Ketone Bodies as Anti-Seizure Agents

There is growing evidence that ketone bodies (KB)-derived from fatty acid oxidation and produced during fasting or consumption of high-fat diets-can exert broad neuroprotective effects. With respect to epilepsy, KB (such as β-hydroxybutyrate or BHB, acetoacetate and acetone) have been shown to block acutely induced and spontaneous recurrent seizures in various animal models. Although the mechanisms underlying the anti-seizure effects of KB have not been fully elucidated, recent experimental studies have invoked ketone-mediated effects on both inhibitory (e.g., GABAergic, purinergic and ATP-sensitive potassium channels) and excitatory (e.g., vesicular glutamate transporters) neurotransmission, as well as mitochondrial targets (e.g., respiratory chain and mitochondrial permeability transition). Moreover, BHB appears to exert both epigenetic (i.e., inhibition of histone deacetylases or HDACs) and anti-inflammatory (i.e., peripheral modulation of hydroxycarboxylic acid receptor and inhibition of the NOD-like receptor protein 3 or NRLP3 inflammasome) activity. While the latter two effects of BHB have yet to be directly linked to ictogenesis and/or epileptogenesis, parallel lines of evidence indicate that HDAC inhibition and a reduction in neuroinflammation alone or collectively can block seizure activity. Nevertheless, the notion that KB are themselves anti-seizure agents requires clinical validation, as prior studies have not revealed a clear correlation between blood ketone levels and seizure control. Notwithstanding this limitation, there is growing evidence that KB are more than just cellular fuels, and can exert profound biochemical, cellular and epigenetic changes favoring an overall attenuation in brain network excitability.