title: N-methyl-D-aspartate receptor channel blockers prevent pentylenetetrazole-induced convulsions and morphological changes in rat brain neurons.
abstract: Alterations in inhibitory and excitatory neurotransmission play a central role in the etiology of epilepsy, with overstimulation of glutamate receptors influencing epileptic activity and corresponding neuronal damage. N-methyl-D-aspartate (NMDA) receptors, which belong to a class of ionotropic glutamate receptors, play a primary role in this process. This study compared the anticonvulsant properties of two NMDA receptor channel blockers, memantine and 1-phenylcyclohexylamine (IEM-1921), in a pentylenetetrazole (PTZ) model of seizures in rats and investigated their potencies in preventing PTZ-induced morphological changes in the brain. The anticonvulsant properties of IEM-1921 (5 mg/kg) were more pronounced than those of memantine at the same dose. IEM-1921 and memantine decreased the duration of convulsions by 82% and 37%, respectively. Both compounds were relatively effective at preventing the tonic component of seizures but not myoclonic seizures. Memantine significantly reduced the lethality caused by PTZ-induced seizures from 42% to 11%, and all animals pretreated with IEM-1921 survived. Morphological examination of the rat brain 24 hr after administration of PTZ revealed alterations in the morphology of 20-25% of neurons in the neocortex and the hippocampus, potentially induced by excessive glutamate. The expression of the excitatory amino acid transporter 1 protein was increased in the hippocampus of the PTZ-treated rats. However, dark neurons did not express caspase-3 and were immunopositive for the neuronal nuclear antigen protein, indicating that these neurons were alive. Both NMDA antagonists prevented neuronal abnormalities in the brain. These results suggest that NMDA receptor channel blockers might be considered possible neuroprotective agents for prolonged seizures or status epilepticus leading to neuronal damage.
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg, Russia.
authors.forename: Aleksey V
authors.initials: AV
authors.lastname: Zaitsev
authors.forename: Kira Kh
authors.initials: KKh
authors.lastname: Kim
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Vasilev
authors.forename: Nera Ya
authors.initials: NY
authors.lastname: Lukomskaya
authors.forename: Valeria V
authors.initials: VV
authors.lastname: Lavrentyeva
authors.forename: Natalia L
authors.initials: NL
authors.lastname: Tumanova
authors.forename: Igor A
authors.initials: IA
authors.lastname: Zhuravin
authors.forename: Lev G
authors.initials: LG
authors.lastname: Magazanik
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D003514:Cyclohexylamines / Q000494:pharmacology / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010433:Pentylenetetrazole; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D003514:Cyclohexylamines; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D053148:Caspase 3; C037320:1-phenylcyclohexylamine; D008559:Memantine; D010433:Pentylenetetrazole
keywords: IEM-1921; dark neuron; epilepsy; glutamate receptor; memantine