title: Antioxidant activity and neuroprotective effects of zolpidem and several synthesis intermediates.
abstract: Structural relationship between the antioxidant melatonin and the non-benzodiazepine hypnotic zolpidem (ZPD) suggests possible direct antioxidant and neuroprotective properties of this compound. In the present work, these effects were analyzed for zolpidem and four of its synthesis intermediates. In vitro assays include lipid peroxidation and protein oxidation studies in liver and brain homogenates. Intracellular antioxidant effects were analyzed by evaluation of free radical formation prevention in HT-22 hippocampal cells treated with glutamate 10mM and measured by flow cytometer DCF fluorescence. The neuroprotective effect of these compounds was evaluated as neuronal death prevention of HT-22 cells treated with the same concentration of glutamate. Zolpidem was found to prevent induced lipid peroxidation in rat liver and brain homogenates showing figures similar to melatonin, although it failed to prevent protein oxidation. ZPD-I was the most effective out of the several zolpidem intermediates studied as it prevented lipid peroxidation with an efficiency higher than melatonin or zolpidem and with an effectiveness similar to estradiol and trolox. ZPD-I prevents protein oxidation, which trolox is known to be unable to prevent. When cellular experiments were undertaken, ZPD-I prevented totally the increase of intracellular free radicals induced by glutamate 10mM in culture medium for 12h, while zolpidem and ZPD-III partially prevented this increase. Also the three compounds protected hippocampal neurons from glutamate-induced death in the same conditions, being their comparative efficacy, ZPD-III > ZPD-I = ZPD.
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina de la Universidad de Oviedo, c/Julian Clavería, Oviedo, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Santos
authors.forename: Federico
authors.initials: F
authors.lastname: Herrera
authors.forename: Vanesa
authors.initials: V
authors.lastname: Martín
authors.forename: Jezabel
authors.initials: J
authors.lastname: Rodriguez-Blanco
authors.forename: Isaac
authors.initials: I
authors.lastname: Antolín
authors.forename: Felix
authors.initials: F
authors.lastname: Fernández-Marí
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005296:Ferrous Compounds / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000077334:Zolpidem
chemical_list: D000975:Antioxidants; D002839:Chromans; D005296:Ferrous Compounds; D018696:Neuroprotective Agents; D011506:Proteins; D011725:Pyridines; D017382:Reactive Oxygen Species; C020748:ferrous sulfate; D018698:Glutamic Acid; D004958:Estradiol; D000077334:Zolpidem; D008550:Melatonin; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid