The voltage-gated proton channel Hv1 contributes to neuronal injury and motor deficits in a mouse model of spinal cord i
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RESEARCH
The voltage‑gated proton channel Hv1 contributes to neuronal injury and motor deficits in a mouse model of spinal cord injury Madhuvika Murugan1,2†, Jiaying Zheng1,2†, Gongxiong Wu3, Rochelle Mogilevsky2, Xin Zheng2, Peiwen Hu2, Junfang Wu4* and Long‑Jun Wu1,2,5,6*
Abstract Traumatic injury to the spinal cord initiates a series of pathological cellular processes that exacerbate tissue damage at and beyond the original site of injury. This secondary damage includes oxidative stress and inflammatory cascades that can lead to further neuronal loss and motor deficits. Microglial activation is an essential component of these secondary signaling cascades. The voltage-gated proton channel, Hv1, functionally expressed in microglia has been implicated in microglia polarization and oxidative stress in ischemic stroke. Here, we investigate whether Hv1 medi‑ ates microglial/macrophage activation and aggravates secondary damage following spinal cord injury (SCI). Following contusion SCI, wild-type (WT) mice showed significant tissue damage, white matter damage and impaired motor recovery. However, mice lacking Hv1 (Hv1−/−) showed significant white matter sparing and improved motor recovery. The improved motor recovery in Hv1−/− mice was associated with decreased interleukin-1β, reactive oxygen/ nitrogen species production and reduced neuronal loss. Further, deficiency of Hv1 directly influenced microglia activation as noted by decrease in microglia numbers, soma size and reduced outward rectifier K + current density in Hv1−/− mice compared to WT mice at 7 d following SCI. Our results therefore implicate that Hv1 may be a promising potential therapeutic target to alleviate secondary damage following SCI caused by microglia/macrophage activation. Keywords: Microglia, Spinal cord injury, Hv1, Voltage-gated proton channel, ROS, Neuroinflammation, Interleukin-1β Highlights Microglial activation after spinal cord injury is regulated by voltage-gated proton channel Hv1. Mice lacking Hv1(Hv1−/−) display reduced cytokine production and oxidative stress responses. Hv1−/− mice exhibit improved pathology and motor recovery outcomes following spinal cord injury.
*Correspondence: [email protected]; [email protected] † Madhuvika Murugan and Jiaying Zheng contributed equally to this work 1 Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA 4 Department of Anesthesiology, University of Maryland, Baltimore, MD 21201, USA Full list of author information is available at the end of the article
Introduction Injury to the spinal cord initiates a complex cascade of oxidative stress and inflammatory responses at and beyond the original site of insult and aggravates tissue damage [1]. These secondary cascades that occur from minutes to weeks after primary injury, can lead to further demyelination, glial scar formation, and additional neuronal loss [2]. Hence, therapeutic intervention during the window of secondary injury is key to influence the tissue and behavioral recovery following spinal cord inju
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