Seizure 52 (2017) 15–19

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Seizure
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Review

The mechanisms mediating the antiepileptic effects of the ketogenic

diet, and potential opportunities for improvement with
metabolism-altering drugs
Neil A. Youngsona,b,* , Margaret J. Morrisa , J. William O. Ballardb
a
Department of Pharmacology, School of Medical Sciences, UNSW Sydney, NSW, 2052, Australia
b
School of Biotechnology and Biomolecular Sciences, UNSW Sydney, NSW, 2052, Australia

A R T I C L E I N F O A B S T R A C T

Article history:
Received 2 August 2017 The ketogenic diet (KD) is increasingly being used to treat patients with intractable epilepsy. Despite
Received in revised form 9 September 2017 decades of research, the reason for its success, when anticonvulsants have failed, is still not completely
Accepted 11 September 2017 understood. There are, however, many candidate mechanisms which can be grouped into those that alter
neuronal excitability at the synapse, and those that confer neuroprotection. The molecular underpinning
Keywords: of these mechanisms centres on the shift from glucose- to lipid-based energy generation that
Ketogenic diet accompanies a high fat/low carbohydrate diet. Here we describe how changes in the relative abundances
Ketogenesis of energy substrates (ketone bodies), intermediates of glycolysis and fat metabolism, and metabolic end
Liver energy metabolism
products (ATP, reactive oxygen species) underlie many of the antiepileptic effects of the KD. We propose
that the success of the KD for treating epilepsy lies in the large variety of antiepileptic mechanisms that it
confers. Different subsets of the mechanisms may be clinically relevant in different patients. We extend
this to suggest that the broad benefits of the KD could therefore be achieved by pharmacologically
promoting the production of ketone bodies in the liver as they represent a key mediator that is common
to all of the proposed mechanisms.
© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction
The use of the ketogenic diet (KD) as a therapy for epilepsy
developed from observations that fasting could reduce seizures, a
strategy that was in use as far back as ancient Greece [1]. Fasting
continued as a treatment up to the 1920s, but work around that
time also revealed that both starvation and high fat/low carbohy-
drate diets increase plasma levels of the ketone bodies acetoace-
tate and b-hydroxybutyrate [2]. It was also proposed that these
metabolic products may benefit children with neurological
disorders [3]. In 1928 a study by Barborka [4] confirmed the
effectiveness of the KD for treating epilepsy, as seizures in adults
receiving the diet were completely controlled or improved in 56
out of 100 patients. From then on the KD was a common epilepsy
treatment until it was gradually superseded by anticonvulsant
drugs, so that by the 1980s it was rarely used. However, there has
been a resurgence of interest and usage of the KD for epilepsy since
* Corresponding author at: School of Biotechnology and Biomolecular Sciences,
UNSW Sydney, NSW, 2052, Australia
E-mail address: n.youngson@unsw.edu.au (N.A. Youngson).
the turn of the century, particularly for the 30% of patients with
intractable epilepsy. New variants of the KD have been developed
with slightly increased carbohydrate or protein content and/or
medium chain triglycerides rather than the longer chain trigly-
cerides of the traditional KD. Nonetheless all the variants are
essentially high fat/low carbohydrate diets that induce the
production of ketone bodies (KBs) in the liver through fatty acid
catabolism. The KBs then enter the bloodstream and are taken up
by organs including the brain where they are further metabolised
in mitochondria to generate energy. Currently the KD is commonly
used in children who have not improved after trialling two to three
anti-epileptic drugs, although recent studies have confirmed its
effectiveness in adults [5,6]. Patients typically undergo a three
month trial to see if the KD is effective, and if so they can remain on
it for several years until they are seizure-free, significantly
improved or stop using it due to the difficulties in complying
with such a restrictive regime. As for a reason why a high fat diet is
beneficial for a neuronal disorder, one possible explanation is that
KBs are a major fuel source for brain development in utero and in
infancy [1,7]. Perhaps the similarities between development and
repair mean that the reinstatement of KB-based brain metabolism

