Capacities of metabotropic glutamate modulators in counteracting soman-induced seizures in rats

Current treatment of nerve agent poisoning with ionotropic drugs proves inadequate, and alternative treatment strategies are searched for. Based on positive findings with metabotropic glutamate modulators in microinfusion studies, the present study was initiated to examine anticonvulsant effects of...

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Veröffentlicht in:European journal of pharmacology 2013-10, Vol.718 (1-3), p.253-260
Hauptverfasser: Myhrer, Trond, Mariussen, Espen, Enger, Siri, Aas, Pål
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Mariussen, Espen
Enger, Siri
Aas, Pål
description Current treatment of nerve agent poisoning with ionotropic drugs proves inadequate, and alternative treatment strategies are searched for. Based on positive findings with metabotropic glutamate modulators in microinfusion studies, the present study was initiated to examine anticonvulsant effects of MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride), a metabotropic glutamate receptor 5 antagonist, and DCG-IV ((2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine), a metabotropic glutamate receptor 2/3 agonist, when administered systemically in combinations with HI-6 (1-[([4-(aminocarbonyl)pyridino]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) and procyclidine or HI-6 and levetiracetam relative to the combination of HI-6, procyclidine, and levetiracetam. The results showed that MPEP or DCG-IV combined with HI-6 and procyclidine resulted in substantial antidotal efficacy when administered 20min after onset of seizures elicited by soman. MPEP or DCG-IV combined with HI-6 and levetiracetam did not terminate seizures and preserve lives. When given 20min before challenge with soman, DCG-IV in combination with HI-6 and procyclidine provided protection, whereas MPEP combined with HI-6 and procyclidine did not. Combinations with metabotropic glutamate receptor modulators did not achieve the same high level of antidotal efficacy as the combination of HI-6, procyclidine, and levetiracetam. MPEP alone inhibited pseudocholinesterase activity in the brain markedly. A positive correlation was found between latency to seizure onset or full protection and level of pseudocholinesterase activity in brain. MPEP and DCG-IV can serve as effective anticonvulsants against nerve agent poisoning when combined with HI-6 and procyclidine. Metabotropic glutamate receptor modulators may represent an alternative or supplement to treatment with ionotropic drugs.
doi_str_mv 10.1016/j.ejphar.2013.08.024
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Based on positive findings with metabotropic glutamate modulators in microinfusion studies, the present study was initiated to examine anticonvulsant effects of MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride), a metabotropic glutamate receptor 5 antagonist, and DCG-IV ((2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine), a metabotropic glutamate receptor 2/3 agonist, when administered systemically in combinations with HI-6 (1-[([4-(aminocarbonyl)pyridino]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) and procyclidine or HI-6 and levetiracetam relative to the combination of HI-6, procyclidine, and levetiracetam. The results showed that MPEP or DCG-IV combined with HI-6 and procyclidine resulted in substantial antidotal efficacy when administered 20min after onset of seizures elicited by soman. MPEP or DCG-IV combined with HI-6 and levetiracetam did not terminate seizures and preserve lives. When given 20min before challenge with soman, DCG-IV in combination with HI-6 and procyclidine provided protection, whereas MPEP combined with HI-6 and procyclidine did not. Combinations with metabotropic glutamate receptor modulators did not achieve the same high level of antidotal efficacy as the combination of HI-6, procyclidine, and levetiracetam. MPEP alone inhibited pseudocholinesterase activity in the brain markedly. A positive correlation was found between latency to seizure onset or full protection and level of pseudocholinesterase activity in brain. MPEP and DCG-IV can serve as effective anticonvulsants against nerve agent poisoning when combined with HI-6 and procyclidine. 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Based on positive findings with metabotropic glutamate modulators in microinfusion studies, the present study was initiated to examine anticonvulsant effects of MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride), a metabotropic glutamate receptor 5 antagonist, and DCG-IV ((2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine), a metabotropic glutamate receptor 2/3 agonist, when administered systemically in combinations with HI-6 (1-[([4-(aminocarbonyl)pyridino]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) and procyclidine or HI-6 and levetiracetam relative to the combination of HI-6, procyclidine, and levetiracetam. The results showed that MPEP or DCG-IV combined with HI-6 and procyclidine resulted in substantial antidotal efficacy when administered 20min after onset of seizures elicited by soman. MPEP or DCG-IV combined with HI-6 and levetiracetam did not terminate seizures and preserve lives. When given 20min before challenge with soman, DCG-IV in combination with HI-6 and procyclidine provided protection, whereas MPEP combined with HI-6 and procyclidine did not. Combinations with metabotropic glutamate receptor modulators did not achieve the same high level of antidotal efficacy as the combination of HI-6, procyclidine, and levetiracetam. MPEP alone inhibited pseudocholinesterase activity in the brain markedly. A positive correlation was found between latency to seizure onset or full protection and level of pseudocholinesterase activity in brain. MPEP and DCG-IV can serve as effective anticonvulsants against nerve agent poisoning when combined with HI-6 and procyclidine. Metabotropic glutamate receptor modulators may represent an alternative or supplement to treatment with ionotropic drugs.