Neuroprotective and disease-modifying effects of the Ketogenic
diet
Maciej Gasiora, Michael A. Rogawskia, and Adam L. Hartmana,b
Epilepsy Research Section, National Institute of
Neurological Disorders and Stroke, National Institutes of Health, Bethesda
The John M. Freeman Pediatric Epilepsy Center, Johns Hopkins
Hospital, Baltimore, Maryland, USA
Abstract
The ketogenic diet has been in clinical use for over 80
years, primarily for the symptomatic treatment
of epilepsy. A recent clinical study has raised the
possibility that exposure to the ketogenic diet may
confer long-lasting therapeutic benefits for patients with
epilepsy. Moreover, there is evidence from
uncontrolled clinical trials and studies in animal models
that the ketogenic diet can provide
symptomatic and disease-modifying activity in a broad range
of neurodegenerative disorders
including Alzheimer’s disease and Parkinson’s disease, and
may also be protective in traumatic brain
injury and stroke. These observations are supported by
studies in animal models and isolated cells
that show that ketone bodies, especially β-hydroxybutyrate,
confer neuroprotection against diverse
types of cellular injury. This review summarizes the
experimental, epidemiological and clinical
evidence indicating that the ketogenic diet could have
beneficial effects in a broad range of brain
disorders characterized by the death of neurons. Although
the mechanisms are not yet well defined,
it is plausible that neuroprotection results from enhanced
neuronal energy reserves, which improve
the ability of neurons to resist metabolic challenges, and
possibly through other actions including
antioxidant and anti-inflammatory effects. As the underlying
mechanisms become better understood,
it will be possible to develop alternative strategies that
produce similar or even improved therapeutic
effects without the need for exposure to an unpalatable and
unhealthy, high-fat diet.
Keywords
Alzheimer’s disease; cellular energetics; epilepsy; ketone
bodies; ketogenic diet; mitochondria;
neuroprotection; Parkinson’s disease; stroke; traumatic
brain injury
Introduction
The ketogenic diet is a high-fat content diet in which
carbohydrates are nearly eliminated so
that the body has minimal dietary sources of glucose. Fatty
acids are thus an obligatory source
of cellular energy production by peripheral tissues and also
the brain. Consumption of the
ketogenic diet is characterized by elevated circulating
levels of the ketone bodies acetoacetate,
β-hydroxybutyrate and acetone, produced largely by the
liver. During high rates of fatty acid
oxidation, large amounts of acetyl-CoA are generated. These
exceed the capacity of the
tricarboxylic acid cycle and lead to the synthesis of the
three ketone bodies within liver
mitochondria. Plasma levels of ketone bodies rise, with
acetoacetate and β-hydroxybutyrate
increasing three-fold to four-fold from basal levels of 100
and 200 µmol/l, respectively (MusaVeloso
et al., 2002). In the absence of glucose, the preferred
source of energy (particularly of
Address correspondence to: Michael A. Rogawski, M.D., Ph.D.,
Department of Neurology, University of California, Davis, 4860 Y
Street, Suite 3700, Sacramento, California 95817, E-mail:
rogawski@ucdavis.edu.
NIH Public Access
Author Manuscript
Behav Pharmacol. Author manuscript; available in PMC 2008
May 5.
Published in final edited form as:
Behav Pharmacol. 2006 September ; 17(5-6): 431–439.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA
Author Manuscriptthe brain), the ketone bodies are used as fuel in extrahepatic
tissues. The ketone bodies are
oxidized, releasing acetyl-CoA, which enters the
tricarboxylic acid cycle.
The ketogenic diet is an established and effective
nonpharmacological treatment for epilepsy
(Vining et al., 1998; Stafstrom, 2004; Sinha and Kossoff,
2005). Although the diet is useful in
people of all ages, clinical experience suggests that it may
be more valuable in children, if only
because adults have greater difficulty adhering to it.
Importantly, the diet is often effective in
pharmacoresistant forms of common epilepsies as well as in
the difficult to treat catastrophic
epilepsy syndromes of infancy and early childhood such as
West Syndrome, Lennox–Gastaut
Syndrome, and Dravet Syndrome (Crumrine, 2002; Trevathan,
2002; Caraballo et al., 2005).
Recently, there has been interest in the potential of the
ketogenic diet in the treatment of
neurological disorders other than epilepsy, including
Alzheimer’s disease and Parkinson’s
disease. Studies in these neurodegenerative disorders have
led to the hypothesis that the
ketogenic diet may not only provide symptomatic benefit, but
could have beneficial diseasemodifying
activity applicable to a broad range of brain disorders
characterized by the death of
neurons. Here, we review evidence from clinical studies and
animal models that supports this
concept.
Ketogenic diet
The classic ketogenic diet is a high-fat diet developed in
the 1920s to mimic the biochemical
changes associated with periods of limited food availability
(Kossoff, 2004). The diet is
composed of 80–90% fat, with carbohydrate and protein
constituting the remainder of the
intake. The diet provides sufficient protein for growth, but
insufficient amounts of
carbohydrates for the body’s metabolic needs. Energy is
largely derived from the utilization
of body fat and by fat delivered in the diet. These fats are
converted to the ketone bodies β-
hydroxybutyrate, acetoacetate, and acetone, which represent
an alternative energy source to
glucose. In comparison with glucose, ketone bodies have a
higher inherent energy (Pan et
al., 2002; Cahill and Veech, 2003). In adults, glucose is
the preferred substrate for energy
production, particularly by the brain. Ketone bodies are,
however, a principal source of energy
during early postnatal development (Nehlig, 2004). In
addition, ketone bodies, especially
acetoacetate, are preferred substrates for the synthesis of
neural lipids. Ketone bodies readily
cross the blood–brain barrier either by simple diffusion
(acetone) or with the aid of
monocarboxylic transporters (β-hydroxybutyrate,
acetoacetate), whose expression is related
to the level of ketosis (Pan et al., 2002; Pierre and
Pellerin, 2005).
Today, several types of ketogenic diets are employed for
treatment purposes. The most
frequently used is the traditional ketogenic diet originally
developed by Wilder in 1921, which
is based on long-chain fatty acids (Wilder, 1921). In the
1950s, a medium-chain triglyceride
diet was introduced, which produces greater ketosis
(Huttenlocher et al., 1971). This
modification has not been widely accepted because it is
associated with bloating and abdominal
discomfort and is no more efficacious than the traditional
ketogenic diet. A third variation on
the diet, known as the Radcliffe Infirmary diet, represents
a combination of the traditional and
medium-chain triglyceride diets (Schwartz et al., 1989). Its
efficacy is also similar to the
traditional ketogenic diet.
Although the ketogenic diet was a popular treatment approach
for epilepsy in the 1920s and
1930s, its medical use waned after the introduction of
phenytoin in 1938. The recognition that
the diet may be an effective therapeutic approach in some
drug-resistant epilepsies, particularly
in children, has led to a resurgence of interest in the last
15 years. The popularization of various
low carbohydrate diets for weight loss, such as the Atkins
diet (Acheson, 2004), probably also
has increased interest in the dietary therapy of epilepsy.
In fact, a modified form of the Atkins
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the traditional ketogenic diet, may
be an effective epilepsy treatment approach (Kossoff et al.,
2006).
Clinical studies
Epilepsy
At present, strong evidence exists that the ketogenic diet
protects against seizures in children
with difficult-to-treat epilepsy (Freeman et al., 1998).
Recent reports have raised the possibility
that the diet may also improve the long-term outcome in such
children (Hemingway et al.,
2001; Marsh et al., 2006). In these studies, children with
intractable epilepsy who remained
on the ketogenic diet for more than 1 year and who
experienced a good response to the diet,
often had positive outcomes at long-term follow-up 3–6 years
after the initiation of diet. Fortynine
percent of the children in this cohort experienced a nearly
complete (≥ 90%) resolution
in seizures. Surprisingly, even those children who remained
on the diet for 6 months or less
(most of these children terminated the diet because of an
inadequate response) may have
obtained a long-term benefit from exposure to the diet.