http://dx.doi.org/10.1016/j.seizure.2017.09.005
1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
16 N.A. Youngson et al. / Seizure 52 (2017) 15–19
creates an environment in which brain cells can repair the
structural damage associated with epileptogenesis.
Despite the success of the KD in reducing seizures, and also the
considerable amount of research into the cellular and molecular
changes that the diet induces, no single mechanism has been
identified that explains its efficacy. The question, “How does the
ketogenic diet reduce seizures” is an unusually challenging one.
Finding the answer is complicated by both the extreme variability
of the causes of epilepsy as well as the extensive changes in
physiology induced by the diet. The shift in energy generation from
carbohydrate sources to lipid essentially rewires many fundamen-
tal biological systems, and as with all therapies that alter
metabolism, both the molecular end products and intermediates
in a pathway can be potentially therapeutic. Furthermore, research
that goes deeper into the molecular changes induced by the KD,
rather than supporting or refuting existing hypotheses, often ends
up providing yet more potentially seizure-reducing mechanisms
[1,8]. Finally, translation of discoveries in animal models into
clinical studies is complicated by the huge inter-individual
variability in the underlying causes of epilepsy. This means that
rejection of a proposed mechanism would require its examination
in multiple groups that represent the various forms of epilepsy
(potentially at multiple ages, and/or severities), which is beyond
the scope of most research projects.
However, despite these challenges, several KD-induced changes
have been identified that are beneficial to neuronal structure and/
or function. They can be broadly grouped into changes that alter
neurotransmission at synapses, and those that improve neuronal
structure and homeostasis, though there are many overlapping
molecules and processes. Recent reviews have described these in
more detail [1,8,9].
2. The ketogenic diet changes energy metabolism in the liver
and the brain
In a carbohydrate rich diet, glucose is the preferred substrate for
energy production in the brain. Glucose is initially catabolised in
the cytoplasm of a neuron or glial cell through the process of
glycolysis which produces ATP and NADH. The latter can be used in
the mitochondrial electron transport chain (ETC) to create the
proton gradient across the inner mitochondrial membrane which
is used in oxidative phosphorylation to produce more ATP. The end
product of glycolysis is pyruvate which enters the mitochondria
and is converted to acetyl-CoA. This central molecule of energy
metabolism can then combine with oxaloacetate to enter the
tricarboxylic acid (TCA) cycle and produce more NADH that can be
used in the ETC.
All of the variants of the KD instigate shifts in body-wide
energy metabolism away from glucose-based and towards fat-
based energy generation. The ingested fatty acids are metabolised
in liver mitochondria into KBs which are then released into the
blood stream and are taken up by multiple organs including the
brain. In the mitochondria of neurons and glial cells KBs are
catabolised to acetyl-CoA, which can then enter the TCA cycle for
energy generation (producing NADH and ultimately ATP), or it can
be used in lipogenesis to produce fatty acids. A consequence of
the increased dependence on mitochondria for energy generation
with the KD is that the numbers of that organelle increase in
neurons and glia. This is one proposed contributor to the
observation that ketones and the KD lead to high levels of ATP
production [10,11].
With the KD the reduction in the use of glucose as an energy
source is compounded as not only is there simply less dietary
carbohydrate, but glycolysis is additionally inhibited by shifts in
the mitochondrial ratios of acetyl-CoA/CoA and NADH/NAD+
[12,13].
