KATP Channel Opener Diazoxide Prevents Neurodegeneration: A New Mechanism of Action via Antioxidative Pathway Activation
Open Access
- 11 September 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (9), e75189
- https://doi.org/10.1371/journal.pone.0075189
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.Keywords
This publication has 69 references indexed in Scilit:
- Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of NeuroinflammationPLOS ONE, 2013
- The mitochondrial KATP channel—Fact or fiction?Journal of Molecular and Cellular Cardiology, 2012
- Neuroprotective function for ramified microglia in hippocampal excitotoxicityJournal of Neuroinflammation, 2012
- Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosisJournal of Neuroinflammation, 2011
- Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitisBrain, Behavior, and Immunity, 2011
- Subsecond regulation of striatal dopamine release by pre‐synaptic KATP channelsJournal of Neurochemistry, 2011
- Efficacy of Fumaric Acid Esters in the R6/2 and YAC128 Models of Huntington's DiseasePLOS ONE, 2011
- Diazoxide Promotes Oligodendrocyte Precursor Cell Proliferation and MyelinationPLOS ONE, 2010
- Mitochondrial-mediated suppression of ROS production upon exposure of neurons to lethal stress: Mitochondrial targeted preconditioningAdvanced Drug Delivery Reviews, 2008
- ɛPKC phosphorylates the mitochondrial K+ATP channel during induction of ischemic preconditioning in the rat hippocampusBrain Research, 2007