Thirty-two percent of these children
had a ≥ 90% decrease in their seizures and 22% became
seizure free even without surgery. The
diet also allowed a decrease or discontinuation of
medications without a relapse in seizures.
Of course, in the absence of a control group, it is not
possible to be certain that the apparent
good response in these children is simply the natural
history of the epilepsy in the cohort
studied, although these children had, by definition,
intractable epilepsy before starting the diet.
In any case, the results raise the possibility that the
ketogenic diet, in addition to its ability to
protect against seizures, may have disease-modifying
activity leading to an improved longterm
outcome. It is noteworthy that none of the currently
marketed antiepileptic drugs has been
demonstrated clinically to possess such a disease-modifying
effect (Schachter, 2002; Benardo,
2003). Determining whether the ketogenic diet truly alters
long-term outcome will require
prospective controlled trials.
Alzheimer’s disease
Recent studies have raised the possibility that the
ketogenic diet could provide symptomatic
benefit and might even be disease modifying in Alzheimer’s
disease. Thus, Reger et al.
(2004) found that acute administration of medium-chain
triglycerides improves memory
performance in Alzheimer’s disease patients. Further, the
degree of memory improvement was
positively correlated with plasma levels of
β-hydroxybutyrate produced by oxidation of the
medium-chain triglycerides. If β-hydroxybutyrate is
responsible for the memory improvement,
then the ketogenic diet, which results in elevated
β-hydroxybutyrate levels, would also be
expected to improve memory function. When a patient is
treated for epilepsy with the ketogenic
diet, a high carbohydrate meal can rapidly reverse the
antiseizure effect of the diet
(Huttenlocher, 1976). It is therefore of interest that high
carbohydrate intake worsens cognitive
performance and behavior in patients with Alzheimer’s
disease (Henderson, 2004; Young et
al., 2005).
It is also possible that the ketogenic diet could ameliorate
Alzheimer’s disease by providing
greater amounts of essential fatty acids than normal or high
carbohydrate diets (Cunnane et
al., 2002; Henderson, 2004). This is because consumption of
foods or artificial supplements
rich in essential fatty acids may decrease the risk of
developing Alzheimer’s disease
(Ruitenberg et al., 2001; Barberger-Gateau et al., 2002;
Morris et al., 2003a, b).
Parkinson’s disease
One recently published clinical study tested the effects of
the ketogenic diet on symptoms of
Parkinson’s disease (VanItallie et al., 2005). In this
uncontrolled study, Parkinson’s disease
patients experienced a mean of 43% reduction in Unified
Parkinson’s Disease Rating Scale
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participating patients reported
moderate to very good improvement in symptoms. Further, as
in Alzheimer’s disease,
consumption of foods containing increased amounts of
essential fatty acids has been associated
with a lower risk of developing Parkinson’s disease (de Lau
et al., 2005).
Studies in animal models
Epilepsy
Anticonvulsant properties of the ketogenic diet have been
documented in acute seizure models
in rodents (Appleton and De Vivo, 1973; Huttenlocher, 1976;
Hori et al., 1997; Stafstrom,
1999; Likhodii et al., 2000; Thavendiranathan et al., 2000,
2003; Bough et al., 2002).
Moreover, there is accumulating evidence from studies in
models of chronic epilepsy that the
ketogenic diet has antiepileptogenic properties that extend
beyond its anticonvulsant efficacy.
Thus, in the rat kainic acid model of temporal lobe
epilepsy, the development of spontaneous
seizures was attenuated by the ketogenic diet and there was
a reduction in the severity of the
seizures that did occur (Muller-Schwarze et al., 1999;
Stafstrom et al., 1999; Su et al., 2000).
In addition, animals fed the diet have reduced hippocampal
excitability and decreased
supragranular mossy fiber sprouting in comparison with rats
fed a normal diet. Further evidence
supporting the antiepileptogenic activity of the ketogenic
diet is the demonstration that the
development of spontaneous seizures in inbred EL/Suz mice, a
genetic model of idiopathic
epilepsy, is retarded by the diet (Todorova et al., 2000).
In other studies, caloric restriction,
which often occurs with the ketogenic diet, has also been
demonstrated to have
antiepileptogenic effects in EL/Suz mice (Greene et al.,
2001; Mantis et al., 2004). (Although
the ketogenic diet is designed to provide calories adequate
for growth, patients and animals
may eat less because the diet may be unpalatable to some.
Thus, the ketogenic diet may be
accompanied by an unintentional caloric restriction.)
Alzheimer’s disease
Epidemiological studies have implicated diets rich in
saturated fat with the development of
Alzheimer’s disease (Kalmijn et al., 1997; Grant, 1999;
Morris et al., 2003a, b, 2004; but see
Engelhart et al., 2002). Moreover, in transgenic mouse
models, high-fat diets increase the
deposition of amyloid β (Aβ) peptides (Levin-Allerhand et
al., 2002; Shie et al., 2002; George
et al., 2004; Ho et al., 2004). These studies, however, did
not examine the effects of ketogenic
diets rich in fats, when the high lipid content is
administered along with severe carbohydrate
restriction. Indeed, in a recent series of experiments using
a transgenic mouse model of
Alzheimer’s disease, a ketogenic diet was found to improve
Alzheimer’s pathology. The mice
used in this study, which express a human amyloid precursor
protein gene containing the
London mutation (APP/V717I), exhibit significant levels of
soluble Aβ in the brain as early
as 3 months of age and show extensive plaque deposition by
12–14 months (Van der Auwera
et al., 2005). They also demonstrate early behavioral
deficits in an object recognition task.
Exposure to a ketogenic diet for 43 days resulted in a 25%
reduction in soluble Aβ(1–40) and
Aβ(1–42) in brain homogenates, but did not affect
performance on the object recognition task.
Caloric restriction has also been demonstrated to attenuate
β-amyloid depositions in mouse
models of Alzheimer disease (Patel et al., 2005; Wang et
al., 2005). How the ketogenic diet
and caloric restriction affect β-amyloid levels and whether
this effect could be disease
modifying in Alzheimer’s disease requires further study.
The ketogenic diet could have beneficial effects in
Alzheimer’s disease apart from effects on
β-amyloid disposition. For example, essential fatty acids in
the diet may have beneficial effects
on learning, as demonstrated with studies of spatial
recognition learning in rodent models of
Alzheimer’s disease (Hashimoto et al., 2002, 2005; Lim et
al., 2005). Alternatively, the diet
might protect against β-amyloid toxicity. Thus, direct application
of β-hydroxybutyrate in
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to protect hippocampal neurons
from toxicity induced by Aβ(1–42) (Kashiwaya et al., 2000).
Parkinson’s disease
The most widely used animal model of Parkinson’s disease is
based on the neurotoxin MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Exposure to
MPTP causes degeneration of
mesencephalic dopamine neurons, as in the human clinical
condition, and is associated with
parkinsonian clinical features. The ketogenic diet has not
yet been studied in the MPTP or other
animal models of Parkinson’s disease. As in epilepsy and
Alzheimer’s disease models,
however, caloric restriction has been found to have
beneficial effects in MPTP models of
Parkinson’s disease. This was first demonstrated in rats fed
on an alternate-day schedule so
that they consume 30–40% less calories than animals with
free access to food. The calorierestricted
animals were found to exhibit resistance to MPTP-induced
loss of dopamine neurons
and less severe motor deficits than animals on the normal
diet (Duan and Mattson, 1999). More
recently, it has been reported that adult male rhesus
monkeys maintained chronically on a
calorie-restricted diet are also resistant to MPTP
neurotoxicity (Maswood et al., 2004; Holmer
et al., 2005). These animals had less depletion of striatal
dopamine and dopamine metabolites
and substantially improved motor function than did animals
receiving a normal diet. In other
studies in mice, caloric restriction has been reported to
have beneficial effects even when begun
after exposure to MPTP (Holmer et al., 2005).
