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Generation and On-Demand Initiation of Acute Ictal Activity in Rodent and Human Tissue
Published on: January 19, 2019
Evidence that phospholipase D activation prevents group I mGluR-induced persistent prolongation of epileptiform
Marjorie J Rico1, Lisa R Merlin
1Neural and Behavioral Science Program, School of Graduate Studies, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Abstract:
Selective activation of group I metabotropic glutamate receptors (mGluRs) with (S)-3,5-dihydroxyphenylglycine (DHPG) in guinea pig hippocampal slices converts 275- to 475-ms picrotoxin-induced interictal bursts into persistent seizure-length discharges typically over 1 s in duration. Here we report that l-cysteine sulfinic acid (CSA), a sulfur-containing amino acid, prevented the induction of this persistent group I mGluR-mediated epileptiform burst prolongation. However, CSA had no effect on baseline interictal bursting activity and failed to suppress the expression of the group I mGluR-induced persistent prolonged bursts once they were fully induced. (2R,1'S,2'R,3'S)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-13), a selective antagonist at the phospholipase D (PLD)-coupled mGluR, had no effect of its own on DHPG-induced burst prolongation; however, CSA applied in the presence of PCCG-13 could no longer fully block the burst prolongation induced by DHPG, suggesting that CSA's antiepileptogenic effect is mediated by agonist action at this PLD-coupled receptor. These data parallel our previous data revealing that protein synthesis inhibitors prevent induction but not expression of group I mGluR-mediated persistent seizure-length discharges. Hence, PLD activation with CSA may prevent the synthesis of a protein critical for the induction of group I mGluR-mediated epileptogenesis.
Insights
L-cysteine sulfinic acid (CSA) prevents the development of prolonged seizure-like activity by acting on specific glutamate receptors. This amino acid blocks the induction phase, not the expression, suggesting a role in preventing protein synthesis essential for epileptogenesis.
Area of Science:
- Neuroscience
- Neuropharmacology
- Epilepsy Research
Background:
- Group I metabotropic glutamate receptors (mGluRs) play a role in epileptiform activity.
- Selective activation of group I mGluRs can induce persistent, seizure-length discharges.
Purpose of the Study:
- To investigate the effect of L-cysteine sulfinic acid (CSA) on group I mGluR-mediated epileptiform burst prolongation.
- To determine the mechanism of CSA's action in preventing epileptogenesis.
Main Methods:
- Using guinea pig hippocampal slices.
- Inducing interictal bursts with picrotoxin and selectively activating group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG).
- Testing the effects of CSA and a phospholipase D (PLD)-coupled mGluR antagonist (PCCG-13) on burst prolongation.
Main Results:
- CSA prevented the induction of DHPG-induced burst prolongation but did not affect baseline activity or fully induced bursts.
- CSA's effect was blocked when co-administered with PCCG-13, indicating agonist action at PLD-coupled mGluRs.
- These findings suggest CSA acts during the induction phase, similar to protein synthesis inhibitors.
Conclusions:
- CSA exhibits an antiepileptogenic effect by preventing the induction of persistent seizure-length discharges.
- CSA likely acts as an agonist at PLD-coupled group I mGluRs.
- CSA may prevent epileptogenesis by inhibiting the synthesis of a critical protein involved in group I mGluR-mediated mechanisms.
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