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. Author manuscript; available in PMC: 2018 Apr 1.
Published in final edited form as: Curr Opin Neurol. 2017 Apr;30(2):187–192. doi: 10.1097/WCO.0000000000000432

New insights into the mechanisms of the ketogenic diet

Detlev Boison 1
PMCID: PMC5409832  NIHMSID: NIHMS856759  PMID: 28141738

Abstract

Purpose of review

High-fat, low-carbohydrate ketogenic diets (KDs) have been used for almost a century for the treatment of epilepsy. Used traditionally for the treatment of refractory pediatric epilepsies, in recent years the use of KDs has experienced a revival to include the treatment of adulthood epilepsies as well as conditions ranging from autism to chronic pain and cancer. Despite the ability of KD therapy to suppress seizures refractory to antiepileptic drugs and reports of lasting seizure freedom, the underlying mechanisms are poorly understood. This review explores new insights into mechanisms mobilized by KD therapies.

Recent findings

KDs act through a combination of mechanisms, which are linked to the effects of ketones and glucose restriction, and to interactions with receptors, channels, and metabolic enzymes. Decanoic acid, a component of medium chain triclycerides, contributes to seizure control through direct AMPA receptor inhibition, whereas drugs targeting lactate dehydrogenase reduce seizures through inhibition of a metabolic pathway. KD therapy also affects DNA methylation, a novel epigenetic mechanism of the diet.

Summary

KD therapy combines several beneficial mechanisms that provide broad benefits for the treatment of epilepsy with the potential to not only suppress seizures but also to modify the course of the epilepsy.

Keywords: metabolism, ketones, seizure suppression, epileptogenesis, epigenetics

Introduction

Since ancient times it was known that sustained fasting or a ‘water diet’ can be used to control seizures in epilepsy. In the 1920s it was found that a diet composed mostly of fats, i.e. a high-fat low-carbohydrate ‘ketogenic diet’, could replicate the effects of fasting, and those beneficial effects were ascribed to the production of ketones, such as β-hydroxybutyrate (BHB), acetoacetate, and acetone in the liver [1]. Despite early successes of KD therapies, the advent of antiepileptic drugs (AEDs) in the 1940s pushed KD therapy to the sidelines. However, the clinical use of KD therapies received increased attention in the 1990s, and KD therapy is now an established therapy for difficult-to-treat epilepsies in addition to a wider use in a variety of neurological disorders [2]. Seizure freedom during KD treatment is a clinical reality with one study reporting a 24% rate of seizure freedom, however there is still a risk of breakthrough seizures [3]. Core mechanisms of the diet have been covered in excellent recent reviews [4–6]. This review focuses on new mechanistic findings, which support the concept that the broad success of KD therapy is based on a combination of multiple beneficial mechanisms. The purpose of this review is not to provide a comprehensive overview of all potential mechanisms, but to guide the reader to areas of current research interest.

Clinical associations

Clinical studies can be used to associate metabolites or neurotransmitters/modulators mobilized by KD therapy with treatment success and to identify predictors for successful therapeutic outcomes. For example, it is well known that high blood BHB levels correlate with positive treatment outcome. Similarly, an increase in cholecystokinin-8, a peptide with antiepileptic properties, and a decrease in leptin associated with seizure suppression in patients with refractory epilepsy [7]. On the amino acid level it was found that changes in cerebrospinal fluid (CSF) lysine and arginine associated with >50% seizure reduction in a study involving 60 children [8]. On the genomic level single nucleotide polymorphisms (SNPs) can be used to associate gene variants with treatment success. However, variants in KCNJ11 and Bcl-2-associated death promoter (BAD), two key metabolic regulators, were recently shown to not predict response to KD therapy [9].

