuronal cell death induced by excitotoxicity both in vitro and in vivo [ 34 ]. SRC belongs to the SRC family of nonreceptor protein tyrosine kinases, is expressed in the central nervous system, and participates in many cellular functions.…”