title: Mediatory role of NMDA, AMPA/kainate, GABAAand Alpha2receptors in topiramate neuroprotective effects against methylphenidate induced neurotoxicity in rat.
abstract: Prolonged abuse of methylphenidate (MPH) often causes neuronal damage. Topiramate (TPM) has neuroprotective properties, but its mechanism of action remains unclear. The current study evaluates in vivo role of various doses of TPM (10, 30, 50, 70 and 100mg/kg) and its possible mechanisms against MPH-induced hippocampal oxidative stress, inflammation and apoptosis, in absence and presence of different receptor agonists and antagonists. Domoic acid (DOM) as AMPA/kainate receptor agonist, bicuculline (BIC) as GABAAreceptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as ɑ2adrenergic receptor antagonist and haloperidole (HAL) as D2dopamine receptor antagonist was used. Open Field Test (OFT) was used to investigate the disturbances in motor activity. Hippocampal oxidative, anti-oxidant and inflammatory parameters and apoptotic factors were studied. Expressions of BDNF at gene and protein levels were also evaluated. Crystal violet staining was performed to determine neuronal cell density. TPM (70 and 100mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1β and TNF-α levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased BDNF gene and protein expressions, Bcl-2 expression, the level of reduced form of glutathione (GSH) and activities of enzymes superoxide dismutase, glutathione peroxidase and glutathione reductase.TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM-induced neuroprotection and increased oxidative stress, neuroinflammation, neuroapoptosis and neurodegeneration while reducing BDNF expressions. Thus, TPM by interacting with AMPA/kainate, GABAA, NMDA and ɑ2-adrenergic receptors improves BDNF expression and acts as a neuroprotective agent against MPH-induced neurodegeneration.
authors.affiliation: Razi Drug Research Center, Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Motaghinejad
authors.affiliation: Razi Drug Research Center, Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.. Electronic address: manijeh.motevalian@gmail.com.
authors.forename: Manijeh
authors.initials: M
authors.lastname: Motevalian
authors.affiliation: Department of Physiology, Tehran University of Medical Sciences, International Campus, Teharn, Iran.
authors.forename: Sulai
authors.initials: S
authors.lastname: Fatima
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D000077236:Topiramate
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D018341:Receptors, Adrenergic, alpha-2; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D000077236:Topiramate; D008774:Methylphenidate; D005632:Fructose
keywords: BDNF; Methylphenidate; Neurodegeneration; Topiramate