Ketosis and ketone bodies

Ketone bodies, such as BHB, and their derivatives have received most attention as mediators of the anti-seizure, neuroprotective, and anti-inflammatory effects of KD therapy [1,10,11]. In neurons BHB can compete with glucose for energy generation by inhibiting glycolytic flux upstream of pyruvate kinase [12•]. KDs can thereby shunt ketones into oxidative metabolism in the brain, which also enhances the capacity to produce amino acids such as GABA [13]. BHB levels in plasma are generally taken as indicator for ketosis but interactions with conventional antiepileptic drugs may exist [14]. Traditionally, BHB has been considered as the main effector of the therapeutic benefits of KD therapy. BHB in turn appears to have pleiotropic effects. In one mechanistic study BHB was shown to support synaptic vesicle recycling with a net effect of endocytosis exceeding exocytosis, a mechanism with possible anticonvulsant outcome [15]. BHB can also have direct effects by acting as endogenous ligand of the hydroxyl-carboxylic acid receptor 2 (HCA2) [11]. Activation of HCA2 on a subset of macrophages induces a neuroprotective phenotype depending on prostaglandin D2 production, whereas the genetic ablation of HCA2 abolished BHB-induced neuroprotection in a murine stroke model [11]. One therapeutic goal is to replace the KD, and its strict requirements for adherence, with dietary supplements that can produce sustained ketosis. Ketone esters, such as R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) are currently considered as a substitute to KD therapy in efforts to develop a ‘ketogenic diet in a pill’. In support of therapeutic efficacy BD-AcAc2 was shown to increase the thresholds for pentylenetetrazole induced seizures in the rat [16] and to ameliorate seizures in a mouse model of Angelman syndrome [17].

Medium-chain fatty acids

The medium chain triglyceride (MCT) KD is commonly used for the treatment of refractory childhood epilepsy. Importantly, one on one comparisons of a variety of medium chain fatty acids with valproic acid (VPA), a conventional AED, showed enhanced anti-seizure efficacy of medium chain fatty acids with reduced toxicities compared to VPA in a panel of in vitro and in vivo assays [18]. Medium chain fatty acids, such as heptanoic acid, octanoic acid, or decanoic acid, exert pleiotropic anti-seizure effects and have therefore been considered as add-ons to KDs or to regular non-KDs. Heptanoic acid can supply the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish the cycle. It has been shown that heptanoic acid can lead to increased levels of glutamine in the brains of glucose transporter I deficient mice suggesting a role for glial metabolism of heptanoate [19]. A small scale open-label case series tested the effects of triheptanoin-supplemented diets in 14 patients with inborn glucose transporter type I deficiency. The authors of this study reported a modest improvement in ictal events, but the underlying mechanisms were not further evaluated [20]. Branched octanoic acid compounds have been generated that show promising antiseizure activity in in vitro and in vivo seizure models, without affecting histone deacetylase activity [21]. Chronic feeding of diet with 35% of the calories derived from tridecanoin but not from trioctanoin was anticonvulsant in two mouse models in the absence of increased plasma and brain BHB [22•]. Only tridecanoin but not trioctanoin improved mitochondrial metabolic functions and antioxidant capacity [22]. Specifically, decanoic acid but not octanoic acid improved mitochondrial biogenesis as well as mitochondrial numbers through a PPARγ-mediated mechanism in neuronal cell culture systems [23,24]; decanoic acid led to an increase in the transcription of genes related to fatty acid metabolism, while downregulating genes involved in glucose metabolism [23]. Using single-cell imaging in pluripotent stem cell-derived human astrocytes and neurons it was found that decanoic acid promoted astrocytic but not neuronal glycolysis and lactate formation, whereas octanoic acid did not affect glycolysis but increased astroglial ketogenesis [25]. The authors of this study concluded that medium chain fatty acids modulate astrocyte metabolism by providing lactate and ketones as fuel for neighboring neurons via the glial/neuronal shuttle system [25•]. Medium chain fatty acids were also shown to affect amino acid metabolism, with an increase of tryptophan in the brain associated with reduced hippocampal excitability [26]. Finally, a recent seminal study from Chang et al., identified an exciting novel mechanism, by which decanoic acid directly reduces neuronal excitability by inhibition of AMPA receptor activity; importantly, it was shown that decanoic acid, acts as a non-competetive AMPA receptor antagonist binding to a site that is distinct from the perampanel binding site of the receptor [27••]. These findings suggest the existence of a powerful anticonvulsant mechanism of medium chain triglyceride ketogenic diets, which is based on the direct inhibition of excitatory neurotransmission by decanoic acid.

