Optimizing ketone metabolic therapy and identifying biomarkers for mitigation and prediction of CNS oxygen toxicity: animal studies
Abstract
Naval unique Special Warfare and Special Operations diving maneuvers and submarine operations are limited by health risks associated with breathing oxygen at hyperbaric pressures. These conditions can result in Central Nervous System-Oxygen Toxicity (CNS-OT), the most fatal symptom of which is seizure (Sz) underwater. Several FDA-approved antiepileptic drugs (AEDs) are known to significantly delay onset of CNS-OT, and in general, work by reducing excitabilityof the CNS. AEDs have adverse side effects that can compromise safety and impair cognitive and physical functions that may limit warfighter performance and ability to complete mission tasks. Ketogenic metabolic therapy (KMT) is an alternative mitigation strategy against CNS-OT. We previously discovered that oral supplementation with the R,S-1,3-butanediol diacetoacetate ketoneester (KE) delays latency to onset of CNS-OT in the unanesthetized, freely moving SD rat model by nearly 600%. Thus, KMT represents a promising prevention strategy against CNS-OT, but to fully understand it???s optimal, safe, and effective use in humans, several questions remain to be answered.Firstly, several candidate ketogenic agents (KA) are now in existence, so it is unknown if KE is the optimal agent for delaying or preventing CNS-OT. Thus, the optimal KA formulation and dose for delaying CNS-OT are unknown, as are their potential effects on cognitive or motor performance. The first goal of this project is to optimize the formulation and dosage of KA(s) that induce therapeutic ketosis for purposes of delaying CNS-OT (EEG measurement), withoutimpairing cognitive or motor performance. Secondly, there remains a crucial need to identify early physiological predictors of CNS-OT onset, both within and outside the context of ketogenic intervention. Doing so may allow sufficient time to reduce inspired pO2 and safely avert Sz onset. Thus, the second goal of this project is to determine the effects of hyperbaric oxygen KA on presumptive physiological markers (e.g. respiration, body temperature) that can bemonitored in real time to predict an impending oxygen Sz. Finally, the molecular mechanisms of the anti-convulsant effects of KMT in CNS-OT remain unelucidated, but are important for translating and advancing the use of KMT in humans. The third goal of this project is to study the anti-convulsant mechanisms of therapeutic ketosis by measuring expression of candidatesignaling molecules in brains of animals that have been exposed to protracted HBO2 resulting in no Sz versus Sz. As designed, the proposed studies will answer crucial questions to benefit the United States Navy and field of hyperbaric medicine, thereby advancing the science and application of KMT for CNS-OT.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Sep 04, 2018
- Source ID
- N000141812701
Entities
People
- Dominic D Agostino
Organizations
- Office of Naval Research
- United States Navy
- University of South Florida