Ion channel inhibition to minimize stroke's secondary damage
Inventors: David Clapham, Magdalene Moran, Jayhong Chong, Ian Ramsey
Invention Types: Therapeutics
Research Areas: Immunology, Neurology/Neuroscience
Keywords: Drug ScreeningFor More Information Contact: Miracco, Amy
Voltage-gated proton channels are ion channels that have the unique property of opening with depolarization in a strongly pH-sensitive manner. These channels open only when the electrochemical gradient is outward thereby only allowing protons to leave cells. This invention is based on the discovery of a novel voltage-gated proton-selective channel designated Hv1. Hv1 is primarily expressed in immune tissue such as lymph node, monocytes and spleen, but is also present in cells associated with nervous tissue. Hv1 modulates B-cell activation, basophil histamine release, and acid secretion from airway epithelium and human spermatozoa. Our recent work shows that mouse and human brain microglia, but not neurons or astrocytes, expressed large Hv1-mediated currents. Hv1 was required for NOX-dependent ROS generation in brain microglia in situ and in vivo. Mice lacking Hv1 were protected from NOX-mediated neuronal death and brain damage 24 h after stroke. These results indicate that Hv1-dependent ROS production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke and provide a rationale for Hv1 as a therapeutic target for the treatment of ischemic stroke.
Our recent findings suggest Hv1 as a therapeutic target for the treatment of ischemic stroke. In addition, Hv1 targeting has therapeutic potential to treat diseases associated with dysfunctional cellular immune response (respiratory burst), neurodegenerative diseases, chronic granulomatous disease (lack of functional NADPH oxidase), a rare yet potentially fatal hereditary disease. In conditions associated with abnormally low proton pumping activity, drugs that increase Hv1 activity could be used to treat defective carbon dioxide exchange and associated conditions, such as chronic obstructive pulmonary disease (COPD), by increasing the flux of protons (and associated bicarbonate anions) across the alveolar membrane. Since proton pumping increases intracellular pH and decreases extracellular pH, conditions related to acidity/alkalinity can be treated by modulating Hv1 activity, such as renal tubular acidosis, gallstones, and acid-related pain sensing.
Key Publications: Ramsey SI, Moran MM, Chong JA, Clapham DE. A voltage-gated proton-selective channel lacking the pore domain. Nature. 2006 Apr 27;440(7088): 1213-1216.
Wu L-J, Wu G, Sharif MRA, et al. The voltage-gated proton channel, Hv1, enhances brain damage from ischemic stroke. Nat Neurosci. 2012 Apr; 15(4): 565-573.
Related Publications: US 9,068,018 B2