Inhibition of AKT/GSK3β/CREB Pathway Improves the Responsiveness to AMPA Receptor Antagonists by Regulating GRIA1 Surface Expression in Chronic Epilepsy Rats

Kim, Jieun; Lee, Duk-Shin; Park, Hana; Kim, Tae Hyun; Kang, Tae‐Cheon

doi:10.3390/biomedicines9040425

Cited by 16 publications

(27 citation statements)

References 57 publications

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“…A higher expression of Ca 2+ -permeable AMPAR in the epileptic hippocampus results in a subsequent elevated Ca 2+ influx followed by PP2B activation [55][56][57]. AMPAR antagonists decrease GRIA1/GRIA2 ratio in responders by reducing GRIA1, but not GRIA2, surface expression [4,10,26]. The present study also demonstrates that AMPAR antagonists increased GRIA1 ubiquitination in responders, which indicates the decreased Ca 2+ -permeable AMPAR level.…”

Section: Discussionsupporting

confidence: 65%

“…Under physiological conditions, AMPARs contain the GRIA2 subunit, which are permeable to Na + and K + , but not Ca 2+ [54]. In chronic epilepsy rats, membrane GRIA1/GRIA2 ratio is significantly higher than that in control animals, indicating a preponderance of GRIA2-lacking (Ca 2+ -permeable) AMPAR [4,10,26]. A higher expression of Ca 2+ -permeable AMPAR in the epileptic hippocampus results in a subsequent elevated Ca 2+ influx followed by PP2B activation [55][56][57].…”

Section: Discussionmentioning

confidence: 99%

“…Drug Trials, EEG Analysis and Quantification of Behavioral Seizure Activity 2.4.1. Experiment I Figure 1 illustrates the design of the drug trial methodology, which was a modified protocol based on previous studies [10,26,30,31]. After baseline seizure activity was determined over three days, perampanel (8 mg/kg, i.p, Eisai Korea Inc., Seoul, Korea), GYKI 52466 (10 mg/kg, i.p.)…”

Section: Surgerymentioning

confidence: 99%

“…Finally, we investigated whether PP2B inhibition affects ubiquitination of NEDD4-2 and GRIA1 in the hippocampus of non-responders, since perampanel reduces total GRIA1 protein level in responders and NEDD4-2 phosphorylation facilitates GRIA1 ubiquitination [4,10,17,26,30].…”

Section: Csa Co-treatment Reversely Regulates Ubiquitination Of Nedd4-2 and Gria1 In Non-respondersmentioning

confidence: 99%

“…On the other hand, multifactorial events are involved in the underlying mechanisms of pharmacoresistant epilepsy: (1) a reduced yield of AED concentration in the brain by hyper-activation of drug efflux transporter or sustained inflammatory conditions [23,24], (2) dysfunctions of ion/neurotransmitter channels of transporters [25], and (3) abnormal neural networks [25]. Interestingly, GRIA1 surface expression is higher in the hippocampus of chronic epilepsy rats than that of normal rats, which is attenuated by AMPAR antagonists (such as perampanel and GYKI 52466) in responders whose seizure activities are reduced by them [4,10,26]. Since ubiquitination of GRIA1 is linked to AMPAR surface expression and trafficking [27][28][29], it is postulated that AMPAR antagonists may modulate NEDD4-2 activity that is required for limiting GluA1 surface expression and functionality of AMPAR in the epileptic hippocampus.…”

Section: Introductionmentioning

confidence: 99%

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AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

et al. 2021

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The neural precursor cell expressed by developmentally downregulated gene 4-2 (NEDD4-2) is a ubiquitin E3 ligase that has a high affinity toward binding and ubiquitinating glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type subunit 1 (GRIA1, also referred to GluR1 or GluA1). Since dysregulation of GRIA1 surface expression is relevant to the responsiveness to AMPA receptor (AMPAR) antagonists (perampanel and GYKI 52466) in chronic epilepsy rats, it is likely that NEDD4-2 may be involved in the pathogenesis of intractable epilepsy. However, the role of NEDD4-2-mediated GRIA1 ubiquitination in refractory seizures to AMPAR antagonists is still unknown. In the present study, both AMPAR antagonists recovered the impaired GRIA1 ubiquitination by regulating protein phosphatase 2B (PP2B)-extracellular signal-regulated kinase 1/2 (ERK1/2)-serum and glucocorticoid-regulated kinase 1 (SGK1)-NEDD4-2 signaling pathway in responders (whose seizure activities are responsive to AMPAR), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). In addition, cyclosporin A (CsA, a PP2B inhibitor) co-treatment improved the effects of AMPAR antagonists in non-responders, independent of AKT signaling pathway. Therefore, our findings suggest that dysregulation of PP2B-ERK1/2-SGK1-NEDD4-2-mediated GRIA1 ubiquitination may be responsible for refractory seizures and that this pathway may be a potential therapeutic target for improving the treatment of intractable epilepsy in response to AMPAR antagonists.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Surgerymentioning

