Dextrometrophan (DM), widely used as an antitussive, has recently generated interest as an anticonvulsant drug. Some effects of dextrometrophan are associated with alterations in several pathways, such as inhibition of nitric oxide synthase (NOS) enzyme and N-methyl D-aspartate (NMDA) receptors. In this study, we aimed to investigate the anticonvulsant effect of acute administration of dextrometrophan on pentylenetetrazole (PTZ)-induced seizures and the probable involvement of the nitric oxide (NO) pathway and NMDA receptors in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Our results demonstrate that acute DM treatment (10–100 mg/kg) increased the seizure threshold. In addition, the nonselective NOS inhibitor L-NAME (10 mg/kg) and the neural NOS inhibitor, 7-nitroindazole (40 mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of DM (3 mg/kg), while the inducible NOS inhibitor, aminoguanidine (100 mg/kg), did not affect the anticonvulsant effect of DM. Moreover, the NOS substrate L-arginine (60 mg/kg) blunted the anticonvulsant effect of DM (100 mg/kg). Also, NMDA antagonists, ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg), augmented the anticonvulsant effect of DM (3 mg/kg). In conclusion, we demonstrated that the anticonvulsant effect of DM is mediated by a decline in neural nitric oxide activity and inhibition of NMDA receptors. © 2016 Elsevier Inc.
|EMTREE drug terms:||7 nitroindazoleaminoguanidineargininedextromethorphandizocilpineketaminen methyl dextro aspartic acid receptorn(g) nitroarginine methyl esternitric oxidepentetrazoleamino acid receptor blocking agentanticonvulsive agentdextromethorphanenzyme inhibitorn methyl dextro aspartic acid receptornitric oxidenitric oxide synthasepentetrazole|
|EMTREE medical terms:||acute drug administrationanimal experimentanimal modelanticonvulsant activityArticlecontrolled studydose responsedrug dose comparisondrug effectmalemousenonhumanpentylenetetrazole-induced seizureseizureseizure thresholdanimalantagonists and inhibitorschemically inducedmetabolismSeizurestreatment outcome|
|MeSH:||AnimalsAnticonvulsantsDextromethorphanDose-Response Relationship, DrugEnzyme InhibitorsExcitatory Amino Acid AntagonistsMaleMiceNitric OxideNitric Oxide SynthasePentylenetetrazoleReceptors, N-Methyl-D-AspartateSeizuresTreatment Outcome|
7 nitroindazole, 2942-42-9; aminoguanidine, 1068-42-4, 2582-30-1, 79-17-4; arginine, 1119-34-2, 15595-35-4, 7004-12-8, 74-79-3; dextromethorphan, 125-69-9, 125-71-3; dizocilpine, 77086-21-6; ketamine, 1867-66-9, 6740-88-1, 81771-21-3; n(g) nitroarginine methyl ester, 50903-99-6; nitric oxide, 10102-43-9; pentetrazole, 54-95-5; nitric oxide synthase, 125978-95-2;
Anticonvulsants; Dextromethorphan; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Nitric Oxide; Nitric Oxide Synthase; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate
Sigma, United States
Dehpour, A.-R.; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran; email:[email protected]
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