Polyunsaturated fatty acids (PUFAs)

A classic KD consists mostly of long-chain saturated triglycerides; however, polyunsaturated fatty acids (PUFAs) may also decrease neuronal excitation and provide neuroprotection by inducing the opening of voltage-gated potassium channels through binding to a newly identified PUFA binding site in the open state of the channel [28]. However, a recent study suggests that a PUFA diet, or a KD supplemented with PUFA did not reduce spontaneous recurrent seizures (SRS) in a kainic acid (KA)-induced rat model of epileptogenesis compared to control diet or KD, respectively [29•].

PPARs and inflammatory pathways

Inflammatory pathways and oxidative stress play a major role in the pathophysiology of epilepsy. Of interest, KD therapy exerts a major inherent anti-inflammatory activity, which appears to be independent of PUFA’s [30•]. The metabolically regulated transcription factors of the family of peroxisome proliferator activated receptors (PPAR) are involved in mitochondrial biogenesis and the control of genes involved in anti-inflammatory and anti-oxidant pathways. PPARα is activated by X-box binding protein 1 (XBP1), which is activated by hepatic serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), which in turn functions as a nutrient sensor that regulates metabolic adaptation to fasting [31]. PPARγ is activated by fatty acids, such as decanoic acid, and might therefore mediate anti-inflammatory and anti-oxidant properties of the KD. A PPARγ antagonist abrogated KD-induced seizure protection in Kv1.1 knockout mice, a spontaneously epileptic mouse strain responsive to KD therapy [32], whereas an PPARγ agonist conferred seizure protection; in line with these findings KD therapy was ineffective in preventing seizures in PPARγ knockout mice [33•]. Since seizure suppression was associated with a PPARγ induced increase in PPARγ2 expression, the authors of this study concluded that PPARγ2 contributes to the anti-seizure effects of KD therapy.

KATP Channels

The ATP-sensitive potassium (KATP) channel is a sensor for the energy state of the cell and acts as a feedback system to restrict neuronal firing, when energy levels are low. KATP activity is determined by phosphoregulation of BAD, a protein with dual functions in apoptosis and glucose metabolism. Genetic manipulation of BAD designed to reduce glucose metabolism produced an increase in the activity of neuronal KATP channels and resistance to seizures in vivo [34]. In line with those findings, pharmacological inhibition or genetic manipulation of KATP function abrogated or attenuated ketone-induced neuroprotection and seizure resistance [34,35•]. In the substantia nigra KATP channels are activated under conditions that favor decreased mitochondrial respiration [36]. Together these findings suggest a tight mechanistic link between metabolism, BAD, KATP channel function and the control of neuronal excitation.

Neurotrophic factors

The neurotrophin brain derived neurotrophic factor (BDNF) is linked to both AMP kinase (AMPK) and mammalian target of rapamycin (mTOR signaling) and thought to be implicated in epileptogenesis. A KD, but not a high fat or a low fat diet, led to a circadian shift in the expression of brain and liver BDNF, suggesting that a KD might impact (i) circadian activities, and (ii) the expression of BDNF [37]. However, the significance of neurotrophic factors as possible mediators of KD therapy are not yet clear, because in healthy rats a KD reduced BDNF levels in striatum, but not hippocampus, whereas the astrocyte neurotrophic cytokine S100β was not affected in the brain [38].

Increased mitochondrial function and biogenesis

Mitochondrial function is crucial for brain function and several inborn metabolic disorders compromise mitochondrial function and trigger complex clinical phenotypes with seizures. KD therapy is known to improve mitochondrial function and is therefore considered for the treatment of metabolic seizure disorders. One of those conditions is brain aspartate-glutamate carrier (AGC1) deficiency, which affects a transporter that shuttles aspartate from mitochondria to the cytosol and indirectly promotes the transfer of nicotinamide adenine dinucleotide (NADH)-reducing equivalents into mitochondria, and which causes hypotonia, impaired psychomotor development, and seizures. A recent case report demonstrated that KD treatment was able to compensate for the metabolic defects with major improvement of clinical symptoms [39•]. Glucose and mitochondrial hypometabolism contributes to the pathology a Dravet Syndrome (DS), a catastrophic form of childhood epilepsy. A KD formulation rescued mitochondrial respiration and restored glucose metabolism in a zebrafish model of DS [40•]. The underlying molecular mechanism through which a KD in general, and ketone bodies in particular, improve mitochondrial function has been unraveled in a recent study that investigated the effects of ketone bodies on acutely isolated brain mitochondria from Kcna1 knockout mice [41••]. The authors of this study demonstrated that ketone bodies alone suppressed seizures in spontaneously epileptic Kcna1-null mice, restored impaired hippocampal long-term potentiation and learning in those mutants, and raised the threshold for calcium-induced mitochondrial permeability transition (mPT). Importantly, the targeted deletion of the cyclophilin D subunit of the mPT complex uncoupled the effects of ketone bodies on mPT, while mPT was directly related to the antiseizure effects of ketone bodies; therefore, the direct link between ketone bodies, mPT, and seizure control indicates a mechanistic explanation for the antiseizure effects of KD therapy [41].

