Ketone Administration for Seizure Disorders: History and Rationale for Ketone Esters and Metabolic Alternatives

Abstract

The ketogenic diet (KD) is a high-fat, low-carbohydrate treatment for medically intractable epilepsy. One of the hallmark features of the KD is the production of ketone bodies which have long been believed, but not yet proven, to exert direct anti-seizure effects. The prevailing view has been that ketosis is an epiphenomenon during KD treatment, mostly due to clinical observations that blood ketone levels do not correlate well with seizure control. Nevertheless, there is increasing experimental evidence that ketone bodies alone can exert anti-seizure properties through a multiplicity of mechanisms, including but not limited to: (1) activation of inhibitory adenosine and ATP-sensitive potassium channels; (2) enhancement of mitochondrial function and reduction in oxidative stress; (3) attenuation of excitatory neurotransmission; and (4) enhancement of central γ-aminobutyric acid (GABA) synthesis. Other novel actions more recently reported include inhibition of inflammasome assembly and activation of peripheral immune cells, and epigenetic effects by decreasing the activity of histone deacetylases (HDACs). Collectively, the preclinical evidence to date suggests that ketone administration alone might afford anti-seizure benefits for patients with epilepsy. There are, however, pragmatic challenges in administering ketone bodies in humans, but prior concerns may largely be mitigated through the use of ketone esters or balanced ketone electrolyte formulations that can be given orally and induce elevated and sustained hyperketonemia to achieve therapeutic effects.

Applications of Ketogenic Diets in Patients with Headache: Clinical Recommendations

“…Although exogenous ketone sources (salts or esters) are already commercially available and regarded as a promising therapy in both epilepsy [ 155 ] and migraine [ 21 ], no center of those involved in the working group has clinical experience with the use of these supplements. While waiting for data from clinical trials [ 156 ], some concerns were raised however about their use as it may only confer a partial effect compared to that of a KD.…”

β-hydroxybutyrate Impedes the Progression of Alzheimer’s Disease and Atherosclerosis in ApoE-Deficient Mice

“…β-hydroxybutyrate (β-OHB) is a major component of ketone bodies. The efficacy of a ketogenic diet in treating childhood refractory epilepsy and mild cognitive impairment that usually precedes the onset of AD has been well established, and paved the way to evaluate the potential therapeutic effect of β-OHB [8][9][10][11]. However, a common mode of action of β-OHB in AD and other neurodegenerative diseases, as well as atherosclerosis, has yet to be fully elucidated.…”

Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier

“…Relatively less recognized, but biologically important nonetheless, functions of β-hydroxybutyrate include inhibition of class I and III histone deacetylases [ 75 , 76 ] and activation of the G-protein-coupled receptor GPR109A (also known as hydroxycarboxylic acid receptor 2 or HCA2) [ 77 , 78 ]. It has been well established that ketogenic diet protects against epilepsy [ 76 ], and the provision of β-hydroxybutyrate to neurons as an energy substrate under this dietary condition is at least partly responsible for this beneficial therapeutic effect. Similarly, pharmacologic activation of GPR109A has been shown to protect neuronal death in pathological conditions [ 79 ].…”