Blockade of endothelin B receptor improves the efficacy of levetiracetam in chronic epileptic rats

Ko, Ah-Reum; Kang, Tae‐Cheon

doi:10.1016/j.seizure.2015.07.019

Cited by 17 publications

(27 citation statements)

References 45 publications

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“…Therefore, administration of the p38 MAPK inhibitor SB203580 significantly decreased the duration of the first seizure and the Racine scores in rats. These results are consistent with data from previous studies that showed that SB203580 can significantly reduce seizure intensity in a rat model of refractory epilepsy and decrease seizure duration in a rat model of chronic epilepsy ( 18 , 24 ).…”

Section: Discussionsupporting

confidence: 93%

Inhibition of p38 MAPK Signaling Regulates the Expression of EAAT2 in the Brains of Epileptic Rats

Yang

Wang

et al. 2018

Front. Neurol.

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Seizures induce the release of excitatory amino acids (EAAs) from the intracellular fluid to the extracellular fluid, and the released EAAs primarily comprise glutamic acid (Glu) and asparaginic acid (Asp). Glu neurotransmission functions via EAA transporters (EAATs) to maintain low concentrations of Glu in the extracellular space and avoid excitotoxicity. EAAT2, the most abundant Glu transporter subtype in the central nervous system (CNS), plays a key role in the regulation of glutamate transmission. Previous studies have shown that SB203580 promotes EAAT2 expression by inhibiting the p38 mitogen-activated protein kinase (MAPK) signaling pathway, but whether SB203580 upregulates EAAT2 expression in epileptic rats is unknown. This study demonstrated that EAAT2 expression was increased in the brain tissue of epileptic rats. Intraperitoneal injection of a specific inhibitor of p38 MAPK, SB203580, reduced the time to the first epileptic seizure and attenuated the seizure severity. In addition, SB203580 treatment increased the EAAT2 expression levels in the brain tissue of epileptic rats. These results suggest that SB203580 could regulate epileptic seizures via EAAT2.

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Section: Discussionsupporting

confidence: 93%

Inhibition of p38 MAPK Signaling Regulates the Expression of EAAT2 in the Brains of Epileptic Rats

Yang

Wang

et al. 2018

Front. Neurol.

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“…Animals were video-monitored 8 h a day for general behavior and occurrence of spontaneous seizures by 6 weeks after SE. Rats showing spontaneous recurrent seizures were used as chronic epilepsy animals ( Ko and Kang, 2015 ; Kim et al, 2017c ).…”

Section: Methodsmentioning

confidence: 99%

PDI Knockdown Inhibits Seizure Activity in Acute Seizure and Chronic Epilepsy Rat Models via S-Nitrosylation-Independent Thiolation on NMDA Receptor

Jeon

Kim

2018

Front. Cell. Neurosci.

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Redox modulation and S-nitrosylation of cysteine residues are the post-translational modifications of N-methyl-D-aspartate receptor (NMDAR) to regulate its functionality. Recently, we have reported that protein disulfide isomerase (PDI) reduces disulfide bond (S-S) to free thiol (-SH) on NMDAR. Since PDI is a modulator of S-nitrosylation on various proteins, it is noteworthy whether PDI affects S-nitrosylation of NMDAR in acute seizure and chronic epilepsy models. In the present study, we found that acute seizures in response to pilocarpine and spontaneous seizures in chronic epilepsy rats led to the reduction in S-nitrosylated thiol (SNO-thiol)-to-total thiol ratio on NMDAR, while they elevated nitric oxide (NO) level and S-nitrosylation on NMDAR. N-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor) did not affect seizure activities in both models, although it decreased SNO-thiol levels on NMDAR. However, PDI knockdown effectively inhibited pilocarpine-induced acute seizures and spontaneous seizures in chronic epilepsy rats, accompanied by increasing the SNO-thiol-to-total thiol ratio on NMDAR due to diminishing the amounts of total thiols on GluN1 and GluN2A. Therefore, these findings indicate that PDI may not be a NO donor or a denitrosylase for NMDAR, and that PDI knockdown may inhibit seizure activity by the S-nitrosylation-independent thiolation on NMDAR.

