Abstract
Both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) have been reported as targets for treatment of epilepsy. To investigate the roles and interactions of AMPAR and NMDAR in ictogenesis of epileptic hippocampus, we analyzed AMPAR antagonists (perampanel and GYKI 52466)-mediated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulation and glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) tyrosine (Y) 1472 phosphorylation in epilepsy rats. Both perampanel and GYKI 52466 increased PTEN expression and its activity (reduced phosphorylation), concomitant with decreased activities (phosphorylations) of Src family-casein kinase 2 (CK2) signaling pathway. Compatible with these, they also restored the upregulated GluN2B Y1472 and Ca2+/cAMP response element-binding protein (CREB) serine (S) 133 phosphorylations and surface expression of glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) to basal level in the epileptic hippocampus. These effects of perampanel and GYKI 52466 are observed in responders (whose seizure activities are responsive to AMPAR antagonists), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). Therefore, our findings suggest that Src/CK2/PTEN-mediated GluN2B Y1472 and CREB S133 regulations may be one of the responsible signaling pathways for the generation of refractory seizures in non-responders to AMPAR antagonists.
Highlights
Epilepsy is a neurological disorder, which is characterized by the spontaneous seizure episodes due to abnormal neuronal hyperactivities, with the prevalence of 6–8 per 1000 persons
Since glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) Y1472 phosphorylation is involved in the seizure susceptibility and ictogenesis [19,20,21], we investigated the effects of amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) antagonists on its level in the epileptic hippocampus
The present data demonstrate that perampanel and GYKI 52,466 effectively reduced Y1472 phosphorylation ratio in responders, but not non-responders. Since both perampanel and GYKI 52,466 have a minimal effect on N-methyl-D-aspartate receptor (NMDAR) functions [32,55], these findings indicate that AMPAR antagonists may indirectly reduce GluN2B Y1472 phosphorylation via AMPAR-mediated signaling pathways rather than the direct binding to NMDAR
Summary
Epilepsy is a neurological disorder, which is characterized by the spontaneous seizure episodes due to abnormal neuronal hyperactivities, with the prevalence of 6–8 per 1000 persons. Given the partial or total inefficacy of the conventional anti-epileptic drug (AED) treatment and the unrelenting nature of this form of epilepsy [1,2], the need for novel effective treatments is undeniable. The underlying mechanisms of pharmacoresistant epilepsy are still unknown, several potential factors concerning refractory seizures have been proposed: (1) Over-expression or hyper-activation of drug efflux transporter (including ATP-cassette-binding protein) [3], (2) sustained releases of pro-inflammatory factors such as interleukin-1β in epileptic foci [4], (3) dysfunctions of channel/transporters including voltage-gated K+, Na+, Ca2+, or Cl− channels or various ion/neurotransmitter transporters [5,6], (4) aberrant neural networks [6], and (5) maladaptive regulations of synaptic γ-aminobutyric acid (GABA)A and glutamate receptors [7]. Multifactorial events are involved in the generation of refractory seizures, and more studies are needed to elucidate the molecular pathways concerning the pharmacoresistances for improvement of epilepsy therapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