In addition to caloric restriction, several recent reports
have indicated that β-hydroxybutyrate
may be neuroprotective in the MPTP model. MPTP is converted
in vivo to 1-methyl-4-
phenylpyridinium (MPP +), which is believed to be the
principal neurotoxin through its action
on complex 1 of the mitochondrial respiratory chain. In
tissue culture, 4 mmol/l β-
hydroxybutyrate protected mesencephalic neurons from MPP +
toxicity (Kashiwaya et al.,
2000). Moreover, subcutaneous infusion by osmotic minipump
of β-hydroxybutyrate for 7
days in mice conferred partial protection against
MPTP-induced degeneration of dopamine
neurons and parkinsonian motor deficits (Tieu et al., 2003).
It was proposed that the protective
action is mediated by improved oxidative phosphorylation
leading to enhanced ATP
production. This concept was supported by experiments with
the mitochondrial toxin 3-
nitropropionic acid (3-NP). 3-NP inhibits oxidative
phosphorylation by blocking succinate
dehydrogenase, an enzyme of the tricarboxylic acid cycle
that transfers electrons to the electron
transport chain via its complex II function. The protective
effect of β-hydroxybutyrate on
MPTP-induced neurodegeneration in mice was eliminated by
3-NP. Moreover, in experiments
with purified mitochondria, β-hydroxybutyrate markedly
stimulated ATP production and this
stimulatory effect was eliminated by 3-NP. Thus, it seems
likely that β-hydroxybutyrate is
protective in the MPTP model of Parkinson’s disease by
virtue of its ability to improve
mitochondrial ATP production (Tieu et al., 2003). Whether
the ketogenic diet would also be
protective in Parkinson’s disease models as a result of
increased β-hydroxybutyrate production
remains to be determined. It is noteworthy that
β-hydroxybutyrate is not anticonvulsant and is
unlikely to directly account for the antiseizure activity of
the ketogenic diet (Rho et al.,
2002). Whether β-hydroxybutyrate contributes in some other
way to the beneficial activity of
the ketogenic diet in epilepsy therapy remains to be
studied.
Ischemia and traumatic brain injury
Much of the neurological dysfunction that occurs in stroke,
cerebral ischemia, and acute
traumatic brain injury is due to a secondary injury process
involving glutamate-mediated
excitotoxicity, intracellular calcium overload,
mitochondrial dysfunction, and the generation
of reactive oxygen species (ROS) (McIntosh et al., 1998).
Consequently, the underlying
pathophysiological mechanisms may have features in common
with those in classical
neurodegenerative disorders. Recently, Prins et al. (2005)
have reported that the ketogenic diet
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at 7 days after controlled cortical
injury in rats. The beneficial effects of the diet,
administered after the injury, only occurred at
some postnatal ages despite similar availability of ketone
bodies at all ages studied. This led
the authors to conclude that differences in the ability of
the brain to utilize ketones at different
developmental stages may influence the protection conferred
(Rafiki et al., 2003; Vannucci
and Simpson, 2003; Pierre and Pellerin, 2005). In a previous
study, a 48-h fast, which results
in similar short-term ketosis as that achieved by the
ketogenic diet, was found to protect rats
against neuronal loss in the striatum, neocortex, and
hippocampus produced by 30-min fourvessel
occlusion (Marie et al., 1990). There was also a reduction
in mortality and the incidence
of postischemic seizures in fasted animals. Thus, there is
evidence that the ketogenic diet has
neuroprotective activity in both traumatic and ischemic
brain injury. An additional study found
that rats receiving a ketogenic diet are also resistant to
cortical neuron loss occurring in the
setting of insulin-induced hypoglycemia (Yamada et al.,
2005).
Although the mechanism whereby the ketogenic diet confers
protection in these diverse injury
models is not well understood, β-hydroxybutyrate could play
a role. The ketone body would
presumably serve as an alternative energy source to mitigate
injury-induced ATP depletion. In
fact, exogenous administration of β-hydroxybutyrate can
reduce brain damage and improve
neuronal function in models of brain hypoxia, anoxia, and
ischemia (Cherian et al., 1994;
Dardzinski et al., 2000; Suzuki et al., 2001, 2002; Smith et
al., 2005). In addition, the other
ketone bodies, acetoacetate and acetone, which are
β-hydroxybutyrate metabolites and can also
serve as alternative energy sources, have similar
neuroprotective effects (Garcia and Massieu,
2001; Massieu et al., 2001, 2003; Noh et al., 2006).
Interestingly, in rats receiving a ketogenic
diet, neuronal uptake of β-hydroxybutyrate is increased
after cortical impact injury in
comparison with animals receiving a standard diet (Prins et
al., 2004). Thus, the ketogenic diet
may promote delivery of β-hydroxybutyrate to the brain.
Cellular mechanisms underlying the neuroprotective activity
of the ketogenic
diet
Effects on energy metabolism
As noted above, ketone bodies, including β-hydroxybutyrate,
that are produced during
consumption of the ketogenic diet may serve as an alternative
source of energy in states of
metabolic stress, thus contributing to the neuroprotective
activity of the diet. In fact, β-
hydroxybutyrate may provide a more efficient source of
energy for brain per unit oxygen than
glucose (Veech et al., 2001). Recently, using microarrays to
define patterns of gene expression,
Bough et al. (2006) made the remarkable discovery that the
ketogenic diet causes a coordinated
upregulation of hippocampal genes encoding energy metabolism
and mitochondrial enzymes.
Electron micrographs from the dentate/hilar region of the
hippocampus showed a 46% increase
in mitochondrial profiles in rats fed the ketogenic diet.
Thus, the ketogenic diet appears to
stimulate mitochondrial biogenesis. Moreover, there was a
greater phosphocreatine : creatine
ratio in the hippocampal tissue, indicating an increase in
cellular energy reserves, as expected
from the greater abundance of mitochondria. In sum, during
consumption of the ketogenic diet,
two factors may contribute to the ability of neurons to resist
metabolic stress: a larger
mitochondrial load and a more energy-efficient fuel. In
combination, these factors may account
for the enhanced ability of neurons to withstand metabolic
challenges of a degree that would
ordinarily exhaust the resilience of the neurons and result
in cellular demise.
Effects on glutamate-mediated toxicity
Interference with glutamate-mediated toxicity, a major
mechanism underlying neuronal injury,
is an alternative way in which the ketogenic diet could
confer neuroprotection, although the
available evidence supporting this concept is scant. Thus,
acetoacetate has been shown to
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hippocampal neuron cell cultures;
however, a similar effect occurred in an immortalized
hippocampal cell line (HT22) lacking
ionotropic glutamate receptors (Noh et al., 2006).
Acetoacetate also decreased the formation
of early cellular markers of glutamate-induced apoptosis and
necrosis, probably through the
attenuation of glutamate-induced formation of ROS, as
discussed below.
Effects on γ-aminobutyric acid systems
Another possible way in which the ketogenic diet may confer
neuroprotection is through
enhancement of γ-aminobutyric acid (GABA) levels, with a
consequent increase in GABAmediated
inhibition (Yudkoff et al., 2001). Thus, ketone bodies have
been demonstrated to
increase the GABA content in rat brain synaptosomes
(Erecinska et al., 1996), and, using invivo
proton two-dimensional double-quantum spin-echo
spectroscopy, the ketogenic diet was
associated with elevated levels of GABA in some but not all
human subjects studied (Wang
et al., 2003). Rats fed a ketogenic diet did not, however,
show increases in cerebral GABA
(al-Mudallal et al., 1996).
