Effects of D-beta-hydroxybutyrate on electrophysiological correlates of neuronal excitation and synchrony in an epilepsy cell culture model




Whitten, Crystal

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The compound D-beta-hydroxybutyrate (DBH) is a putative endogenous product or partial beta-oxidation of fatty acids. The stimulus to synthesize excess DBH is a high circulating level of free fatty acids. This occurs naturally in conditions of fasting, pregnancy, and excessive physical activity and can also be induced by a very high fat diet with minimal carbohydrate, known as a ketogenic diet (KD). The KD has been used over the past century to treat refractory epilepsy and more recently, the compound DBH has been found to be protective against Parkinson's disease, amyotrophic lateral sclerosis (ALS), chronic pain syndromes, and autism. The objectives of this study were to use electrophysiological techniques to characterize the effects of DBH in neural midbrain cells, to determine the concentration-response effects of DBH in midbrain cells, determine the reversibility of the effects of DBH in midbrain, and to test DBH in a model of hyperexcitation (i.e., epileptiform activity) to determine its ability to attenuate excitation. The neuroprotective potential of DBH was tested using rotenone. Additional studies were done using brain derived neurotrophic factor (BDNF), melatonin, and triiodothyronine. Augmentation of midbrain cells with DBH resulted in less inhibition as measured by spike activity. The presence of DBH was associated with an increase in spikes, bursts, bursting neurons and burst amplitude. DBH caused a decrease in burst period and burst hertz. Increasing the concentration of DBH led to a decrease in spikes at a concentration of 17-20 mM DBH. Measures that showed 100% reversibility for DBH were spikes, bursts, burst amplitude, burst hertz and bursting neurons. Measures that were significantly different were spikes within a burst, and burst duration. The potency and efficacy of DBH to alter the response of midbrain neurons to an "epileptiform" insult using bicuculline was evidenced by attenuation of spike and burst activity and a more asynchronous activity. Additional experiments showed cells pre-exposed to DBH and then exposed to rotenone were more likely to recover activity compared to cells not pre-exposed to DBH. Additional experiments were done using the chemicals BDNF, melatonin and triiodothyronine. The significance of these findings can be used to suggest greater strength of the midbrain in regulating the seizure threshold. An increase in activity with DBH exposure may indicate a greater level of inhibitory neurotransmission which would dampen the activity of the cortex and the transition of burst activity to near synchronous bursting. The findings also suggest the effects of DBH are reversible but at the higher levels, there may be more significant side effects and the long term reversibility is not known. The effects of DBH may also be attributed to its neuroprotective effects in the midbrain against complex I toxins such as rotenone.



Health and environmental sciences, Biological sciences, Epilepsy, Hydroxybutyrate, Ketones, Neuronal excitation, Synchrony