The antiepileptic effects of the KD are thought to be due to
changes in the levels of the molecules or enzymes involved in
energy metabolism. It should be noted that it isn’t just the end-
products glucose- versus fat-based energy metabolism that are
candidates for antiepileptic effects, as proposed mechanisms also
involve the KBs themselves, and the intermediates of their
catabolism. The links between several of these molecules and
neuronal excitability and/or neuroprotection form the basis of our
understanding of the antiepileptic mechanism of the KD and are
described in the next section (Fig. 1).
3. Summary of mechanisms that may explain the anti-seizure
effects of the ketogenic diet
The cellular state associated with seizures is increased neuronal
excitability which involves an increase in action potentials which
are in turn induced by depolarization of the cell membrane at a
synapse. The polarity at a synapse is regulated by inhibitory and
excitatory neurotransmitters which control ion pumps and
channels that facilitate the influx and efflux of ions such as Na2
+
, K+, Cl and Ca2+. Accordingly potential anti-seizure mechanisms
of the KD are linked to changes in the amounts of neuro-
transmitters as well changes that influence neural membrane
polarity. The major excitatory neurotransmitter glutamate can be
synthesised from the TCA cycle intermediate a-ketoglutarate.
Glutamate can then either be converted to the major inhibitory
neurotransmitter GABA, or be transaminated to aspartate in a
reaction that requires another TCA cycle compound, oxaloacetate.
As oxaloacetate is required for energy generation, there is a relative
increase in the amount of glutamate that is converted to GABA [14].
Some human and rat studies support this anti-seizure mechanism
by showing that a KD leads to increased GABA and reduced
glutamate in the brain [15,16]. Another potential player is the
inhibitory neurotransmitter neuropeptide Y (NPY) which would be
increased by ketogenesis or starvation [17], and is known to be
antiepileptic [18].
The increase in ATP generation by the KD provides fertile
ground for theories to explain the anti-seizure effects as a
multitude of cellular processes require ATP. The ATP requirement
of several types of ion channels and transporters is a leading
candidate. Perhaps the best example of the influence of ATP as an
anti-seizure mechanism is the export of ATP from neurons which is
then converted to adenosine in the synapse which activates
adenosine A1 receptors (A1R) leading to activation of potassium
channels thereby leading to hyperpolarization of the cell
membrane and a reduction in excitability (Fig. 1) [19].
ATP and energy metabolism are intimately connected to
another process through which the KD is antiepileptic neuro-
protection. Neuroprotective mechanisms are proposed to both
increase the seizure threshold and to reduce the damage to the
brain that is generated by seizures. As mentioned above the KD is
known to increase the number of mitochondria in brain cells
[20,21]. This is expected to be due to the requirement for
mitochondria for energy generation from fats as well as the
reduction in glycolysis (which doesn’t require mitochondria). At
the onset of the KD the existing mitochondria will experience a
high workload which reduces the efficiency of ATP production
leading to the production of reactive oxygen species (ROS).
Increased ROS levels in seizures are actually a contributor to the
cell damage and death, so the KD-induced increase contradicts the
observed benefits of the KD. However this state of increased
oxidative stress is temporary as the increased ROS induces
mitochondrial biogenesis to deal with the increased workload,
and also induces anti-ROS mechanisms such as glutathione. The
end result is neurons and glia that have an improved cellular
infrastructure for energy generation and reducing oxidative stress
 N.A. Youngson et al. / Seizure 52 (2017) 15–19 17