</description><subject>Acetylcholinesterase - metabolism</subject><subject>agonists</subject><subject>Animals</subject><subject>antagonists</subject><subject>anticonvulsants</subject><subject>Anticonvulsants - pharmacology</subject><subject>Anticonvulsants - therapeutic use</subject><subject>brain</subject><subject>Butyrylcholinesterase - metabolism</subject><subject>Cyclopropanes - pharmacology</subject><subject>Cyclopropanes - therapeutic use</subject><subject>DCG-IV</subject><subject>Drug Interactions</subject><subject>glutamic acid</subject><subject>Glycine - analogs &amp; derivatives</subject><subject>Glycine - pharmacology</subject><subject>Glycine - therapeutic use</subject><subject>HI-6</subject><subject>Levetiracetam</subject><subject>Male</subject><subject>MPEP</subject><subject>nerve tissue</subject><subject>Oximes - pharmacology</subject><subject>Piracetam - analogs &amp; derivatives</subject><subject>Piracetam - pharmacology</subject><subject>poisoning</subject><subject>Procyclidine</subject><subject>Procyclidine - pharmacology</subject><subject>pyridines</subject><subject>Pyridines - pharmacology</subject><subject>Pyridines - therapeutic use</subject><subject>Pyridinium Compounds - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptor, Metabotropic Glutamate 5 - agonists</subject><subject>Receptor, Metabotropic Glutamate 5 - antagonists &amp; inhibitors</subject><subject>seizures</subject><subject>Seizures - chemically induced</subject><subject>Seizures - drug therapy</subject><subject>Seizures - enzymology</subject><subject>Soman</subject><subject>Soman - adverse effects</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtv1TAQRi0EoreFf4AgSzYJfibxBgldQUGqxAK6tpzJ-OKrJA62g1R-PS4pLGE1iznz0HcIecFowyhr35wbPK_fbGw4ZaKhfUO5fEQOrO90TTvGH5MDpUzWXGt9QS5TOlNKlebqKbngknKmRHsg5mhXCz57TFVw1YzZDiHHsHqoTtOW7WwzVnMYt8nmEFPllwrCtmSMFrJfTlUKs11qv4wb4Fgl9D-3iL-5aHN6Rp44OyV8_lCvyO2H91-PH-ubz9efju9uapBM51oo10tBXafUKO3QKkAQDDRwJWFENYgeBgWlbZXSXYutcwCODspp2Qoqrsjrfe8aw_cNUzazT4DTZBcMWzKsF52Qou3k_1GpKOv6kmFB5Y5CDClFdGaNfrbxzjBq7i2Ys9ktmHsLhvamWChjLx8ubMOM49-hP7EX4NUOOBuMPUWfzO2XskEVRZK1HS_E253AEtoPj9Ek8LiUiH1EyGYM_t8__AJ-aaT6</recordid><startdate>20131015</startdate><enddate>20131015</enddate><creator>Myhrer, Trond</creator><creator>Mariussen, Espen</creator><creator>Enger, Siri</creator><creator>Aas, Pål</creator><general>Elsevier B.V</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20131015</creationdate><title>Capacities of metabotropic glutamate modulators in counteracting soman-induced seizures in rats</title><author>Myhrer, Trond ; 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Based on positive findings with metabotropic glutamate modulators in microinfusion studies, the present study was initiated to examine anticonvulsant effects of MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride), a metabotropic glutamate receptor 5 antagonist, and DCG-IV ((2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine), a metabotropic glutamate receptor 2/3 agonist, when administered systemically in combinations with HI-6 (1-[([4-(aminocarbonyl)pyridino]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) and procyclidine or HI-6 and levetiracetam relative to the combination of HI-6, procyclidine, and levetiracetam. The results showed that MPEP or DCG-IV combined with HI-6 and procyclidine resulted in substantial antidotal efficacy when administered 20min after onset of seizures elicited by soman. MPEP or DCG-IV combined with HI-6 and levetiracetam did not terminate seizures and preserve lives. 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subjects Acetylcholinesterase - metabolism
agonists
Animals
antagonists
anticonvulsants
Anticonvulsants - pharmacology
Anticonvulsants - therapeutic use
brain
Butyrylcholinesterase - metabolism
Cyclopropanes - pharmacology
Cyclopropanes - therapeutic use
DCG-IV
Drug Interactions
glutamic acid
Glycine - analogs & derivatives
Glycine - pharmacology
Glycine - therapeutic use
HI-6
Levetiracetam
Male
MPEP
nerve tissue
Oximes - pharmacology
Piracetam - analogs & derivatives
Piracetam - pharmacology
poisoning
Procyclidine
Procyclidine - pharmacology
pyridines
Pyridines - pharmacology
Pyridines - therapeutic use
Pyridinium Compounds - pharmacology
Rats
Rats, Wistar
Receptor, Metabotropic Glutamate 5 - agonists
Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors
seizures
Seizures - chemically induced
Seizures - drug therapy
Seizures - enzymology
Soman
Soman - adverse effects
title Capacities of metabotropic glutamate modulators in counteracting soman-induced seizures in rats
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