Oxidative stress

Among a multitude of detrimental downstream pathways, oxidative stress leads to the formation of reactive lipid fragments that can further aggravate tissue damage. Isotope labelling experiments have shown that KD therapy induces cytochrome P450 4A-dependent ω- and ω-1-hydroxylation of reactive lipid species, a novel mechanism that might contribute to the anti-inflammatory properties of KD therapy [42].

Protein restriction

It needs to be kept in mind that a strict KD regimen not only restricts the supply of carbohydrates, but also of proteins. Protein restriction itself has been shown to enhance the production of the endocrine signal fibroblast growth factor 21 (FGF21) in the liver [43]. FGF21 in turn can increase glucose uptake by adipocytes and reduce blood glucose levels, an additional beneficial effect that might be attributable to low protein content in certain KDs.

Lactate dehydrogenase

The astrocyte to neuron lactate shuttle is a major component of a metabolic route that supplies the neuron with alternate sources of energy. Lactate dehydrogenase (LDH) is a metabolic enzyme mediating this lactate shuttle and needed to supply neurons with glucose-derived energy (via lactate). In a seminal landmark study Tsuyoshi Inoue’s group demonstrated that the inhibition of LDH hyperpolarizes neurons and suppresses seizures [44••]. Remarkably, this enzyme was also found to be a molecular target of stiripentol, a clinically-used antiepileptic drug for Dravet syndrome [44••]. These findings are remarkable and suggest that inhibition of this metabolic pathway can mimic the effects of KD therapy, and might lead to the development of a ‘KD in a pill’.

Disease modifying and epigenetic mechanisms

A series of recent data suggests that KD therapy exerts disease modifying effects in epilepsy and that epigenetic mechanisms might be involved. Strikingly, KD therapy was found to postpone disease progression, delay the onset of severe seizures and to increase the lifespan of Kcna1-null mice, a model of progressive epilepsy and sudden unexpected death in epilepsy (SUDEP) [45••]. A disease modifying epigenetic mechanism of KD therapy is supported by findings that a predominant increase of DNA methylation is associated with chronic epilepsy in the rat and that KD therapy attenuated seizure progression and ameliorated DNA methylation mediated changes in gene expression [46]. A subsequent study showed that a transient KD therapy restored normal adenosine levels and global DNA methylation levels in epileptic rats that were otherwise adenosine deficient and hypermethylated; importantly, transient KD therapy reduced seizure activity long-term, even after diet reversal to control diet [47••]. Because KD therapy increases adenosine [47,48] and because adenosine blocks DNA methylation [49] it is likely that the KD exerts its disease modifying effects through an adenosine-dependent epigenetic mechanism.

Gut microbiome

The gut microbiome is increasingly recognized to play a major role for brain health. A recent study found that KD feeding in the BTBR mouse model of autism resulted in anti-microbial effects and a compositional remodeling of the gut microbiome [50••]. Although the underlying mechanisms remain enigmatic, this is a significant finding suggesting a much broader systemic effect of KD therapy.

Conclusion

The ketogenic diet combines several mechanisms that together reduce neuronal excitability. The identification of specific mechanisms may lead to the development of treatments in which a strict ketogenic diet might be replaced by dietary supplements. The identification of disease-modifying properties of KD therapy may offer hope for long-lasting therapeutic outcomes even after discontinuation of the diet.

Key points.

  • The antiepileptic effects of ketogenic diet therapy are based on a combination of multiple beneficial mechanisms.

  • Certain lipids, such as medium chain fatty acids, have their own independent anticonvulsant effects that may boost the efficacy of KD therapy, or that may lead to replacement therapies.

