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National Institute of Environmental Health Sciences

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Publication Detail

Title: Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage.

Authors: Liu, Junli; Tian, Daishi; Murugan, Madhuvika; Eyo, Ukpong B; Dreyfus, Cheryl F; Wang, Wei; Wu, Long-Jun

Published In J Neurochem, (2015 Oct)

Abstract: NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production in inflammatory cells including microglia plays an important role in demyelination and free radical-mediated tissue injury in multiple sclerosis (MS). However, the mechanism underlying microglial ROS production and demyelination remains largely unknown. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. In the present study, we sought to determine the role of microglial Hv1 proton channels in a mouse model of cuprizone-induced demyelination, a model for MS. Following cuprizone exposure, wild-type mice presented obvious demyelination, decreased myelin basic protein expression, loss of mature oligodendrocytes, and impaired motor coordination in comparison to mice on a normal chow diet. However, mice lacking Hv1 (Hv1(-/-) ) are partially protected from demyelination and motor deficits compared with those in wild-type mice. These rescued phenotypes in Hv1(-/-) mice in cuprizone-induced demyelination is accompanied by reduced ROS production, ameliorated microglial activation, increased oligodendrocyte progenitor cell (NG2) proliferation, and increased number of mature oligodendrocytes. These results demonstrate that the Hv1 proton channel is required for cuprizone-induced microglial oxidative damage and subsequent demyelination. Our study suggests that the microglial Hv1 proton channel is a unique target for controlling NOX-dependent ROS production in the pathogenesis of MS.

PubMed ID: 26173779 Exiting the NIEHS site

MeSH Terms: Animals; Chelating Agents/toxicity*; Cuprizone/toxicity*; Demyelinating Diseases/chemically induced; Demyelinating Diseases/pathology*; Ion Channels/genetics*; Ion Channels/metabolism*; Macrophage Activation/drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia/drug effects; Microglia/metabolism*; Multiple Sclerosis/chemically induced; Multiple Sclerosis/pathology; Myelin Basic Protein/metabolism; NADPH Oxidases/metabolism; Neural Stem Cells/drug effects; Oxidative Stress/drug effects*; Postural Balance/drug effects; Reactive Oxygen Species

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