Mitigation of CNS Oxygen Toxicity: Mitochondria Targeted Anti-Oxidant Therapy and Aquaporin Gas Channels
Abstract
Naval unique Special Warfare/Special Operations diving maneuvers and submarine operations are limited by health risks associated with breathing various gas mixtures at hyperbaric pressure. Included in the list of health risks is central nervous system oxygen toxicity (CNS-OT), which manifests as generalized tonic-clonic seizures that are often preceded by autonomic andcardiorespiratory disturbances. Currently, the only approved strategy for prevention of CNS-OT is reduction of depth and thus, inspired partial pressure of oxygen and/or the duration of exposure to hyperbaric oxygen (HBO2). Currently, exposure limits for breathing HBO2 are highly conservative; e.g., limited to 10 minutes at 50 feet of sea water. Accordingly, the U.S. Navys goal is to expand the envelope of clandestine diving operations; that is, longer and safer dives while breathing HBO2.The proposed 6.2 project focuses on the mitigation of CNS-OT by targeting two, subcellular targets in the mammalian CNS that are thought to contribute to the pathogenesis of seizures during exposure to HBO2: 1) mitochondrial superoxide generation and its downstream reaction productions, and 2) O2-/CO2-permeabilities through the gas channel aquaporin-4 (AQP4) at the blood-brain barrier. The first three research objectives focus on a novel, untested mitigationstrategy for delaying and possibly preventing CNS-OT through mitochondria-targeted antioxidant therapy (MitoTAT). Mitochondria-targeted ubiquinol/ubiquinone (Mitoquinone, MitoQ) will be used; MitoQ is an antioxidant supplement that is already approved for human consumption. Animal experiments using rodents will be done employing pressure chambers, radio-telemetry,and in vitro electrophysiology and fluorescence imaging; all techniques have been safely adapted for use under HBO2 conditions. We postulate that MitoTAT will delay or prevent onset of CNS-OT seizures. The underlying mechanism, we predict, will include decreased reactive oxygen and nitrogen species production and decreased neuronal excitability during hyperoxia.The fourth research objective focuses on AQP4 gas channels as a potential target for reducing uptake of molecular O2 during exposure to HBO2 and molecular CO2 during respiratory acidosis caused by alveolar hypoventilation and CO2 rebreathing. Whole animal experiments will employ AQP4 knockout mice and wild type controls under conditions of HBO2 CO2 exposures.Oxidative preconditioning will be used to upregulate AQP4 expression in the blood brain barrier of wild type mice. We predict that AQP4-knockout mice will display increased tolerance for HBO2 CO2. Conversely, wildtype mice overexpressing AQP4 will have decreased tolerance for HBO2.Experiments proposed for Objective 4, if successful, are the genetic proof of principle that eliminating the contribution of AQP4 O2/CO2 uptake in the brain will delay onset of CNS-OT. In conclusion, successful outcome of this project will identify two important subcellular targets for increasing tolerance during exposure to HBO2; mitochondrial superoxide and its reaction byproducts and AQP4 gas channels.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 08, 2020
- Source ID
- N000142012434
Entities
People
- Jay B. Dean
Organizations
- Office of Naval Research
- United States Navy
- University of South Florida