Seizures induced in immature rats by homocysteic acid and the associated brain damage are prevented by group II metabotropic glutamate receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate.
The present study has examined the anticonvulsant and neuroprotective effect of group II metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion. Comparable time intervals were used for sacrificing the pups which had received 2R,4R-APDC. Low doses of 2R,4R-APDC (0.05 nmol/side) provided a pronounced anticonvulsant effect which was abolished by pretreatment with a selective group II mGluR antagonist LY341495. Generalized clonic-tonic seizures were completely suppressed and cortical energy metabolite changes which normally accompany these seizures were either normalized (decrease of glucose and glycogen) or markedly reduced (an accumulation of lactate). EEG recordings support the marked anticonvulsant effect of 2R,4R-APDC, nevertheless, this was only partial. In spite of the absence of obvious motor phenomena, isolated spikes or even short periods of partial ictal activity could be observed. Isolated spikes could also be seen in some animals after application of 2R,4R-APDC alone, reflecting most likely subclinical proconvulsant activity of this agonist. The neuroprotective effect of 2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration, as revealed by Fluoro-Jade B staining, was observed in a number of brain regions following infusion of DL-HCA alone (seizure group), whereas 2R,4R-APDC pretreatment provided substantial neuroprotection. The present findings support the possibility that group II mGluRs are a promising target for a novel approach to treating epilepsy.
Folbergrová
Jaroslava
J
Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenská 1083, 142 20 Prague 4, Czech Republic. folbergr@biomed.cas.cz
Druga
Rastislav
R
Otáhal
Jakub
J
Haugvicová
Renata
R
Mares
Pavel
P
Kubová
Hana
H
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000627:therapeutic use; D001522:Behavior, Animal; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects; D001930:Brain Injuries / Q000209:etiology* / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007839:Functional Laterality; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control; D009930:Organic Chemicals; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012640:Seizures / Q000139:chemically induced / Q000150:complications*; D013997:Time Factors; D014966:Xanthenes / Q000494:pharmacology
C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D000596:Amino Acids; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D005452:Fluoresceins; D005456:Fluorescent Dyes; C114624:LY 341495; D009930:Organic Chemicals; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C435731:fluoro jade; D006710:Homocysteine; C007956:homocysteic acid; D019344:Lactic Acid; D006003:Glycogen; D011392:Proline; D005947:Glucose