Antioxidant mechanisms
Enhancement of antioxidant mechanisms represents an
additional potential mechanism of
neuroprotection. For example, ketone bodies have been shown
to reduce the amount of
coenzyme Q semiquinone, thereby decreasing free radical
production (Veech, 2004).
A key enzyme in the control of ROS formation is glutathione
peroxidase, a peroxidase found
in erythrocytes that prevents lipid peroxidation by reducing
lipid hydroperoxides to their
corresponding alcohols and reducing free hydrogen peroxide
to water. The ketogenic diet
induces glutathione peroxidase activity in the rat
hippocampus (Ziegler et al., 2003).
The ketogenic diet also increases production of specific
mitochondrial uncoupling proteins
(UCPs) (Sullivan et al., 2004). For example, in mice fed a
ketogenic diet, UCP2, UCP4, and
UCP5 were increased, particularly in the dentate gyrus. UCPs
serve to dissipate the
mitochondrial membrane potential, which, in turn, decreases
the formation of ROS. Thus,
juvenile mice fed a ketogenic diet had higher maximum
mitochondrial respiration rates than
those fed a control diet. Oligomycin-induced ROS production
was also lower in the ketogenic
diet-fed group. The ketogenic diet likely induces UCP
production via fatty acids (Freeman et
al., 2006). Levels of many polyunsaturated fatty acids are
elevated in human patients on the
ketogenic diet (Fraser et al., 2003). In fact, in patients
with epilepsy, levels of one
polyunsaturated fatty acid, arachidonate, were found to
correlate with seizure control, although
it has not yet been shown that arachidonate induces UCP
production.
Effects on programmed cell death
The ketogenic diet may also protect against various forms of
cell death. For example, the diet
was protective against apoptotic cell death in mice induced
by the glutamate receptor agonist
and excitotoxin kainate, as evidenced by reductions of
markers of apoptosis, including terminal
deoxynucleotidyl transferase-mediated deoxyuridine
triphosphate-biotin nick-end labeling
and caspase-3 staining, in neurons in the CA1 and CA3
regions of the hippocampus (Noh et
al., 2003). Activation of caspase-3, a member of a larger
family of cysteine proteases, has been
implicated in neuronal cell death produced by different
brain insults including seizures and
ischemia (Gillardon et al., 1997; Chen et al., 1998).
Apoptosis in seizure models can proceed
via a number of molecular pathways (McIntosh et al., 1998;
Fujikawa, 2005). One molecule
that may play a role is calbindin, which is increased in
mice on the ketogenic diet (McIntosh
et al., 1998; Noh et al., 2005a). Calbindin is believed to
have neuroprotective activity through
its capacity to buffer intracellular calcium, which is a
mediator of cell death (Mattson et al.,
1995; Bellido et al., 2000). Further, protection by the
ketogenic diet may be mediated by the
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clusterin (Noh et al., 2005b),
which can act as a prodeath signal (Jones and Jomary, 2002).
Anti-inflammatory effects
It is well recognized that inflammatory mechanisms play a
role in the pathophysiology of acute
and chronic neurodegenerative disorders (Neuroinflammation
Working Group, 2000; Pratico
and Trojanowski, 2000; Chamorro and Hallenbeck, 2006).
Inflammation has also been
hypothesized to contribute to the development of chronic
epilepsy (Vezzani and Granata,
2005). It is therefore of interest that fasting (a state
associated with ketonemia, as in the
ketogenic diet) or a high-fat diet has been associated with
effects on inflammatory mechanisms
(Palmblad et al., 1991; Stamp et al., 2005). A link between
the ketogenic diet, antiinflammatory
mechanisms, and disease modification of neurological disease
is still highly
tentative. It is, however, noteworthy that intermittently
fasted rats have increased expression
of the cytokine interferon-γ in the hippocampus, and it was
further shown that the cytokine
conferred protection against excitotoxic cell death (Lee et
al., 2006). The high fatty acid load
of the ketogenic diet may also activate anti-inflammatory
mechanisms. For example, it has
been shown that fatty acids activate peroxisome
proliferator-activated receptor α, which may,
in turn, have inhibitory effects on the proinflammatory
transcription factors nuclear factor-κB
and activation protein-1 (Cullingford, 2004).
Carbohydrate restriction as a protective mechanism
A key aspect of the ketogenic diet is carbohydrate
restriction. The role of decreased
carbohydrates in neuroprotection has been investigated
through the use of 2-deoxy-D-glucose
(2-DG), a glucose analog that is not metabolized by
glycolysis. Lee et al. (1999) found that
administration of 2-DG to adult rats at a nontoxic dose (200
mg/kg) for 7 consecutive days
produced dramatic protection against hippocampal damage and
functional neurological deficits
induced by the seizure-inducing excitotoxin kainate. In
addition, 2-DG was protective against
glutamate-induced and oxidative stress-induced neuronal
death in cell culture. The authors also
found that reduced glucose availability induces stress
proteins, including GRP78 and HSP70,
which they proposed act to suppress ROS production,
stabilize intracellular calcium, and
maintain mitochondrial function.
Conclusions
A wide variety of evidence suggests that the ketogenic diet
could have beneficial diseasemodifying
effects in epilepsy and also in a broad range of
neurological disorders characterized
by death of neurons. Although the mechanism by which the
diet confers neuroprotection is not
fully understood, effects on cellular energetics are likely
to play a key role. It has long been
recognized that the ketogenic diet is associated with
increased circulating levels of ketone
bodies, which represent a more efficient fuel in the brain,
and there may also be increased
numbers of brain mitochondria. It is plausible that the
enhanced energy production capacity
resulting from these effects would confer neurons with
greater ability to resist metabolic
challenges. Additionally, biochemical changes induced by the
diet – including the ketosis, high
serum fat levels, and low serum glucose levels – could
contribute to protection against neuronal
death by apoptosis and necrosis through a multitude of
additional mechanisms, including
antioxidant and antiinflammatory actions. Theoretically, the
ketogenic diet might have greater
efficacy in children than in adults, inasmuch as younger
brains have greater capacity to
transport and utilize ketone bodies as an energy source
(Rafiki et al., 2003; Vannucci and
Simpson, 2003; Pierre and Pellerin, 2005).
Controlled clinical trials are required to confirm the
utility of the diet as a disease-modifying
approach in any of the conditions in which it has been
proposed to be effective. A greater
Gasior et al. Page 8
Behav Pharmacol. Author manuscript; available in PMC 2008
May 5.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA
Author Manuscriptunderstanding of the underlying mechanisms, however, should
allow the diet to be more
appropriately studied. Indeed, there are many as yet
unanswered questions about the use of the
diet. For example, in epilepsy, how long an exposure to the
diet is necessary? Do short periods
of exposure to the diet confer long-term benefit? Why can
the protective effects of the diet be
readily reversed by exposure to carbohydrates in some but
not all patients? In situations of
acute neuronal injury, can the diet be administered after
the neuronal injury, and if so, what
time window is available? Does monitoring the diet through
measurements of biochemical
parameters improve efficacy and, if so, what is the best
marker to monitor? Finally, the most
fundamental research questions are what role ketosis plays,
if any, in the therapeutic effects of
the diet, and whether low glucose levels contribute to or
are necessary for its symptomatic or
proposed disease-modifying activity.
Moreover, a better understanding of the mechanisms may
provide insights into ketogenic dietinspired
therapeutic approaches that eliminate the need for strict
adherence to the diet, which
is unpalatable, difficult to maintain, and is associated
with side effects such as hyperuricemia
and nephrolithiasis, and adverse effects on bone health and
the liver (Freeman et al., 2006). A
variety of approaches have been devised that allow ketosis
to be obtained without the need to
consume a high fat, low carbohydrate diet. The simplest is
the direct administration of ketone
bodies, such as through the use of the sodium salt form of
β-hydroxybutyrate. Toxicological
studies in animals have demonstrated that β-hydroxybutyrate
sodium is well tolerated, and that
theoretical risks such as acidosis and sodium and osmotic
overload can be avoided by careful
monitoring of blood parameters (Smith et al., 2005).
