Oxidative tissue damage mitigation after exposure to HBO2 using FDA approved anti-epileptic drugs (AEDs)
Abstract
Support from ONR has allowed us to pursue studies on the mechanisms by which hyperbaric oxygen (HBO2) elicits acute CNS toxicity with the goal of safely expanding depth-time exposures to hyperbaric hyperoxia for military divers, personnel in a disabled submarine, and patients receiving therapeutic hyperbaric oxygen. HBO2 neurotoxicity, especially seizures, are a neurological emergency for which the only effective prevention has been the employment of empirical schedules for limiting depth and duration of exposures. These schedules result in severely limited exposure times at each pressure. Because HBO2 seizures share pathophysiological features with acquired or idiopathic epilepsies, we tested antiepileptic drugs (AEDs) for the idiopathic disorders for CNS O2 toxicity prevention. We evaluated ten AEDs that act on specific molecular targets implicated in seizure generation as experimental probes and found that sodium-channel antagonists, carbamazepine (CMZ) and lamotrigine (LTG), and GABA transmission enhancers, tiagabine (TGB) and gabapentin (GBP), displayed very high efficacy against HBO2 seizures. We tested the efficacy of selected FDA-approved AEDs in combinations and found that combinations of one agent from each class prolonged the seizure latency by five- to six-fold, but without decreasing the cerebral vascular response to HBO2. Since blood flow response to HBO2 is unaffected, the tissue PO2 remains high, which may lead to oxidative disuse damage during the prolonged exposure.Our main hypothesis is that each AED combination will prevent seizures and limit oxidative tissue damage in the brain despite the persistence of cerebral hyperemia that precedes the seizures. Our ancillary hypotheses is that despite the neuroprotection by AEDs, the lungs will still be damaged directly by the period of HBO2. Our scientific objective is to study how each of these two AED combinations allow sub-cellular oxidative, nitrosative, and neurochemical attack in the brains and lungs of mice to 5ATA HBO2. We will measure in awake mice a battery of oxidative and neurochemical tests, brain edema, BAL fluid, Motor function and lung function (Flexivent) with and without the two AED combinations. Our technical objective is to provide scientific support for safe and effective pharmacologic interventions that significantly extend the time and/or depth of human exposures to HBO2 that are practical for use in conditions relevant to military operations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 27, 2018
- Source ID
- N000141812702
Entities
People
- Claude A. Piantadosi
Organizations
- Duke University
- Office of Naval Research
- United States Navy