title: Neuroprotective effect of dimebon against ischemic neuronal damage.
abstract: Dimebon (dimebolin or latrepirdine), originally developed as an anti-histaminic drug, has been investigated and proposed as a cognitive enhancer for treating neurodegenerative disorders such as Alzheimer's and Huntington's diseases, and more recently schizophrenia. This study was conducted to evaluate the potential neuroprotective effect of dimebon during brain ischemia using rat hippocampal slices subjected to oxygen and glucose deprivation followed by a reoxygenation period (OGD/Reox) or glutamate excitotoxicity. Dimebon, incubated during the OGD/Reox period, caused a concentration -dependent protective effect of hippocampal slices; maximum protection (85%) was achieved at 30μM. Mitochondrial membrane depolarization, reactive oxygen species of oxygen (ROS) production, nitric oxide synthase (iNOS) induction and translocation of p65 to the nucleus induced by OGD/Reox were significantly reduced in dimebon-treated hippocampal slices. In the glutamate-induced excitotoxicity model, dimebon also afforded a concentration-dependent protective effect that was significantly higher than that obtained with memantine, a non-competitive N-methyl-d-aspartate (NMDA) antagonist. When changes in the intracellular calcium concentration were evaluated in Fluo-4-loaded rat hippocampal neurons, glutamate-induced calcium transients were reduced by 20% with dimebon. These results suggest that dimebon could counteract different pathophysiological processes during ischemic brain damage and, could therefore, be considered as a novel therapeutic strategy for cerebral ischemia-reoxygenation injury.
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Egea
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: manarome@ucm.es.
authors.forename: A
authors.initials: A
authors.lastname: Romero
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Parada
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria Hospital Universitario la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: León
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: T
authors.initials: T
authors.lastname: Dal-Cim
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: M G
authors.initials: MG
authors.lastname: López
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000473:pathology*; D000860:Hypoxia / Q000473:pathology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007511:Ischemia / Q000473:pathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D007211:Indoles; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D005947:Glucose; C010119:latrepirdine
keywords: dimebon; hippocampal neurons; hippocampal slices; ischemia; neuroprotection; oxygen–glucose deprivation