title: K(ATP) channel opener diazoxide prevents neurodegeneration: a new mechanism of action via antioxidative pathway activation.
abstract: Pharmacological modulation of ATP-sensitive potassium channels has become a promising new therapeutic approach for the treatment of neurodegenerative diseases due to their role in mitochondrial and cellular protection. For instance, diazoxide, a well-known ATP-sensitive potassium channel activator with high affinity for mitochondrial component of the channel has been proved to be effective in animal models for different diseases such as Alzheimer's disease, stroke or multiple sclerosis. Here, we analyzed the ability of diazoxide for protecting neurons front different neurotoxic insults in vitro and ex vivo. Results showed that diazoxide effectively protects NSC-34 motoneurons from glutamatergic, oxidative and inflammatory damage. Moreover, diazoxide decreased neuronal death in organotypic hippocampal slice cultures after exicitotoxicity and preserved myelin sheath in organotypic cerebellar cultures exposed to pro-inflammatory demyelinating damage. In addition, we demonstrated that one of the mechanisms of actions implied in the neuroprotective role of diazoxide is mediated by the activation of Nrf2 expression and nuclear translocation. Nrf2 expression was increased in NSC-34 neurons in vitro as well as in the spinal cord of experimental autoimmune encephalomyelitis animals orally administered with diazoxide. Thus, diazoxide is a neuroprotective agent against oxidative stress-induced damage and cellular dysfunction that can be beneficial for diseases such as multiple sclerosis.
authors.affiliation: Neurotec Pharma S.L., Bioincubadora PCB-Santander, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Virgili
authors.forename: Pilar
authors.initials: P
authors.lastname: Mancera
authors.forename: Blanca
authors.initials: B
authors.lastname: Wappenhans
authors.forename: Georgina
authors.initials: G
authors.lastname: Sorrosal
authors.forename: Knut
authors.initials: K
authors.lastname: Biber
authors.forename: Marco
authors.initials: M
authors.lastname: Pugliese
authors.forename: Juan F
authors.initials: JF
authors.lastname: Espinosa-Parrilla
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology; D003981:Diazoxide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000166:cytology; D015640:Ion Channel Gating / Q000187:drug effects*; D054086:KATP Channels / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D013116:Spinal Cord / Q000473:pathology
chemical_list: D000975:Antioxidants; D054086:KATP Channels; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D009498:Neurotoxins; C495636:Nfe2l2 protein, mouse; D003981:Diazoxide
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