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“…Animals were video-monitored 8 h a day, for general behavior and occurrence of spontaneous seizures by 6 weeks after SE. Rats showing spontaneous recurrent seizures were used as epileptic animals [5,41,42].…”

Section: Epileptic Rat Modelmentioning

confidence: 99%

“…We applied a modified protocol for the effect of PDI knockdown on spontaneous seizure activity in epileptic rats, based on our previous reports [5,42]. Epileptic rats were anesthetized with Isoflurane (3% induction, 1.5%-2% for surgery and 1.5% maintenance in a 65:35 mixture of N2O:O2).…”

Section: Pdi Knockdown and Analysis Of Chronic Seizure Activitymentioning

confidence: 99%

PDI-Mediated Reduction of Disulfide Bond on PSD95 Increases Spontaneous Seizure Activity by Regulating NR2A–PSD95 Interaction in Epileptic Rats Independent of S-Nitrosylation

Lee

Kim

2020

IJMS

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Postsynaptic density-95 (PSD95), a major scaffolding protein, is critical in coupling N-methyl-D-aspartate receptor (NMDAR) to cellular signaling networks in the central nervous system. A couple of cysteine residues in the N-terminus of PSD95 are potential sites for disulfide bonding, S-nitrosylation and/or palmitoylation. Protein disulfide isomerase (PDI) reduces disulfide bonds (S-S) to free thiol (-SH) on various proteins. However, the involvement of PDI in disulfide bond formation/S-nitrosylation of PSD95 and its role in epilepsy are still unknown. In the present study, acute seizure activity significantly increased the bindings of PDI to NR2A, but not to PSD95, while it decreased the NR2A-PSD95 binding. In addition, pilocarpine-induced seizures increased the amount of nitrosylated (SNO-) thiols, not total (free and SNO-) thiols, on PSD95. Unlike acute seizure, spontaneous seizing rats showed the increases in PDI-PSD95 binding, total-and SNO-thiol levels on PSD95, and NR2A-PSD95 interaction. PDI siRNA effectively reduced spontaneous seizure activity with decreases in total thiol level on PSD95 and NR2A-PSD95 association. These findings indicate that PDI-mediated reduction of disulfide-bond formations may facilitate the NR2A-PSD95 binding and contribute to spontaneous seizure generation in epileptic animals. N-terminal of the first two PDZ domains of the PSD95 recognizes a four amino acid consensus sequence (-E-S/T-D-V) and allows it to bivalently link various ion channels, including NR2 subunits [11][12][13]. PSD95 is also required for NMDAR-mediated neuronal nitric oxide synthase (nNOS) activation [14]. Indeed, suppression of PSD95 expression inhibits NMDAR-mediated NOS activation and neuronal excitotoxicity [14]. However, synaptic NMDAR currents, subunit expression, localization and synaptic morphology remain unaltered in transgenic mice lacking PSD95, but they also shift the frequency dependence of NMDAR-mediated synaptic plasticity and impair spatial learning [15]. Thus, it is emphasized that PSD95 is critical in coupling NMDAR to cellular signaling networks and plays an important role in their biological functions within the central nervous system.On the other hand, the N-terminus of PSD95 contains a pair of cysteine residue (cysteine 3 and 5 sites). These cysteine residues are potential sites for disulfide-bond formation, S-nitrosylation and/or palmitoylation [16,17]. In addition, disulfide linkage of each PSD95 protein in these sites mediates its multimerization as supramolecular aggregates [18] and facilitates receptor-clustering activity [19]. S-nitrosylation of these sites also influences PSD95 palmitoylation and its clustering at synapses [20]. Given the reductive role of PDI in disulfide bonds, it is interesting to evaluate whether PDI mediates disulfide-bond formation or S-nitrosylation on PSD95 during seizure generation. Here, we demonstrate that PILO-induced acute seizure activity significantly increased the bindings of PDI to NR2A, but not to PSD95, while it decreased the NR2A-PSD95. In additi...

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Blockade of endothelin B receptor improves the efficacy of levetiracetam in chronic epileptic rats

Cited by 17 publications

References 45 publications

Inhibition of p38 MAPK Signaling Regulates the Expression of EAAT2 in the Brains of Epileptic Rats

Inhibition of p38 MAPK Signaling Regulates the Expression of EAAT2 in the Brains of Epileptic Rats

PDI Knockdown Inhibits Seizure Activity in Acute Seizure and Chronic Epilepsy Rat Models via S-Nitrosylation-Independent Thiolation on NMDA Receptor

PDI-Mediated Reduction of Disulfide Bond on PSD95 Increases Spontaneous Seizure Activity by Regulating NR2A–PSD95 Interaction in Epileptic Rats Independent of S-Nitrosylation

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