Antiepileptic popular ketogenic diet: emerging twists in an ancient story

doi:10.1016/j.pneurobio.2004.11.003

Progress in Neurobiology

Volume 75, Issue 1, January 2005, Pages 1-28

https://doi.org/10.1016/j.pneurobio.2004.11.003 Get rights and content

Abstract

The antiepileptic activity associated with ketogenic diets (KD) have been known for some time. First reports date back to the Middle Ages and even Biblical times where KD was achieved by fasting (i.e. “water diet”) [see Swink, T.D., Vining, E.P.G., Freeman, J.M., 1997. The ketogenic diet: 1997. Adv. Pediatr. 44, 297–329, and references therein]. In the early 20th century, changes in the design of the KD were introduced, shifting the so-called “water diet” to a high-fat diet. Initial clinical evaluations undertaken between the 1920s and 1940s were enthusiastic, but the popularity of the KD was retrograded upon clinical introduction of phenytoin and subsequently other antiepileptic drugs. Today, despite a pharmacological arsenal targeting cerebral receptors and specific events in seizure initiation and development, about 30–40% patients are still refractory to available medications. Thus, the KD has been re-introduced in recent years as an alternative therapy, averring to be efficacious against some instances of resistant or intractable epilepsy. Despite a long historical background and enlarged clinical use, identification of the underlying anticonvulsant mechanisms associated with this nonpharmacological approach is still in stagnation. The present review is an attempt to encourage current research orientation through well-based and directed proposals for putative emerging candidates mediating KD anticonvulsant mechanisms. The reader is provided with a special emphasis on ATP-sensitive and recently cloned two-pore (or tandem) domain potassium channels, as well as several emerging conceptual views and advances such as nuclear receptors, uncoupling proteins and gap junctions that the authors speculate may contribute to understanding the basic mechanisms linked to the KD.

Section snippets

Synopsis

References exist that date back to Biblical times and during the Middle Ages for the use of starvation (the so-called “water diet”) to control seizures and epilepsy. These efforts have been mimicked by a more well-known intervention called the ketogenic diet (KD). This treatment was formally introduced at the beginning of the last century. Implementation of the diet places the body in a state of ketogenesis, a common feature shared in the historical fasting treatments. Relative to any

Historical background: ketosis and epilepsy

As previously mentioned, fasting treatments for epilepsy are assumed to date back to Biblical times and have been described in the literature of the Middle Ages (Lennox and Lennox, 1960, Swink et al., 1997, and references therein). The medical utility of such high-fat diets referred to as ketogenic diets (KD) was again emphasized in the 1920s for the successful treatment of epilepsy (Geyelin, 1921, Wilder, 1921, Peterman, 1925, Helmholz, 1927, Helmholz and Keith, 1930, Wilkins, 1937). In the

The KD induces general metabolic and cellular changes

The KD actually combines low carbohydrate and low protein intake along with a high-fat diet supply. These changes in nutrient subclass inputs not only induces ketosis, mild acidosis and dehydration, but affects the body's general metabolic fluxes and regulatory/hormonal pathways as well as many biological aspects of cell function. Table 1 offers a non-exhaustive overview of key determinants in cell regulation and signaling upon introduction of low carbohydrate and high-fat dietary intake. These

K_ATP-channels are hetero-octameric complexes comprising a tetrameric pore-forming subunit and a tetrameric regulatory subunit

K_ATP-channels are hetero-octameric complexes consisting of a single pore-forming tetrameric subunit formed by Kir6.x (Kir6.1 or Kir6.2) monomers (Kir stands for member of the inward rectifier K⁺ channel family) and a regulatory tetrameric subunit comprising SUR monomers (SUR stands for sulfonylureas receptor which belong to members of the ATP-binding cassette, ABC, protein super-family) (Fig. 1) (for reviews, see Huopio et al., 2002, Mikhailov et al., 2002, Seino and Miki, 2003). Two isoforms,

K_2P-channels are a non-exclusive KD target alternative to K_ATP-channels

As developed by the group of Heurteaux and Lazdunski, ischemic and convulsive preconditioning exhibit both early and delayed neuroprotection in a given time window, depending on species (Blondeau et al., 2000, Blondeau et al., 2002). Involvement of several key events such as induction of a HSP70 and depression of pro-apoptotic factors (cell death commitment markers) such as Bax have been well documented (Blondeau et al., 2000, Blondeau et al., 2002). Interestingly, perhaps the most important

Nuclear receptors

As mentioned above and emphasized by Table 1, the KD modulates the activity of several transcriptional factors/nuclear receptors. Briefly, the resulting impact on cell function is large, and involves much up- and down-regulation of enzymes. For instance, PPAR activation has antioxidant and anti-inflammatory properties via down-regulation of NF-κB signalling. The neuroprotective potential of the latter antioxidant result has to be, however, challenged by the involvement of NF-κB in

Perspective for future study

An appreciable portion of energy taken up by a human organism (about a quarter of glucose present in a mixed diet) is consumed by brain. Most of this energy is actually devoted to maintain the various ion gradients in excitable and non-excitable nervous cells. It is clear in these conditions that substantial changes in energy supply and disposition modulate cellular pump functioning, and consequently cell excitability. In this respect, it is not surprising that several pathologies affecting

