Related Experiment Video
Updated: Apr 7, 2026
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage
Junli Liu1,2, Daishi Tian2,3, Madhuvika Murugan2
1Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
The voltage-gated proton channel Hv1 in microglia drives oxidative damage and demyelination in a mouse model of multiple sclerosis (MS). Inhibiting Hv1 reduces damage, suggesting it as a therapeutic target for MS.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia-driven reactive oxygen species (ROS) production is implicated in multiple sclerosis (MS) pathogenesis, contributing to demyelination and tissue injury.
- The voltage-gated proton channel Hv1 is crucial for NADPH oxidase (NOX)-dependent ROS generation and is specifically expressed in microglia.
Purpose of the Study:
- To investigate the role of microglial Hv1 proton channels in cuprizone-induced demyelination, a mouse model mimicking MS.
- To elucidate the mechanisms by which Hv1 influences microglial activation, ROS production, and oligodendrocyte damage.
Main Methods:
- Utilized a cuprizone-induced demyelination mouse model.
- Compared wild-type mice with mice lacking the Hv1 channel (Hv1(-/-)).
- Assessed demyelination, myelin basic protein expression, oligodendrocyte counts, motor function, and ROS production.
Main Results:
- Wild-type mice exposed to cuprizone showed significant demyelination, reduced myelin basic protein, oligodendrocyte loss, and motor deficits.
- Hv1(-/-) mice were partially protected from demyelination and motor impairments.
- Hv1 deficiency led to reduced ROS production, decreased microglial activation, and increased oligodendrocyte progenitor cell proliferation and mature oligodendrocyte numbers.
Conclusions:
- The Hv1 proton channel is essential for cuprizone-induced microglial oxidative stress and subsequent demyelination in this MS model.
- Targeting microglial Hv1 presents a potential therapeutic strategy for mitigating NOX-dependent ROS production and neuroinflammation in MS.