Intravenous β-hydroxybutyrate has the
potential to provide neuroprotection against ischemia during
some surgical procedures, such
as cardiopulmonary bypass. Owing to its short half-life,
β-hydroxybutyrate sodium is,
however, not suitable for long-term therapy in the treatment
of chronic neurodegenerative
disorders. In these circumstances, orally bioavailable
polymers of β-hydroxybutyrate and its
derivatives with improved pharmacokinetic properties may be
of utility (Veech, 2004; Smith
et al., 2005). Another interesting alternative to the
ketogenic diet is the administration of
metabolic precursors of ketone bodies. Among potential
precursor molecules, 1,3-butanediol
and 1,3-butanediol acetoacetate esters have been most
extensively studied. These compounds
are metabolized in a chain of enzymatic reactions in the
plasma and liver to the same ketone
bodies that are produced during the ketogenic diet
(Desrochers et al., 1992, 1995; Ciraolo et
al., 1995). Although each of the aforementioned alternatives
is still early in development, the
idea of developing the ketogenic diet in a ‘pill’ is very
attractive and may be approachable.
Acknowledgements
We thank Amy French and Jessica Yankura for their helpful
comments.
Sponsorship: This work was supported by the Intramural
Research Program of the NINDS, NIH.
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FASEB J 2005;19:659–661. [PubMed:
15650008]Neuroprotective and disease-modifying effects of the Ketogenic
diet
Maciej Gasiora, Michael A. Rogawskia, and Adam L. Hartmana,b
Epilepsy Research Section, National Institute of
Neurological Disorders and Stroke, National Institutes of
Health, Bethesda
The John M. Freeman Pediatric Epilepsy Center, Johns Hopkins
Hospital, Baltimore, Maryland, USA
Abstract
The ketogenic diet has been in clinical use for over 80
years, primarily for the symptomatic treatment
of epilepsy. A recent clinical study has raised the
possibility that exposure to the ketogenic diet may
confer long-lasting therapeutic benefits for patients with
epilepsy. Moreover, there is evidence from
uncontrolled clinical trials and studies in animal models
that the ketogenic diet can provide
symptomatic and disease-modifying activity in a broad range
of neurodegenerative disorders
including Alzheimer’s disease and Parkinson’s disease, and
may also be protective in traumatic brain
injury and stroke. These observations are supported by
studies in animal models and isolated cells
that show that ketone bodies, especially β-hydroxybutyrate,
confer neuroprotection against diverse
types of cellular injury. This review summarizes the
experimental, epidemiological and clinical
evidence indicating that the ketogenic diet could have
beneficial effects in a broad range of brain
disorders characterized by the death of neurons. Although
the mechanisms are not yet well defined,
it is plausible that neuroprotection results from enhanced
neuronal energy reserves, which improve
the ability of neurons to resist metabolic challenges, and
possibly through other actions including
antioxidant and anti-inflammatory effects. As the underlying
mechanisms become better understood,
it will be possible to develop alternative strategies that
produce similar or even improved therapeutic
effects without the need for exposure to an unpalatable and
unhealthy, high-fat diet.
Keywords
Alzheimer’s disease; cellular energetics; epilepsy; ketone
bodies; ketogenic diet; mitochondria;
neuroprotection; Parkinson’s disease; stroke; traumatic
brain injury
Introduction
The ketogenic diet is a high-fat content diet in which
carbohydrates are nearly eliminated so
that the body has minimal dietary sources of glucose. Fatty
acids are thus an obligatory source
of cellular energy production by peripheral tissues and also
the brain. Consumption of the
ketogenic diet is characterized by elevated circulating
levels of the ketone bodies acetoacetate,
β-hydroxybutyrate and acetone, produced largely by the
liver. During high rates of fatty acid
oxidation, large amounts of acetyl-CoA are generated. These
exceed the capacity of the
tricarboxylic acid cycle and lead to the synthesis of the
three ketone bodies within liver
mitochondria. Plasma levels of ketone bodies rise, with
acetoacetate and β-hydroxybutyrate
increasing three-fold to four-fold from basal levels of 100
and 200 µmol/l, respectively (MusaVeloso
et al., 2002). In the absence of glucose, the preferred
source of energy (particularly of
Address correspondence to: Michael A. Rogawski, M.D., Ph.D.,
Department of Neurology, University of California, Davis, 4860 Y
Street, Suite 3700, Sacramento, California 95817, E-mail:
rogawski@ucdavis.edu.
NIH Public Access
Author Manuscript
Behav Pharmacol. Author manuscript; available in PMC 2008
May 5.
Published in final edited form as:
Behav Pharmacol. 2006 September ; 17(5-6): 431–439.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA
Author Manuscriptthe brain), the ketone bodies are used as fuel in extrahepatic
tissues. The ketone bodies are
oxidized, releasing acetyl-CoA, which enters the
tricarboxylic acid cycle.
The ketogenic diet is an established and effective
nonpharmacological treatment for epilepsy
(Vining et al., 1998; Stafstrom, 2004; Sinha and Kossoff,
2005). Although the diet is useful in
people of all ages, clinical experience suggests that it may
be more valuable in children, if only
because adults have greater difficulty adhering to it.
Importantly, the diet is often effective in
pharmacoresistant forms of common epilepsies as well as in
the difficult to treat catastrophic
epilepsy syndromes of infancy and early childhood such as
West Syndrome, Lennox–Gastaut
Syndrome, and Dravet Syndrome (Crumrine, 2002; Trevathan,
2002; Caraballo et al., 2005).
Recently, there has been interest in the potential of the
ketogenic diet in the treatment of
neurological disorders other than epilepsy, including
Alzheimer’s disease and Parkinson’s
disease. Studies in these neurodegenerative disorders have
led to the hypothesis that the
ketogenic diet may not only provide symptomatic benefit, but
could have beneficial diseasemodifying
activity applicable to a broad range of brain disorders
characterized by the death of
neurons. Here, we review evidence from clinical studies and
animal models that supports this
concept.
Ketogenic diet
The classic ketogenic diet is a high-fat diet developed in
the 1920s to mimic the biochemical
changes associated with periods of limited food availability
(Kossoff, 2004). The diet is
composed of 80–90% fat, with carbohydrate and protein
constituting the remainder of the
intake. The diet provides sufficient protein for growth, but
insufficient amounts of
carbohydrates for the body’s metabolic needs. Energy is
largely derived from the utilization
of body fat and by fat delivered in the diet. These fats are
converted to the ketone bodies β-
hydroxybutyrate, acetoacetate, and acetone, which represent
an alternative energy source to
glucose. In comparison with glucose, ketone bodies have a
higher inherent energy (Pan et
al., 2002; Cahill and Veech, 2003). In adults, glucose is
the preferred substrate for energy
production, particularly by the brain. Ketone bodies are,
however, a principal source of energy
during early postnatal development (Nehlig, 2004). In
addition, ketone bodies, especially
acetoacetate, are preferred substrates for the synthesis of
neural lipids. Ketone bodies readily
cross the blood–brain barrier either by simple diffusion
(acetone) or with the aid of
monocarboxylic transporters (β-hydroxybutyrate,
acetoacetate), whose expression is related
to the level of ketosis (Pan et al., 2002; Pierre and
Pellerin, 2005).
Today, several types of ketogenic diets are employed for
treatment purposes. The most
frequently used is the traditional ketogenic diet originally
developed by Wilder in 1921, which
is based on long-chain fatty acids (Wilder, 1921). In the
1950s, a medium-chain triglyceride
diet was introduced, which produces greater ketosis
(Huttenlocher et al., 1971). This
modification has not been widely accepted because it is
associated with bloating and abdominal
discomfort and is no more efficacious than the traditional
ketogenic diet. A third variation on
the diet, known as the Radcliffe Infirmary diet, represents
a combination of the traditional and
medium-chain triglyceride diets (Schwartz et al., 1989). Its
efficacy is also similar to the
traditional ketogenic diet.