  • Decanoic acid controls seizures through direct AMPA receptor inhibition.

  • Drugs targeting lactate dehydrogenase reduce seizures through inhibition of a metabolic pathway.

  • KD therapy exerts disease modifying, antiepileptogenic effects that are based on an epigenetic mechanism.

Acknowledgments

financial support

The author would like to thank the Good Samaritan Hospital Foundations for generous support. This work has been funded through grants from the NIH (R01 NS084920, R01 NS065957, and R21 NS088024).

Footnotes

Conflicts of interest

The author has no conflicts of interest.

Funding disclosure: The author received funding through the National Institutes of Health (NIH) grants R01 NS084920, R01 NS065957, and R21 NS088024.

References

  • 1.Freeman JM, Kossoff EH. Ketosis and the ketogenic diet, 2010: advances in treating epilepsy and other disorders. Adv Pediatr. 2010;57:315–329. doi: 10.1016/j.yapd.2010.08.003. [DOI] [PubMed] [Google Scholar]
  • 2.Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol. 2012;3:59. doi: 10.3389/fphar.2012.00059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Taub KS, Kessler SK, Bergqvist AG. Risk of seizure recurrence after achieving initial seizure freedom on the ketogenic diet. Epilepsia. 2014;55:579–583. doi: 10.1111/epi.12583. [DOI] [PubMed] [Google Scholar]
  • 4.Rho JM. How does the ketogenic diet induce anti-seizure effects? Neurosci Lett. 2015 doi: 10.1016/j.neulet.2015.07.034. [DOI] [PubMed] [Google Scholar]
  • 5.Masino SA, Rho JM. Mechanisms of Ketogenic Diet Action. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s Basic Mechanisms of the Epilepsies. 4. 2012. [PubMed] [Google Scholar]
  • 6.Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 2013;36:32–40. doi: 10.1016/j.tins.2012.11.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Lambrechts DA, Brandt-Wouters E, Verschuure P, Vles HS, Majoie MJ. A prospective study on changes in blood levels of cholecystokinin-8 and leptin in patients with refractory epilepsy treated with the ketogenic diet. Epilepsy Res. 2016;127:87–92. doi: 10.1016/j.eplepsyres.2016.08.014. [DOI] [PubMed] [Google Scholar]
  • 8.Sariego-Jamardo A, Garcia-Cazorla A, Artuch R, Castejon E, Garcia-Arenas D, Molero-Luis M, Ormazabal A, Sanmarti FX. Efficacy of the Ketogenic Diet for the Treatment of Refractory Childhood Epilepsy: Cerebrospinal Fluid Neurotransmitters and Amino Acid Levels. Pediatr Neurol. 2015;53:422–426. doi: 10.1016/j.pediatrneurol.2015.07.013. [DOI] [PubMed] [Google Scholar]
  • 9.Schoeler NE, Leu C, White J, Plagnol V, Ellard S, Matarin M, Yellen G, Thiele EA, Mackay M, McMahon JM, et al. Variants in KCNJ11 and BAD do not predict response to ketogenic dietary therapies for epilepsy. Epilepsy Res. 2015;118:22–28. doi: 10.1016/j.eplepsyres.2015.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D’Agostino D, Planavsky N, Lupfer C, Kanneganti TD, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–269. doi: 10.1038/nm.3804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Muller-Fielitz H, Pokorna B, Vollbrandt T, Stolting I, Nadrowitz R, et al. The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat Commun. 2014;5:3944. doi: 10.1038/ncomms4944. [DOI] [PubMed] [Google Scholar]
  • 12•.Valente-Silva P, Lemos C, Kofalvi A, Cunha RA, Jones JG. Ketone bodies effectively compete with glucose for neuronal acetyl-CoA generation in rat hippocampal slices. NMR Biomed. 2015;28:1111–1116. doi: 10.1002/nbm.3355. This throrough biochemical study demonstrates that beta-hydroxybutyrate inhibited glycolytic flux upstream of pyruvate kinase. [DOI] [PubMed] [Google Scholar]
  • 13.Zhang Y, Zhang S, Marin-Valencia I, Puchowicz MA. Decreased carbon shunting from glucose toward oxidative metabolism in diet-induced ketotic rat brain. J Neurochem. 2015;132:301–312. doi: 10.1111/jnc.12965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Spilioti M, Pavlou E, Gogou M, Katsanika I, Papadopoulou-Alataki E, Grafakou O, Gkampeta A, Dinopoulos A, Evangeliou A. Valproate effect on ketosis in children under ketogenic diet. Eur J Paediatr Neurol. 2016;20:555–559. doi: 10.1016/j.ejpn.2016.04.003. [DOI] [PubMed] [Google Scholar]
