The Role of GABA in Susceptibility to Oxygen Toxicity with Repeated HBO2 Exposure
Abstract
Hyperbaric oxygen (HBO2) increases the partial pressure of oxygen (PO2) in the lungs, blood and tissues. The pulmonary and central n,ervous systems are very sensitive to changes in PO2, and high levels can cause oxidative tissue damage that can be lethal. The USN e,stablished single-depth oxygen exposure limits that serve to reduce the probability of developing central nervous system oxygen toxi,city (CNS-OT) that may culminate in tonic-clonic seizures, thus are restrictive for depth and time. For this reason, research has be,en directed towards understanding the mechanisms of CNS-OT with the goal of finding targeted prevention strategies. It is known that, increasing the GABA-to-glutamate ratio delays seizure latency, and this can be accomplished by administering FDA approved antiepile,ptic drugs (AEDs). We have determined in mice that a single 60-minute exposure to HBO2 at 5 ATA causes DNA oxidation, inflammation a,nd selective degradation of mitochondria, i.e., mitophagy, mainly in the cerebellum and hippocampus. This is followed by mitochondri,al biogenesis and injury resolution within 72-hours. The AED tiagabine (TGB) attenuated acute brain injury and enhanced mitochondria,l biogenesis. Because exposure to HBO2 increases sensitivity to CNS-OT, which is linked to oxidative lung injury, the main objective, in this application is to determine how HBO2 and GABA influence repeated exposure-sensitivity to oxidative tissue injury. A seconda,ry objective is to determine the impact of elevated GABA levels on running performance after HBO2. Our central hypothesis is that in,creasing the GABA-to-glutamate ratio will shorten the time course of oxidative injury repair, decreasing repeated HBO2 exposure sens,itivity. The rationale is that it will determine if maintaining GABA levels affords protection against oxidative tissue damage with,repeated exposure to HBO2 and offer a strong scientific framework for testing GABAergic AEDs in humans. To test our hypothesis and a,ttain our objective, the following three specific aims will be pursued: 1) Determine in C57BL/6 mice if GABA influences repeated HBO,2 exposure sensitivity to seizures and lung injury. 2) Determine in mito-QC mice the impact of HBO2 and GABA on recovery from oxidat,ive tissue damage. 3) Determine in C57BL/6 mice if increased GABA impairs running performance after HBO2. To accomplish this researc,h, we will use wild type and transgenic mice with fluorescent labels for mitochondrial architecture and mitophagy (mito-QC) and expo,se them to single or repeated HBO2 exposures at 5 ATA. Running performance will be tested after HBO2 at 3 ATA. GABA metabolism and o,xidative injury in the brain and lung will be measured by ultra-performance liquid chromatography-tandem mass spectrometry, immunohi,stochemistry and immunofluorescence, immunoblotting and assays. The proposed research is significant because it will lay the groundw,ork for testing GABAergic AEDs in humans performing work in HBO2. The proximate expected outcomes of this work is knowledge of how G,ABA influences the time course of oxidative injury repair in the brains and lungs of mice exposed to repeated HBO2. The results will, have an important positive impact immediately because they will establish new function(s) of GABA, and potentially lead to increase,d oxygen exposure limits. The proposed research is relevant to warfighters because breathing 100% oxygen during diving operations ca,n impair work performance and mitigation approaches are needed. This proposal addresses two of Undersea Medicine & Performance Conce,ntration Areas: mitigation of hyperbaric oxyge
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Sep 08, 2022
- Source ID
- N000142212749
Entities
People
- Heath G Gasier
Organizations
- Duke University
- Office of Naval Research
- United States Navy