Although the ketogenic diet was a popular treatment approach
for epilepsy in the 1920s and
1930s, its medical use waned after the introduction of
phenytoin in 1938. The recognition that
the diet may be an effective therapeutic approach in some
drug-resistant epilepsies, particularly
in children, has led to a resurgence of interest in the last
15 years. The popularization of various
low carbohydrate diets for weight loss, such as the Atkins
diet (Acheson, 2004), probably also
has increased interest in the dietary therapy of epilepsy.
In fact, a modified form of the Atkins
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the traditional ketogenic diet, may
be an effective epilepsy treatment approach (Kossoff et al.,
2006).
Clinical studies
Epilepsy
At present, strong evidence exists that the ketogenic diet
protects against seizures in children
with difficult-to-treat epilepsy (Freeman et al., 1998).
Recent reports have raised the possibility
that the diet may also improve the long-term outcome in such
children (Hemingway et al.,
2001; Marsh et al., 2006). In these studies, children with
intractable epilepsy who remained
on the ketogenic diet for more than 1 year and who
experienced a good response to the diet,
often had positive outcomes at long-term follow-up 3–6 years
after the initiation of diet. Fortynine
percent of the children in this cohort experienced a nearly
complete (≥ 90%) resolution
in seizures. Surprisingly, even those children who remained
on the diet for 6 months or less
(most of these children terminated the diet because of an
inadequate response) may have
obtained a long-term benefit from exposure to the diet.
Thirty-two percent of these children
had a ≥ 90% decrease in their seizures and 22% became
seizure free even without surgery. The
diet also allowed a decrease or discontinuation of
medications without a relapse in seizures.
Of course, in the absence of a control group, it is not
possible to be certain that the apparent
good response in these children is simply the natural
history of the epilepsy in the cohort
studied, although these children had, by definition,
intractable epilepsy before starting the diet.
In any case, the results raise the possibility that the
ketogenic diet, in addition to its ability to
protect against seizures, may have disease-modifying
activity leading to an improved longterm
outcome. It is noteworthy that none of the currently
marketed antiepileptic drugs has been
demonstrated clinically to possess such a disease-modifying
effect (Schachter, 2002; Benardo,
2003). Determining whether the ketogenic diet truly alters
long-term outcome will require
prospective controlled trials.
Alzheimer’s disease
Recent studies have raised the possibility that the
ketogenic diet could provide symptomatic
benefit and might even be disease modifying in Alzheimer’s
disease. Thus, Reger et al.
(2004) found that acute administration of medium-chain
triglycerides improves memory
performance in Alzheimer’s disease patients. Further, the
degree of memory improvement was
positively correlated with plasma levels of
β-hydroxybutyrate produced by oxidation of the
medium-chain triglycerides. If β-hydroxybutyrate is
responsible for the memory improvement,
then the ketogenic diet, which results in elevated
β-hydroxybutyrate levels, would also be
expected to improve memory function. When a patient is
treated for epilepsy with the ketogenic
diet, a high carbohydrate meal can rapidly reverse the
antiseizure effect of the diet
(Huttenlocher, 1976). It is therefore of interest that high
carbohydrate intake worsens cognitive
performance and behavior in patients with Alzheimer’s
disease (Henderson, 2004; Young et
al., 2005).
It is also possible that the ketogenic diet could ameliorate
Alzheimer’s disease by providing
greater amounts of essential fatty acids than normal or high
carbohydrate diets (Cunnane et
al., 2002; Henderson, 2004). This is because consumption of
foods or artificial supplements
rich in essential fatty acids may decrease the risk of
developing Alzheimer’s disease
(Ruitenberg et al., 2001; Barberger-Gateau et al., 2002;
Morris et al., 2003a, b).
Parkinson’s disease
One recently published clinical study tested the effects of
the ketogenic diet on symptoms of
Parkinson’s disease (VanItallie et al., 2005). In this
uncontrolled study, Parkinson’s disease
patients experienced a mean of 43% reduction in Unified
Parkinson’s Disease Rating Scale
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participating patients reported
moderate to very good improvement in symptoms. Further, as
in Alzheimer’s disease,
consumption of foods containing increased amounts of
essential fatty acids has been associated
with a lower risk of developing Parkinson’s disease (de Lau
et al., 2005).
Studies in animal models
Epilepsy
Anticonvulsant properties of the ketogenic diet have been
documented in acute seizure models
in rodents (Appleton and De Vivo, 1973; Huttenlocher, 1976;
Hori et al., 1997; Stafstrom,
1999; Likhodii et al., 2000; Thavendiranathan et al., 2000,
2003; Bough et al., 2002).
Moreover, there is accumulating evidence from studies in
models of chronic epilepsy that the
ketogenic diet has antiepileptogenic properties that extend
beyond its anticonvulsant efficacy.
Thus, in the rat kainic acid model of temporal lobe
epilepsy, the development of spontaneous
seizures was attenuated by the ketogenic diet and there was
a reduction in the severity of the
seizures that did occur (Muller-Schwarze et al., 1999;
Stafstrom et al., 1999; Su et al., 2000).
In addition, animals fed the diet have reduced hippocampal
excitability and decreased
supragranular mossy fiber sprouting in comparison with rats
fed a normal diet. Further evidence
supporting the antiepileptogenic activity of the ketogenic
diet is the demonstration that the
development of spontaneous seizures in inbred EL/Suz mice, a
genetic model of idiopathic
epilepsy, is retarded by the diet (Todorova et al., 2000).
In other studies, caloric restriction,
which often occurs with the ketogenic diet, has also been
demonstrated to have
antiepileptogenic effects in EL/Suz mice (Greene et al.,
2001; Mantis et al., 2004). (Although
the ketogenic diet is designed to provide calories adequate
for growth, patients and animals
may eat less because the diet may be unpalatable to some.
Thus, the ketogenic diet may be
accompanied by an unintentional caloric restriction.)
Alzheimer’s disease
Epidemiological studies have implicated diets rich in
saturated fat with the development of
Alzheimer’s disease (Kalmijn et al., 1997; Grant, 1999;
Morris et al., 2003a, b, 2004; but see
Engelhart et al., 2002). Moreover, in transgenic mouse
models, high-fat diets increase the
deposition of amyloid β (Aβ) peptides (Levin-Allerhand et
al., 2002; Shie et al., 2002; George
et al., 2004; Ho et al., 2004). These studies, however, did
not examine the effects of ketogenic
diets rich in fats, when the high lipid content is
administered along with severe carbohydrate
restriction. Indeed, in a recent series of experiments using
a transgenic mouse model of
Alzheimer’s disease, a ketogenic diet was found to improve
Alzheimer’s pathology. The mice
used in this study, which express a human amyloid precursor
protein gene containing the
London mutation (APP/V717I), exhibit significant levels of
soluble Aβ in the brain as early
as 3 months of age and show extensive plaque deposition by
12–14 months (Van der Auwera
et al., 2005). They also demonstrate early behavioral
deficits in an object recognition task.
Exposure to a ketogenic diet for 43 days resulted in a 25%
reduction in soluble Aβ(1–40) and
Aβ(1–42) in brain homogenates, but did not affect
performance on the object recognition task.
Caloric restriction has also been demonstrated to attenuate
β-amyloid depositions in mouse
models of Alzheimer disease (Patel et al., 2005; Wang et
al., 2005). How the ketogenic diet
and caloric restriction affect β-amyloid levels and whether
this effect could be disease
modifying in Alzheimer’s disease requires further study.