  • 15.Hrynevich SV, Waseem TV, Hebert A, Pellerin L, Fedorovich SV. beta-Hydroxybutyrate supports synaptic vesicle cycling but reduces endocytosis and exocytosis in rat brain synaptosomes. Neurochem Int. 2016;93:73–81. doi: 10.1016/j.neuint.2015.12.014. [DOI] [PubMed] [Google Scholar]
  • 16.Viggiano A, Pilla R, Arnold P, Monda M, D’Agostino D, Coppola G. Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure. Brain Res. 2015;1618:50–54. doi: 10.1016/j.brainres.2015.05.023. [DOI] [PubMed] [Google Scholar]
  • 17.Ciarlone SL, Grieco JC, D’Agostino DP, Weeber EJ. Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model. Neurobiol Dis. 2016;96:38–46. doi: 10.1016/j.nbd.2016.08.002. [DOI] [PubMed] [Google Scholar]
  • 18.Chang P, Terbach N, Plant N, Chen PE, Walker MC, Williams RS. Seizure control by ketogenic diet-associated medium chain fatty acids. Neuropharmacology. 2013;69:105–114. doi: 10.1016/j.neuropharm.2012.11.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Marin-Valencia I, Good LB, Ma Q, Malloy CR, Pascual JM. Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain. J Cereb Blood Flow Metab. 2013;33:175–182. doi: 10.1038/jcbfm.2012.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Pascual JM, Liu P, Mao D, Kelly DI, Hernandez A, Sheng M, Good LB, Ma Q, Marin-Valencia I, Zhang X, et al. Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement. JAMA Neurol. 2014;71:1255–1265. doi: 10.1001/jamaneurol.2014.1584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Chang P, Zuckermann AM, Williams S, Close AJ, Cano-Jaimez M, McEvoy JP, Spencer J, Walker MC, Williams RS. Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency. J Pharmacol Exp Ther. 2015;352:43–52. doi: 10.1124/jpet.114.218768. [DOI] [PubMed] [Google Scholar]
  • 22•.Tan KN, Carrasco-Pozo C, McDonald TS, Puchowicz M, Borges K. Tridecanoin is anticonvulsant, antioxidant, and improves mitochondrial function. J Cereb Blood Flow Metab. 2016 doi: 10.1177/0271678X16659498. in press. This study suggests that the addition of decanoic acid to a normal diet can exert ketogenic diet-like anticonvulsant effects. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Kanabus M, Fassone E, Hughes SD, Bilooei SF, Rutherford T, Donnell MO, Heales SJ, Rahman S. The pleiotropic effects of decanoic acid treatment on mitochondrial function in fibroblasts from patients with complex I deficient Leigh syndrome. J Inherit Metab Dis. 2016;39:415–426. doi: 10.1007/s10545-016-9930-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Hughes SD, Kanabus M, Anderson G, Hargreaves IP, Rutherford T, O’Donnell M, Cross JH, Rahman S, Eaton S, Heales SJ. The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells. J Neurochem. 2014;129:426–433. doi: 10.1111/jnc.12646. [DOI] [PubMed] [Google Scholar]
  • 25•.Thevenet J, De Marchi U, Domingo JS, Christinat N, Bultot L, Lefebvre G, Sakamoto K, Descombes P, Masoodi M, Wiederkehr A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. FASEB J. 2016;30:1913–1926. doi: 10.1096/fj.201500182. This is an important study showing that medium chain fatty acids affect astrocyte metabolism, thereby enabling astrocytes to provide adjacent neurons with fuel in the form of lactate and ketone bodies. [DOI] [PubMed] [Google Scholar]
  • 26.Maciejak P, Szyndler J, Turzynska D, Sobolewska A, Kolosowska K, Krzascik P, Plaznik A. Is the interaction between fatty acids and tryptophan responsible for the efficacy of a ketogenic diet in epilepsy? The new hypothesis of action. Neuroscience. 2016;313:130–148. doi: 10.1016/j.neuroscience.2015.11.029. [DOI] [PubMed] [Google Scholar]