Fig. 1. Multiple proposed anti-epileptogenic effects of the ketogenic diet involve the metabolism of ketone bodies in the mitochondria. A. products of mitochondrial
metabolism of ketone bodies in neurons (or in astrocytes with subsequent transfer of the products to neurons) that are proposed to confer anti-epileptic effects. B. The effects
of certain products from A on ion transfer at the synapse. A1R, adenosine A1 receptor; ACA, acetoacetate; b-HB, beta hydroxybutyrate; PUFA, polyunsaturated fatty acid; ROS,
reactive oxygen species.

[20]. The former change increases the ‘energy reserve’ of neurons,
improving neuronal homeostasis before seizures and also reduces
the impacts of the high energy drain during seizures. The latter is
proposed to improve the resilience of brain cells to the damagingly
high levels of ROS that are generated in a seizure [22].
Increases in the biosynthesis of certain fat species in patients on
the KD provide other neuroprotective mechanisms. Hypomyeli-
nation is a feature of some epilepsies. The KD increases brain levels
of acetyl-CoA (from KBs) and aspartate (from TCA-cycle inter-
mediates) which both contribute to the synthesis of myelin [8].
Another product of fat metabolism with multiple anti-seizure
effects is poly-unsaturated fatty acids (PUFAs). These fat species
are increased in the brain of patients on the KD and they are
thought to protect neurons through simulating mitochondrial
uncoupling proteins which reduce ROS production, and PUFAs can
also directly modulate different types of ion pumps and channels
thereby reducing neuronal hyperexcitability [23].
There is evidence that the decrease in glycolysis in patients on
the KD contributes to the improved seizure control and reduced
epileptogenesis. Indeed, there is a rapid resumption of seizures
when patients on a KD ingest carbohydrates or glucose [24]. In
animal models treatment with inhibitors of glycolysis can have
rapid anticonvulsant effects [25,26]. The effects may be linked to
reductions in lactate (which is produced by glycolysis) which can
alter neuronal membrane polarity through ATP-dependent potas-
sium channels [27,28].
Research has also been undertaken to determine whether
ketone bodies themselves have direct antiepileptic actions in the
brain. b-hydroxybutyrate can slow spontaneous neuronal firing by
opening ATP-dependent potassium channels [29]. Furthermore,

Table 1
Potential drugs to promote ketogenesis in liver.