The ketogenic diet could have beneficial effects in
Alzheimer’s disease apart from effects on
β-amyloid disposition. For example, essential fatty acids in
the diet may have beneficial effects
on learning, as demonstrated with studies of spatial
recognition learning in rodent models of
Alzheimer’s disease (Hashimoto et al., 2002, 2005; Lim et
al., 2005). Alternatively, the diet
might protect against β-amyloid toxicity. Thus, direct application
of β-hydroxybutyrate in
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to protect hippocampal neurons
from toxicity induced by Aβ(1–42) (Kashiwaya et al., 2000).
Parkinson’s disease
The most widely used animal model of Parkinson’s disease is
based on the neurotoxin MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Exposure to
MPTP causes degeneration of
mesencephalic dopamine neurons, as in the human clinical
condition, and is associated with
parkinsonian clinical features. The ketogenic diet has not
yet been studied in the MPTP or other
animal models of Parkinson’s disease. As in epilepsy and
Alzheimer’s disease models,
however, caloric restriction has been found to have
beneficial effects in MPTP models of
Parkinson’s disease. This was first demonstrated in rats fed
on an alternate-day schedule so
that they consume 30–40% less calories than animals with
free access to food. The calorierestricted
animals were found to exhibit resistance to MPTP-induced
loss of dopamine neurons
and less severe motor deficits than animals on the normal
diet (Duan and Mattson, 1999). More
recently, it has been reported that adult male rhesus
monkeys maintained chronically on a
calorie-restricted diet are also resistant to MPTP
neurotoxicity (Maswood et al., 2004; Holmer
et al., 2005). These animals had less depletion of striatal
dopamine and dopamine metabolites
and substantially improved motor function than did animals
receiving a normal diet. In other
studies in mice, caloric restriction has been reported to
have beneficial effects even when begun
after exposure to MPTP (Holmer et al., 2005).
In addition to caloric restriction, several recent reports
have indicated that β-hydroxybutyrate
may be neuroprotective in the MPTP model. MPTP is converted
in vivo to 1-methyl-4-
phenylpyridinium (MPP +), which is believed to be the
principal neurotoxin through its action
on complex 1 of the mitochondrial respiratory chain. In
tissue culture, 4 mmol/l β-
hydroxybutyrate protected mesencephalic neurons from MPP +
toxicity (Kashiwaya et al.,
2000). Moreover, subcutaneous infusion by osmotic minipump
of β-hydroxybutyrate for 7
days in mice conferred partial protection against
MPTP-induced degeneration of dopamine
neurons and parkinsonian motor deficits (Tieu et al., 2003).
It was proposed that the protective
action is mediated by improved oxidative phosphorylation
leading to enhanced ATP
production. This concept was supported by experiments with
the mitochondrial toxin 3-
nitropropionic acid (3-NP). 3-NP inhibits oxidative
phosphorylation by blocking succinate
dehydrogenase, an enzyme of the tricarboxylic acid cycle
that transfers electrons to the electron
transport chain via its complex II function. The protective
effect of β-hydroxybutyrate on
MPTP-induced neurodegeneration in mice was eliminated by
3-NP. Moreover, in experiments
with purified mitochondria, β-hydroxybutyrate markedly
stimulated ATP production and this
stimulatory effect was eliminated by 3-NP. Thus, it seems
likely that β-hydroxybutyrate is
protective in the MPTP model of Parkinson’s disease by
virtue of its ability to improve
mitochondrial ATP production (Tieu et al., 2003). Whether
the ketogenic diet would also be
protective in Parkinson’s disease models as a result of
increased β-hydroxybutyrate production
remains to be determined. It is noteworthy that
β-hydroxybutyrate is not anticonvulsant and is
unlikely to directly account for the antiseizure activity of
the ketogenic diet (Rho et al.,
2002). Whether β-hydroxybutyrate contributes in some other
way to the beneficial activity of
the ketogenic diet in epilepsy therapy remains to be
studied.
Ischemia and traumatic brain injury
Much of the neurological dysfunction that occurs in stroke,
cerebral ischemia, and acute
traumatic brain injury is due to a secondary injury process
involving glutamate-mediated
excitotoxicity, intracellular calcium overload,
mitochondrial dysfunction, and the generation
of reactive oxygen species (ROS) (McIntosh et al., 1998).
Consequently, the underlying
pathophysiological mechanisms may have features in common
with those in classical
neurodegenerative disorders. Recently, Prins et al. (2005)
have reported that the ketogenic diet
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at 7 days after controlled cortical
injury in rats. The beneficial effects of the diet,
administered after the injury, only occurred at
some postnatal ages despite similar availability of ketone
bodies at all ages studied. This led
the authors to conclude that differences in the ability of
the brain to utilize ketones at different
developmental stages may influence the protection conferred
(Rafiki et al., 2003; Vannucci
and Simpson, 2003; Pierre and Pellerin, 2005). In a previous
study, a 48-h fast, which results
in similar short-term ketosis as that achieved by the
ketogenic diet, was found to protect rats
against neuronal loss in the striatum, neocortex, and
hippocampus produced by 30-min fourvessel
occlusion (Marie et al., 1990). There was also a reduction
in mortality and the incidence
of postischemic seizures in fasted animals. Thus, there is
evidence that the ketogenic diet has
neuroprotective activity in both traumatic and ischemic
brain injury. An additional study found
that rats receiving a ketogenic diet are also resistant to
cortical neuron loss occurring in the
setting of insulin-induced hypoglycemia (Yamada et al.,
2005).
Although the mechanism whereby the ketogenic diet confers
protection in these diverse injury
models is not well understood, β-hydroxybutyrate could play
a role. The ketone body would
presumably serve as an alternative energy source to mitigate
injury-induced ATP depletion. In
fact, exogenous administration of β-hydroxybutyrate can
reduce brain damage and improve
neuronal function in models of brain hypoxia, anoxia, and
ischemia (Cherian et al., 1994;
Dardzinski et al., 2000; Suzuki et al., 2001, 2002; Smith et
al., 2005). In addition, the other
ketone bodies, acetoacetate and acetone, which are
β-hydroxybutyrate metabolites and can also
serve as alternative energy sources, have similar
neuroprotective effects (Garcia and Massieu,
2001; Massieu et al., 2001, 2003; Noh et al., 2006).
Interestingly, in rats receiving a ketogenic
diet, neuronal uptake of β-hydroxybutyrate is increased
after cortical impact injury in
comparison with animals receiving a standard diet (Prins et
al., 2004). Thus, the ketogenic diet
may promote delivery of β-hydroxybutyrate to the brain.
Cellular mechanisms underlying the neuroprotective activity
of the ketogenic
diet
Effects on energy metabolism
As noted above, ketone bodies, including β-hydroxybutyrate,
that are produced during
consumption of the ketogenic diet may serve as an alternative
source of energy in states of
metabolic stress, thus contributing to the neuroprotective
activity of the diet. In fact, β-
hydroxybutyrate may provide a more efficient source of
energy for brain per unit oxygen than
glucose (Veech et al., 2001). Recently, using microarrays to
define patterns of gene expression,
Bough et al. (2006) made the remarkable discovery that the
ketogenic diet causes a coordinated
upregulation of hippocampal genes encoding energy metabolism
and mitochondrial enzymes.
Electron micrographs from the dentate/hilar region of the
hippocampus showed a 46% increase
in mitochondrial profiles in rats fed the ketogenic diet.
Thus, the ketogenic diet appears to
stimulate mitochondrial biogenesis. Moreover, there was a
greater phosphocreatine : creatine
ratio in the hippocampal tissue, indicating an increase in
cellular energy reserves, as expected
from the greater abundance of mitochondria. In sum, during
consumption of the ketogenic diet,
two factors may contribute to the ability of neurons to resist
metabolic stress: a larger
mitochondrial load and a more energy-efficient fuel. In
combination, these factors may account
for the enhanced ability of neurons to withstand metabolic
challenges of a degree that would
ordinarily exhaust the resilience of the neurons and result
in cellular demise.
