AMN 082, an agonist of mGluR7, exhibits mixed anti- and proconvulsant effects in developing rats.
Metabotropic glutamate receptors (mGluRs) represent a potential therapeutic target. Possible anticonvulsant action of AMN 082, an agonist of mGluR7 subtype, was studied in immature rats using pentylenetetrazol (PTZ)-induced seizures as a model. Five age groups of rats (7-, 12-, 18-, 25-day-old and adult animals) were pretreated with AMN 082 in doses of 0.5, 1, 2, and 5 mg/kg i.p. and 30 min later PTZ was administered (100 mg/kg s.c.). Controls received saline instead of the agonist. AMN 082 did not exhibit clear anticonvulsant action with the exception of suppression of the tonic phase of generalized tonic-clonic seizures (GTCS) in 12-day-old rats. Shorter latencies of GTCS after AMN 082 pretreatment indicate a proconvulsant action. Involuntary movements (mostly tremor) appeared after AMN 082 before PTZ administration, therefore we performed another experimental series with AMN 082 only (1, 2, 5, and 10 mg/kg i.p.). During 60-min observation period tremor appeared in all age groups; sensitivity to this action decreased with age from the 2 mg/kg dose in 7- and 12-day-old rats to the 10 mg/kg dose in adult rats. Mixed anti- and proconvulsant actions of AMN 082 together with unwanted motor effects makes clinical use of this drug highly improbable.
Mares
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Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. maresp@biomed.cas.cz
D000367:Age Factors; D000375:Aging; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001559:Benzhydryl Compounds / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*
D000927:Anticonvulsants; D001559:Benzhydryl Compounds; D018690:Excitatory Amino Acid Agonists; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D010433:Pentylenetetrazole