confidence: 99%

Section: Csa Co-treatment Reversely Regulates Ubiquitination Of Nedd4-2 and Gria1 In Non-respondersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

et al. 2021

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Efficacy of perampanel in pediatric epilepsy with known and presumed genetic etiology

Miao

Zhu²,

Jin

et al. 2023

Ann Clin Transl Neurol

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ObjectiveThe efficacy of perampanel (PER) in pediatric epilepsy with specific etiologies has not been well established. Here, we investigated outcome and predictors of PER treatment in a pediatric cohort with known and presumed genetic etiology.MethodsWe included pediatric patients with potential genetic epilepsy who received PER treatment and underwent whole‐exome sequencing (WES) from January 2020 to September 2021. All patients were followed up for >12 months.ResultsA total of 124 patients were included. Overall response rates were 51.6% and 49.6% at 6 months and 12 months, respectively. Pathogenic or likely pathogenic variants in 27 multiple genes were detected among 58 patients (46.8%) by WES. On performing multivariate logistic regression analysis, only developmental delay (OR = 0.406, P = 0.042) was a negative predictor of treatment response. However, the seizure onset age, positive WES results, and number of ASMs before PER administration were not significantly. Thirteen carriers with variants in the SCN1A gene showed a better response compared to eight patients with other sodium channels (P = 0.007), and to the other 45 patients with positive WES results (OR = 7.124, 95% CI = 1.306–38.860, P = 0.023). Adverse events were only reported in 23 patients, the most common being emotional problems.InterpretationPER is safe and efficacious in pediatric patients with known and presumed genetic etiology. The response rate is comparable to that reported in other pediatric populations, and lower among those with developmental delay. A gene‐specific response to PER is found along with better efficacy links to pathogenic variants in the SCN1A gene.

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Brain glycogen content is increased in the acute and interictal chronic stages of the mouse pilocarpine model of epilepsy

et al. 2022

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Glucose is the main brain fuel in fed conditions, while astrocytic glycogen is used as supplemental fuel when the brain is stimulated. Brain glycogen levels are decreased shortly after induced seizures in rodents, but little is known about how glycogen levels are affected interictally in chronic models of epilepsy. Reduced glutamine synthetase activity has been suggested to lead to increased brain glycogen levels in humans with chronic epilepsy. Here, we used the mouse pilocarpine model of epilepsy to investigate whether brain glycogen levels are altered, both acutely and in the chronic stage of the model. One day after pilocarpine‐induced convulsive status epilepticus (CSE), glycogen levels were higher in the hippocampal formation, cerebral cortex, and cerebellum. Opposite to expected, this was accompanied by elevated glutamine synthetase activity in the hippocampus but not the cortex. Increased interictal glycogen amounts were seen in the hippocampal formation and cerebral cortex in the chronic stage of the model (21 days post‐CSE), suggesting long‐lasting alterations in glycogen metabolism. Glycogen solubility in the cerebral cortex was unaltered in this epilepsy mouse model. Glycogen synthase kinase 3 beta (Gsk3b) mRNA levels were reduced in the hippocampal formations of mice in the chronic stage, which may underlie the elevated brain glycogen content in this model. This is the first report of elevated interictal glycogen levels in a chronic epilepsy model. Increased glycogen amounts in the brain may influence seizure susceptibility in this model, and this warrants further investigation.

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Inhibition of AKT/GSK3β/CREB Pathway Improves the Responsiveness to AMPA Receptor Antagonists by Regulating GRIA1 Surface Expression in Chronic Epilepsy Rats

Cited by 16 publications

References 57 publications

AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

Efficacy of perampanel in pediatric epilepsy with known and presumed genetic etiology

Brain glycogen content is increased in the acute and interictal chronic stages of the mouse pilocarpine model of epilepsy

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