  • 27••.Chang P, Augustin K, Boddum K, Williams S, Sun M, Terschak JA, Hardege JD, Chen PE, Walker MC, Williams RS. Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain. 2016;139:431–443. doi: 10.1093/brain/awv325. This seminal study reports the discovery of a novel mechanism of action whereby decanoic acid suppresses neuronal hyperexcitability and seizures through direct activation of AMPA receptors. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Yazdi S, Stein M, Elinder F, Andersson M, Lindahl E. The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel. PLoS Comput Biol. 2016;12:e1004704. doi: 10.1371/journal.pcbi.1004704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29•.Dustin SM, Stafstrom CE. Ketogenic Diet, but Not Polyunsaturated Fatty Acid Diet, Reduces Spontaneous Seizures in Juvenile Rats with Kainic Acid-induced Epilepsy. J Epilepsy Res. 2016;6:1–7. doi: 10.14581/jer.16001. This study sheds a critical light on the efficacy of polyunsaturated fatty acids in seizure control. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30•.Dupuis N, Curatolo N, Benoist JF, Auvin S. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia. 2015;56:e95–98. doi: 10.1111/epi.13038. This study suggests that the anti-inflammatory properties of KD therapy are not based on an increase in anti-inflammatory polyunsaturated fatty acids. [DOI] [PubMed] [Google Scholar]
  • 31.Shao M, Shan B, Liu Y, Deng Y, Yan C, Wu Y, Mao T, Qiu Y, Zhou Y, Jiang S, et al. Hepatic IRE1alpha regulates fasting-induced metabolic adaptive programs through the XBP1s-PPARalpha axis signalling. Nat Commun. 2014;5:3528. doi: 10.1038/ncomms4528. [DOI] [PubMed] [Google Scholar]
  • 32.Simeone TA, Samson KK, Matthews SA, Simeone KA. In vivo ketogenic diet treatment attenuates pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices from epileptic Kv 1. 1alpha knockout mice. Epilepsia. 2014;55:e44–49. doi: 10.1111/epi.12603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33•.Simeone TA, Matthews SA, Samson KK, Simeone KA. Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy. Exp Neurol. 2016 doi: 10.1016/j.expneurol.2016.08.006. Epub ahead of print. This study describes an important anti-inflammatory mechanism of the ketogenic diet. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Gimenez-Cassina A, Martinez-Francois JR, Fisher JK, Szlyk B, Polak K, Wiwczar J, Tanner GR, Lutas A, Yellen G, Danial NN. BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron. 2012;74:719–730. doi: 10.1016/j.neuron.2012.03.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35•.Kim DY, Abdelwahab MG, Lee SH, O’Neill D, Thompson RJ, Duff HJ, Sullivan PG, Rho JM. Ketones prevent oxidative impairment of hippocampal synaptic integrity through KATP channels. PLoS One. 2015;10:e0119316. doi: 10.1371/journal.pone.0119316. This study shows that under conditions of oxidative injury, ketons induce synaptic protection through a mechanism that involves activation of KATP channels. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Lutas A, Birnbaumer L, Yellen G. Metabolism regulates the spontaneous firing of substantia nigra pars reticulata neurons via KATP and nonselective cation channels. J Neurosci. 2014;34:16336–16347. doi: 10.1523/JNEUROSCI.1357-14.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Genzer Y, Dadon M, Burg C, Chapnik N, Froy O. Effect of dietary fat and the circadian clock on the expression of brain-derived neurotrophic factor (BDNF) Mol Cell Endocrinol. 2016;430:49–55. doi: 10.1016/j.mce.2016.04.015. [DOI] [PubMed] [Google Scholar]
  • 38.Vizuete AF, de Souza DF, Guerra MC, Batassini C, Dutra MF, Bernardi C, Costa AP, Goncalves CA. Brain changes in BDNF and S100B induced by ketogenic diets in Wistar rats. Life Sci. 2013;92:923–928. doi: 10.1016/j.lfs.2013.03.004. [DOI] [PubMed] [Google Scholar]
  • 39•.Dahlin M, Martin DA, Hedlund Z, Jonsson M, von Dobeln U, Wedell A. The ketogenic diet compensates for AGC1 deficiency and improves myelination. Epilepsia. 2015;56:e176–181. doi: 10.1111/epi.13193. This is the first human case report in which a ketogenic diet improved a hypomyelination phenotype. [DOI] [PubMed] [Google Scholar]