Effect on liver metabolism Candidate drugs (those with evidence of having antiepileptic properties in bold) Reference
Activate hepatic b-oxidation Sirtuin activators e.g. Resveratrol, NMN Milne et al. [36]
PARP inhibitors Uddin et al. [37]
Thiazolidinediones Gariani et al. [38]
PPARa activators (synthetic ligands) Grabacka et al. [41]
Inhibit hepatic lipogenesis Acetyl-CoA Carboxylase inhibitors Corbett et al. [39]
Griffith et al. [47]
Inhibit hepatic glycolysis (Randle cycle manipulation) Lactate dehydrogenase inhibitor stiripentol Sada et al. [28]
Glucagon McGarry et al. [48]
Glycolysis inhibitors developed for cancer Pelicano et al. [40]
PPARa activators(synthetic ligands) Grabacka et al. [41]
Inhibit mitochondrial pyruvate carrier (MPC) Thiazolidinediones e.g. Rosiglitazone and Pioglitazone Simeone et al. [43]
UK5099 Mishra et al. [44]
Vacanti et al. [49]
Hildyard et al. [50]
Inhibit liver mitochondrial complex I to favour fat metabolism Metformin Yang et al. [46]
18 N.A. Youngson et al. / Seizure 52 (2017) 15–19
recent evidence has identified that KBs also function as extracel-
lular signalling ligands [30], that can activate stress-response and
anti-inflammatory pathways [31]. Within the cell, KBs and
intermediates of their catabolism can also have strong effects on
the epigenetic state of genes which facilitates the changes in
cellular metabolism and resistance to ROS [32,33].
4. Future possibilities for the diet – pharmacological
enhancement
As mentioned in the introduction there are difficulties in
compliance with the KD. This is due to the restrictive and less
palatable nature of the diet and side-effects such as gastrointesti-
nal problems. Consequently, one of the aims of research into anti-
seizure mechanisms of KD has been to identify if it is possible to
achieve the same benefits with a drug or supplement. These efforts
have included drugs that increase levels of GABA, PUFAs and
antioxidants [34] or reducing glycolysis in the brain [28]. However,
none have yet demonstrated such consistent antiepileptic effects
as the KD. The challenge of replicating the benefits of the KD with a
drug may be linked to the difficulty of identifying one main
mechanism that underpins its effectiveness. Perhaps a clue to this
puzzle lies in the fact that KD has been shown to improve seizures
in patients with a variety of forms of epilepsy. It is possible that
there is a different subset of the seizure-reducing mechanisms that
are beneficial in each patient. Therefore one solution to the
challenge of developing a drug that mimics the KD may be, instead
of pharmacologically manipulating the terminal processes (e.g.
neurotransmitter actions), and thereby limiting the treatment to
altering a subset of the anti-seizure mechanisms, why not focus on
manipulating the upstream steps of the KD which are common to
all of the mechanisms? This strategy would theoretically maintain
the multi-mechanism aspect of the KD which may allow for the
utility of the drug across a broad range of epilepsies. Therefore
drugs that promote ketogenesis in the liver may be candidates for
future research (Table 1/Fig. 2).
The liver is an extremely important metabolic organ. Depend-
ing on the hormonal signals it receives and its existing energy
stores (glycogen or lipids) it will switch between multiple
processes of energy storage (gluconeogenesis, glycogenesis,
lipogenesis) and mobilisation of energy supplies for itself and
the rest of the body (glycolysis, glycogenolysis, b-oxidation,
ketogenesis). Ketogenesis is primarily a response to starvation
when carbohydrate stores are depleted and the lipid stores in the
liver or adipose tissue are mobilised, converted to KBs in the liver
and released into the blood [35]. The signalling- and gene-
Fig. 2. Promotion of liver ketogenesis as a pharmacological replacement for the
ketogenic diet. ACA, acetoacetate; b-HB, beta hydroxybutyrate.
regulatory pathways that activate energy storage often also repress
those of energy release, and vice versa [12]. Therefore pharmaco-
logical strategies that either inhibit energy storage, or promote
energy release (often by mimicking starvation signals) in the liver
will promote ketogenesis.
Table 1 contains several drugs that in theory could promote
liver ketogenesis. Due to the multifunctional activities of metabo-
lism regulatory signals there is some overlap between the
mechanisms, but they can be separated into four main groups.
Ketogenesis could be enhanced by increasing the total acetyl-CoA
through activating b-oxidation [36–38,41]. Similarly, the propor-
tion of acetyl-CoA that is available for ketogenesis can be increased
by repression of other processes that utilise it (e.g. lipogenesis)
[39,47]. Several of the drugs in these groups have been developed
for tackling obesity and type 2 diabetes as they can increase the
oxidation of fat stores in the liver and other organs [36–38] and/or
prevent lipid storage [39]. The third group either inhibits glycolysis
[28,40,41,50] or the transfer of the end product of glycolysis
(pyruvate) into the mitochondria (MPC1 inhibition) [43,44,49,50].
Inhibition of glycolysis pushes the hepatocyte away from glucose-
and towards fat-metabolism in a reciprocal process called the
Randle cycle [12]. Several candidate drugs in this category for
increasing ketogenesis have been developed as cancer therapies as
tumour cells often favour glycolysis for energy generation [40,41].
The fourth group involves liver-specific inhibition of mitochondrial
complex I (the main entry-point for electrons that are sourced from
glucose metabolism) which can push mitochondrial metabolism to
favour fat metabolism (which has a reduced requirement for
complex I) and thereby increase acetyl-CoA levels [42,46]. This
inhibition may need to be liver-specific as complex I inhibition or
dysfunction in the brain is associated with increased seizure risk.
Interestingly, many of the drugs in Table 1 have also been found to
have anticonvulsant properties [28,43–46].
In summary we propose that stimulation of ketogenesis in the
liver could be a useful alternative or adjunct to the KD in
management of epilepsy. Application of these drugs in combina-
tion with the KD, or a less restrictive KD (i.e. that allows increased
dietary carbohydrates) could improve the compliance to the diet,
or possibly be used to perpetuate ketogenesis at a clinically-
effective level after the patient ends the diet.
Conflicts of interest
None.
Funding sources
This research was funded by an Australian Research Council
(ARC) Project Grant to Prof. Ballard (DP160102575). Work in the
Morris lab is funded by the ARC and Australian National Health and
Medical Research Council (NHMRC).
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