Effects of Exogenous Ketone Therapy on Performance, Cardiorespiration, and Seizure Genesis During Exposure to HBO2 in the Sprague Dawley Rat
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Jay B. Dean, Ph.D.
Bill Baker, Ph.D.
Dominic D'Agostino, Ph.D.
Thomas Taylor-Clark, Ph.D.
Ketone Ester, Oxygen Toxicity, Caudal Solitary Nucleus, Reactive Oxygen and Nitrogen Species, Predictive Physio-Marker, Behavior
Hyperbaric oxygen (HBO2) is used for clinical HBO2 therapy and in undersea and aerospace medicine. HBO2 is a humanmade extreme environment and protracted exposures can cause several adverse physiological effects on the body. For example, HBO2 increases the partial pressure of oxygen (PO2) in the body leading to redox stress. Redox stress is, in part, a cause of oxygen toxicity that manifests as seizures in its most severe form (central nervous system oxygen toxicity, CNS-OT). This dissertation focuses on strategies to be employed specifically for the warfighter breathing HBO2. Currently, the only way to prevent CNS-OT is to lower the level of inspired PO2. Likewise, physiological markers (“physio-markers”) have been identified that predict onset of seizures during exposure to HBO2, e.g., hyperoxic hyperpnea. Finally, previous research has shown that [exogenous] ketone metabolic therapy significantly delays CNS-OT seizures. Accordingly, the goal of my dissertation was to identify an optimal dose of exogenous ketone ester (KE) that delays seizures during exposure to HBO2 without disrupting animal cognition and performance. A second goal was to determine the effects of ketosis on identified and postulated physio-markers of an impending seizure. First, a pharmacokinetic study verified that this new, lower dose induces therapeutic ketosis. Next, we determined that this new dose would not hinder cognitive or motor performance through a series of behavioral animal tests while breathing normobaric air. Third, we confirmed whether the lower dose would delay the onset of CNS-OT. Finally, in offline data analysis, we looked at the physiological markers of temperature, cardiovascular, and respiratory responses to detect if these “physio-markers” could be applied as predictive measures of CNS-OT. Our hypothesis was that the moderate dose of KE would not impair cognition or motor performance while providing neuroprotection and delay onset of CNS-OT. Moreover, we proposed that the physio-markers we assessed could be used to predict CNS-OT and would be unaffected by ketosis. Our results showed that the optimal dose of KE was 7.5g/kg, which maintained a state of ketosis for ~6 hours. Additionally, this [KE] had no deleterious effects on cognitive or motor performance. Furthermore, a single oral dose of KE increased the latency time to seizure by 307% when breathing 5 ATA O2. Lastly, we confirmed that the cardiovascular and respiratory physio-markers—hyperoxic bradycardia and hyperpnea—were changed significantly ~15 minutes prior to seizure onset (CNS-OT). Moreover, these two physio-markers were unchanged by ketone therapy and still predicted seizures ~15 minutes beforehand. By contrast, hyperoxic core hypothermia was not a useful physio-marker of CNS-OT. Taken together these results suggest that the moderate dose of KE used in our study are safe to use in mammals and effectively increase bottom time when breathing HBO2 without adverse effects on cognition, performance, and physio-markers that predict seizure genesis.
Scholar Commons Citation
Stavitzski, Nicole M., "Effects of Exogenous Ketone Therapy on Performance, Cardiorespiration, and Seizure Genesis During Exposure to HBO2 in the Sprague Dawley Rat" (2021). USF Tampa Graduate Theses and Dissertations.