Do ketone bodies mediate the anti-seizure effects of the ketogenic diet?

Abstract

Although the mechanisms underlying the anti-seizure effects of the high-fat ketogenic diet (KD) remain unclear, a long-standing question has been whether ketone bodies (i.e., β-hydroxybutyrate, acetoacetate and acetone), either alone or in combination, contribute mechanistically. The traditional belief has been that while ketone bodies reflect enhanced fatty acid oxidation and a general shift toward intermediary metabolism, they are not likely to be the key mediators of the KD's clinical effects, as blood levels of β-hydroxybutyrate do not correlate consistently with improved seizure control. Against this unresolved backdrop, new data support ketone bodies as having anti-seizure actions. Specifically, β-hydroxybutyrate has been shown to interact with multiple novel molecular targets such as histone deacetylases, hydroxycarboxylic acid receptors on immune cells, and the NLRP3 inflammasome. Clearly, as a diet-based therapy is expected to render a broad array of biochemical, molecular, and cellular changes, no single mechanism can explain how the KD works. Specific metabolic substrates or enzymes are only a few of many important factors influenced by the KD that can collectively influence brain hyperexcitability and hypersynchrony. This review summarizes recent novel experimental findings supporting the anti-seizure and neuroprotective properties of ketone bodies.

Ketogenic Diets for Adult Neurological Disorders

“…An increasing number of experimental studies demonstrate pleiotropic actions of ketone bodies and ketogenic diets [9]. Ketones can induce changes in neurotransmitter concentrations and release, as well as neural membrane polarity which may inhibit increased neuronal excitability.…”

“…One potential explanation for this observation is that fatty acids activate peroxisome proliferator-activated receptor α which then inhibits the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) signal transduction pathway to downregulate expression of two key genes involved in the inflammatory response-COX2 and inducible nitric oxide synthase [35]. Recent studies also show that β-hydroxybutyrate may directly bind to hydroxy-carboxylic acid receptor 2 (HCA2) and/or inhibit the innate immune sensor NOD-like receptor 3 (NLRP3) inflammasome which controls the activation of caspase-1 and the release of pro-inflammatory cytokines IL-1β and IL-18 [9,34,36].…”

Differential Ketogenic Diet-Induced Shift in CSF Lipid/Carbohydrate Metabolome of Pediatric Epilepsy Patients With Optimal Vs. No Anticonvulsant Response

“…Of paramount interest is the identification of compounds that could be mechanistically involved in the anticonvulsant effect of a robust metabolic response. The eponymous products of a KD are an obvious candidate [14]. Beyond being a more efficient fuel for in oxidative metabolism and mitochondrial health, ketone bodies are putative signaling molecules in several pathways that should improve the state of hyperexcitable brain tissue, including inhibitory ion channels [41], vesicular glutamate release [42], inflammation [43], nicotinamide adenine dinucleotide oxidation state [44], and histone deacetylases [45].…”

“…Fasting and adhering to a KD each produce hallmark changes in blood ketone bodies (increased) and glucose (decreased) but it has remained unclear how these changes relate to beneficial effects. For instance, blood ketone body levels do not always correlate with anticonvulsant effects [13], and in general anticonvulsant benefits of ketones versus glucose in clinical and laboratory work is mixed and still under active investigation and debate [14].…”

Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury

“…Long-term exposure to 2-DG, however, has been previously associated with cardiotoxicity (64,65), underscoring that short-term use as a disease-modifying agent (as in our approach) is preferable over chronic use as an anticonvulsant. Finally, there is abundant evidence supporting the use of the ketogenic diet (which results in decreased glycolysis and increased ketosis) as a strategy to manipulate neural network activity in animals and humans (reviewed in (66)(67)(68)(69)(70)(71)(72)). While dietary approaches and glycolytic inhibition have shown efficacy in controlling seizure activity, manipulations of glucose metabolism have not yet been harnessed effectively in the context of TBI.…”