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.
Highlights
The traditional paradigm for discovery of new anti-seizure drugs (ASDs, referred to as antiepileptic drugs or AEDs) has involved the assessment of agents blocking acutely provoked or kindled seizures, and which has led to the development of medications that largely influence cellular membrane-bound ion channels and transporters localized to synapses in the central nervous system (CNS) (Rogawski et al, 2016)
Among the most intriguing are the following: (1) systemic anti-inflammatory effects induced by BHB via inhibition of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome assembly (Youm et al, 2015); (2) neuroprotective and antiinflammatory effects of BHB through an interaction with the hydroxycarboxylic acid 2 (HCA2) receptor (Rahman et al, 2014); and (3) inhibition of histone deacetylases (HDACs) and antioxidant effects in renal tissue by BHB (Shimazu et al, 2013)
Considering the promising results of the recent preclinical studies described here, along with advancements in optimizing ketone supplement formulations, it is possible that many of the seizure conditions which are known to benefit from the ketogenic diet (KD) could receive some benefit from exogenous ketone supplementation by elevating blood ketones and lowering blood glucose
Summary
- Cellular metabolism plays a key role in the modulation of neuronal excitability. - The high-fat, low-carbohydrate ketogenic diet (KD) is a validated treatment for persons with epilepsy. and is effective in preventing seizures in animal models. - Cellular metabolism plays a key role in the modulation of neuronal excitability. - The high-fat, low-carbohydrate ketogenic diet (KD) is a validated treatment for persons with epilepsy. Is effective in preventing seizures in animal models. - Beta-hydroxybutyrate (βHB) and acetoacetate (AcAc), the ketone bodies that increase during KD treatment, exert anti-seizure effects in animal models of epilepsy and neurometabolic disorders. - human clinical trials are still needed, therapeutic ketosis with ketone esters represents a clinically viable formulation for the potential treatment of epilepsy and other seizure disorders
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