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K2P channels (two-pore domain potassium channels) are spontaneously active, leading to continuous efflux of potassium ions through the cell membrane, which is necessary for setting a hyperpolarized resting potential of the cell membrane (Hughes et al., 2017). It has been suggested that these channels are activated by KB and certain fatty acids (Vamecq et al., 2005). Activation of K2P channels may regulate neuron membrane excitability (Fig. 2) (Barzegar et al., 2019).
Many treatments have been proposed to control epileptic seizures, such as the ketogenic diet and caloric restriction. However, seizure control has not yet been improved completely in all patients. Probably, due to the lack of understanding regarding this neurological disorder pathogenesis or pathophysiology, including its molecular approach. Currently, there is not much information about the molecular processes and genes involved, and their relation to the possible beneficial effects of diet therapy on epilepsy. The ketogenic diet and caloric restriction are implicated in potential anti-seizure mechanisms related to the gut microbiome, metabolic pathways, hormones and neurotransmitters, mitochondria improvement, a role in inflammation, and oxidative stress, among others. In this review, we pretend to describe the molecular mechanism and the possible genes involved in the different ketogenic diet and caloric restriction mechanisms of action described to decrease neural excitability and, therefore, epileptic seizures, especially when conventional treatment is not enough to achieve control of epilepsy.
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In people with drug-resistant epilepsy (DRE), surgery, dietary modifications, and neurostimulations are other treatment options [3]. Dietary therapies such as ketogenic diet (KD) have been advocated for the treatment of epilepsy since time immemorial [4]. Based on the results of 11 randomized control trials, a Cochrane review concluded that KD is effective in epilepsy [5].
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Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. We have recently shown that a Drosophila model of human ME (ATP6¹) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. We have found that reduction of glycolysis does not confer seizure protection, but that dietary supplementation with ketone bodies or the anaplerotic lipid triheptanoin, which directly replenishes the citric acid cycle, can mimic the success of the ketogenic diet even in the presence of standard carbohydrate levels. We have also shown that the proper functioning of the citric acid cycle is crucial to the success of the KD in the context of ME. Furthermore, our data reveal that multiple seizure models, in addition to ATP6¹, are treatable with the ketogenic diet. Importantly, one of these mutants is TPI^sugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder with severe neurological consequences. Overall, these studies reveal widespread success of the KD in Drosophila, further cementing its status as an excellent model for studies of KD treatment and mechanism, and reveal key insights into the therapeutic potential of dietary therapy against neuronal hyperexcitability in epilepsy and metabolic disease.
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Antiepileptic popular ketogenic diet: emerging twists in an ancient story

Abstract

Section snippets

Synopsis

Historical background: ketosis and epilepsy

The KD induces general metabolic and cellular changes

KATP-channels are hetero-octameric complexes comprising a tetrameric pore-forming subunit and a tetrameric regulatory subunit

K2P-channels are a non-exclusive KD target alternative to KATP-channels

Nuclear receptors

Perspective for future study

Eur. J. Pharmacol.

J Biol Chem

Trends Neurosci.

J. Am. Diet. Assoc.

Neuroscience

Neuroscience

J. Biol. Chem.

J. Biol. Chem.

Neuron

Neuropharmacology

J. Biol. Chem.

Prog. Neurobiol.

Eur. J. Pharmacol.

Trends Neurosci.

Biochem. Pharmacol.

Neuron

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Endocrinol. Metab.

Cell Signal.

J. Biol. Chem.

FEBS Lett.

Neuron

Biochim. Biophys. Acta

Int. J. Biochem. Cell. Biol.

J. Biol. Chem.

Biochem. Pharmacol.

Biochimie

Neuropharmacology

Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion

Science

Diet-induced ketosis does not cause cerebral acidosis

Epilepsia

Role of PPARgamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells

Invest. Ophthalmol. Vis. Sci.

An animal model for the ketogenic diet

Epilepsia

PPARγ, the ultimate thrifty gene

Diabetologia

Palmitoyl carnitine: an endogenous promotor of calcium efflux from rat heart mitochondria

Biochem. Pharmacol.

PKA-mediated phosphorylation of the human KATP channel: separate roles of KIR 6.2 and SUR 1 subunit phosphorylation

EMBO J.

Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet

Epilepsia

Carnitine levels and the ketogenic diet

Epilepsia

Activation of the nuclear factor-kappaB is a key event in brain tolerance

J. Neurosci.

A ketogenic diet increases the resistance to pentylene-tetrazole-induced seizures in the rat

Epilepsia

Path analysis shows that increasing ketogenic ratio, but not beta-hydroxybutirate, elevates seizure threshold in the rat

Dev. Neurosci.

Higher ketogenic diet ratios confer protection from seizures without neurotoxicity

Epilepsy Res

Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR α,β and γ in the adult rat

Endocrinology

The mechanism of the ketogenic diet in epilepsy

Bull. Johns Hopkins Hosp.

Molecular diversity of K+ channels

Ann. N. Y. Acad. Sci.

The role of long-chain fatty acyl-CoA esters in β-cell signal transduction

J. Nutr.

Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetizes rabbit model

Pol. J. Pharmacol.

The effect of ketosis induced by medium-chain triglycerides on intracellular pH of mouse brain

Epilepsia

Peroxisome proliferator-activated receptor alpha activation a s a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment

J. Neurosci.

Starvation and seizures

K_ATP-channels are hetero-octameric complexes comprising a tetrameric pore-forming subunit and a tetrameric regulatory subunit

K_2P-channels are a non-exclusive KD target alternative to K_ATP-channels

Molecular diversity of K⁺ channels

Cardiomyocyte mitochondrial K_ATP channels participate in the antiarrhythmic and antiinfarct effects of K_ATP activators during ischemia and reperfusion in an intact anesthetizes rabbit model