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.

Keywords: Acetoacetate; Beta-hydroxybutyrate; Epilepsy; Ketogenic diet; Ketone bodies; Neuroprotection.

Figure 1

Illustrations depicting potential mechanisms underlying ketone body-mediated attenuation of CNS hyperexcitability and neuroprotection. (A) Ketone bodies (KB) may enhance ATP production by providing acetyl-CoA (Ac) and inhibit production of reactive oxygen species (ROS) and the mitochondrial permeability transition (mPT) pore, thereby protecting the cell against oxidative injury and preventing excessive release of calcium. (B) KB may inhibit vesicular glutamate transporters (VGLUT), decreasing the amount of glutamate loaded in vesicles and reducing the size of glutamate quanta released during synaptic transmission. (C) KB-mediated increases in intracellular ATP and subsequent release through pannexin channels lead to adenosine (ADO) synthesis via ectonucleotidases (ENT) in the extracellular space. ADO in turn binds to inhibitory adenosine type 1 receptors (A₁Rs) which are coupled to the indirect opening of K_ATP channels. (D) KB activate HCA2 receptors and inhibit the assembly of the NRLP3 inflammasome; thus, KB attenuate inflammatory mediators produced by infiltrating macrophages. (E) KB also promote histone and non-histone hyperacetylation by increasing acetyl-CoA, a substrate for histone acetyltransferases (HATs), and directly inhibiting histone deacetylases (HDACs) – with the end result of increasing endogenous anti-oxidants (among other actions).