title: The mGlu(2/3) agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate, is anti- and proconvulsant in DBA/2 mice.
abstract: The anticonvulsant activity of the selective group II metabotropic glutamate receptor (mGlu) agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) has been evaluated in chemoconvulsant and sound-induced models of epileptic seizures in DBA/2 mice. 2R,4R-APDC (> or =10 nmol, intracerebroventricularly (i.c.v.), -15 min) transiently reduced sound-induced seizure activity including clonic seizures to 40% of vehicle at 20 nmol (i.c.v.) and 30% of vehicle at 100 mg/kg (intraperitoneally (i.p.), -15 min). 2R,4R-APDC inhibited clonic seizures induced by the group III mGlu antagonist (R,S)-alpha-methylserine-O-phosphate (2.5 micromol, i.c.v.) when co-injected at 20-40 nmol and inhibited limbic seizure activity induced by the mGlu(1/5) agonist (R,S)-3,5-dihydroxyphenylglycine (1.5 micromol, i.c.v.) when co-injected at 10-40 nmol. A reversal of the anticonvulsant activity of 2R,4R-APDC was observed at (>20 nmol) in each of the chemoconvulsant and sound-induced models of epileptic seizures. 2R,4R-APDC (0.1-1 micromol, i.c.v.) induced stimulus-independent, rapid and dose-dependent clonic seizures. Selective mGlu(2/3) agonists represent a novel class of potential anti-epileptic drugs, however due to the proconvulsant activity observed here, 2R,4R-APDC is obviously limited in this regard.
authors.affiliation: Department of Pharmacology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: R X
authors.initials: RX
authors.lastname: Moldrich
authors.forename: A
authors.initials: A
authors.lastname: Talebi
authors.forename: P M
authors.initials: PM
authors.lastname: Beart
authors.forename: A G
authors.initials: AG
authors.lastname: Chapman
authors.forename: B S
authors.initials: BS
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003292:Convulsants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013016:Sound / Q000009:adverse effects
chemical_list: C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D000927:Anticonvulsants; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D011392:Proline