  • 40•.Kumar MG, Rowley S, Fulton R, Dinday MT, Baraban SC, Patel M. Altered Glycolysis and Mitochondrial Respiration in a Zebrafish Model of Dravet Syndrome. eNeuro. 2016;3 doi: 10.1523/ENEURO.0008-16.2016. This study suggests that glucose and mitochondrial hypometabolism contribute to the pathophysiology of Dravet syndrome. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41••.Kim DY, Simeone KA, Simeone TA, Pandya JD, Wilke JC, Ahn Y, Geddes JW, Sullivan PG, Rho JM. Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann Neurol. 2015;78:77–87. doi: 10.1002/ana.24424. This landmark study provides the first direct mechnaistic link between mitochondrial permeability transition and seizure control as a potential mechanistic explanation for the anti-seizure effects of ketogenic diet therapy. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Jin Z, Berthiaume JM, Li Q, Henry F, Huang Z, Sadhukhan S, Gao P, Tochtrop GP, Puchowicz MA, Zhang GF. Catabolism of (2E)-4-hydroxy-2-nonenal via omega- and omega-1-oxidation stimulated by ketogenic diet. J Biol Chem. 2014;289:32327–32338. doi: 10.1074/jbc.M114.602458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, Munzberg H, Hutson SM, Gettys TW, Schwartz MW, et al. FGF21 is an endocrine signal of protein restriction. J Clin Invest. 2014;124:3913–3922. doi: 10.1172/JCI74915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44••.Sada N, Lee S, Katsu T, Otsuki T, Inoue T. Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science. 2015;347:1362–1367. doi: 10.1126/science.aaa1299. This seminal study identified lactate dehydrogenase inhibitors as effective new class of antiepileptic drugs, which are based on a ketogenic diet-like metabolic mechanism. [DOI] [PubMed] [Google Scholar]
  • 45••.Simeone KA, Matthews SA, Rho JM, Simeone TA. Ketogenic diet treatment increases longevity in Kcna1-null mice, a model of sudden unexpected death in epilepsy. Epilepsia. 2016;57:e178–182. doi: 10.1111/epi.13444. This seminal study supports a potent disease-modifying effect of ketogenic diet therapy. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Kobow K, Kaspi A, Harikrishnan KN, Kiese K, Ziemann M, Khurana I, Fritzsche I, Hauke J, Hahnen E, Coras R, et al. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol. 2013;126:741–756. doi: 10.1007/s00401-013-1168-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47••.Lusardi TA, Akula KK, Coffman SQ, Ruskin DN, Masino SA, Boison D. Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats. Neuropharmacology. 2015;99:500–509. doi: 10.1016/j.neuropharm.2015.08.007. This study reports lasting antiepileptogenic effects of transient ketogenic diet therapy that have been linked to adenosine augmentation and an epigenetic mechanism. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Masino SA, Li T, Theofilas P, Sandau US, Ruskin DN, Fredholm BB, Geiger JD, Aronica E, Boison D. A ketogenic diet suppresses seizures in mice through adenosine A1 receptors. J Clin Inv. 2011;121:2679–2683. doi: 10.1172/JCI57813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Williams-Karnesky RL, Sandau US, Lusardi TA, Lytle NK, Farrell JM, Pritchard EM, Kaplan DL, Boison D. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Inv. 2013;123:3552–3563. doi: 10.1172/JCI65636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50••.Newell C, Bomhof MR, Reimer RA, Hittel DS, Rho JM, Shearer J. Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder. Mol Autism. 2016;7:37. doi: 10.1186/s13229-016-0099-3. This is a landmark study showing for the first time that ketogenic diet therapy affects the microbiome of the gut. This finding has major implication for our understanding of pathogenic mechanisms and dietary therapies. [DOI] [PMC free article] [PubMed] [Google Scholar]

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