Effects on glutamate-mediated toxicity
Interference with glutamate-mediated toxicity, a major
mechanism underlying neuronal injury,
is an alternative way in which the ketogenic diet could
confer neuroprotection, although the
available evidence supporting this concept is scant. Thus,
acetoacetate has been shown to
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hippocampal neuron cell cultures;
however, a similar effect occurred in an immortalized
hippocampal cell line (HT22) lacking
ionotropic glutamate receptors (Noh et al., 2006).
Acetoacetate also decreased the formation
of early cellular markers of glutamate-induced apoptosis and
necrosis, probably through the
attenuation of glutamate-induced formation of ROS, as
discussed below.
Effects on γ-aminobutyric acid systems
Another possible way in which the ketogenic diet may confer
neuroprotection is through
enhancement of γ-aminobutyric acid (GABA) levels, with a
consequent increase in GABAmediated
inhibition (Yudkoff et al., 2001). Thus, ketone bodies have
been demonstrated to
increase the GABA content in rat brain synaptosomes
(Erecinska et al., 1996), and, using invivo
proton two-dimensional double-quantum spin-echo
spectroscopy, the ketogenic diet was
associated with elevated levels of GABA in some but not all
human subjects studied (Wang
et al., 2003). Rats fed a ketogenic diet did not, however,
show increases in cerebral GABA
(al-Mudallal et al., 1996).
Antioxidant mechanisms
Enhancement of antioxidant mechanisms represents an
additional potential mechanism of
neuroprotection. For example, ketone bodies have been shown
to reduce the amount of
coenzyme Q semiquinone, thereby decreasing free radical
production (Veech, 2004).
A key enzyme in the control of ROS formation is glutathione
peroxidase, a peroxidase found
in erythrocytes that prevents lipid peroxidation by reducing
lipid hydroperoxides to their
corresponding alcohols and reducing free hydrogen peroxide
to water. The ketogenic diet
induces glutathione peroxidase activity in the rat
hippocampus (Ziegler et al., 2003).
The ketogenic diet also increases production of specific
mitochondrial uncoupling proteins
(UCPs) (Sullivan et al., 2004). For example, in mice fed a
ketogenic diet, UCP2, UCP4, and
UCP5 were increased, particularly in the dentate gyrus. UCPs
serve to dissipate the
mitochondrial membrane potential, which, in turn, decreases
the formation of ROS. Thus,
juvenile mice fed a ketogenic diet had higher maximum
mitochondrial respiration rates than
those fed a control diet. Oligomycin-induced ROS production
was also lower in the ketogenic
diet-fed group. The ketogenic diet likely induces UCP
production via fatty acids (Freeman et
al., 2006). Levels of many polyunsaturated fatty acids are
elevated in human patients on the
ketogenic diet (Fraser et al., 2003). In fact, in patients
with epilepsy, levels of one
polyunsaturated fatty acid, arachidonate, were found to
correlate with seizure control, although
it has not yet been shown that arachidonate induces UCP
production.
Effects on programmed cell death
The ketogenic diet may also protect against various forms of
cell death. For example, the diet
was protective against apoptotic cell death in mice induced
by the glutamate receptor agonist
and excitotoxin kainate, as evidenced by reductions of
markers of apoptosis, including terminal
deoxynucleotidyl transferase-mediated deoxyuridine
triphosphate-biotin nick-end labeling
and caspase-3 staining, in neurons in the CA1 and CA3
regions of the hippocampus (Noh et
al., 2003). Activation of caspase-3, a member of a larger
family of cysteine proteases, has been
implicated in neuronal cell death produced by different
brain insults including seizures and
ischemia (Gillardon et al., 1997; Chen et al., 1998).
Apoptosis in seizure models can proceed
via a number of molecular pathways (McIntosh et al., 1998;
Fujikawa, 2005). One molecule
that may play a role is calbindin, which is increased in
mice on the ketogenic diet (McIntosh
et al., 1998; Noh et al., 2005a). Calbindin is believed to
have neuroprotective activity through
its capacity to buffer intracellular calcium, which is a
mediator of cell death (Mattson et al.,
1995; Bellido et al., 2000). Further, protection by the
ketogenic diet may be mediated by the
Gasior et al. Page 7
Behav Pharmacol. Author manuscript; available in PMC 2008
May 5.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA
Author Manuscriptprevention of kainic acid-induced accumulation of the protein
clusterin (Noh et al., 2005b),
which can act as a prodeath signal (Jones and Jomary, 2002).
Anti-inflammatory effects
It is well recognized that inflammatory mechanisms play a
role in the pathophysiology of acute
and chronic neurodegenerative disorders (Neuroinflammation
Working Group, 2000; Pratico
and Trojanowski, 2000; Chamorro and Hallenbeck, 2006).
Inflammation has also been
hypothesized to contribute to the development of chronic
epilepsy (Vezzani and Granata,
2005). It is therefore of interest that fasting (a state
associated with ketonemia, as in the
ketogenic diet) or a high-fat diet has been associated with
effects on inflammatory mechanisms
(Palmblad et al., 1991; Stamp et al., 2005). A link between
the ketogenic diet, antiinflammatory
mechanisms, and disease modification of neurological disease
is still highly
tentative. It is, however, noteworthy that intermittently
fasted rats have increased expression
of the cytokine interferon-γ in the hippocampus, and it was
further shown that the cytokine
conferred protection against excitotoxic cell death (Lee et
al., 2006). The high fatty acid load
of the ketogenic diet may also activate anti-inflammatory
mechanisms. For example, it has
been shown that fatty acids activate peroxisome
proliferator-activated receptor α, which may,
in turn, have inhibitory effects on the proinflammatory
transcription factors nuclear factor-κB
and activation protein-1 (Cullingford, 2004).
Carbohydrate restriction as a protective mechanism
A key aspect of the ketogenic diet is carbohydrate
restriction. The role of decreased
carbohydrates in neuroprotection has been investigated
through the use of 2-deoxy-D-glucose
(2-DG), a glucose analog that is not metabolized by
glycolysis. Lee et al. (1999) found that
administration of 2-DG to adult rats at a nontoxic dose (200
mg/kg) for 7 consecutive days
produced dramatic protection against hippocampal damage and
functional neurological deficits
induced by the seizure-inducing excitotoxin kainate. In
addition, 2-DG was protective against
glutamate-induced and oxidative stress-induced neuronal
death in cell culture. The authors also
found that reduced glucose availability induces stress
proteins, including GRP78 and HSP70,
which they proposed act to suppress ROS production,
stabilize intracellular calcium, and
maintain mitochondrial function.
Conclusions
A wide variety of evidence suggests that the ketogenic diet
could have beneficial diseasemodifying
effects in epilepsy and also in a broad range of
neurological disorders characterized
by death of neurons. Although the mechanism by which the
diet confers neuroprotection is not
fully understood, effects on cellular energetics are likely
to play a key role. It has long been
recognized that the ketogenic diet is associated with
increased circulating levels of ketone
bodies, which represent a more efficient fuel in the brain,
and there may also be increased
numbers of brain mitochondria. It is plausible that the
enhanced energy production capacity
resulting from these effects would confer neurons with
greater ability to resist metabolic
challenges. Additionally, biochemical changes induced by the
diet – including the ketosis, high
serum fat levels, and low serum glucose levels – could
contribute to protection against neuronal
death by apoptosis and necrosis through a multitude of
additional mechanisms, including
antioxidant and antiinflammatory actions. Theoretically, the
ketogenic diet might have greater
efficacy in children than in adults, inasmuch as younger
brains have greater capacity to
transport and utilize ketone bodies as an energy source
(Rafiki et al., 2003; Vannucci and
Simpson, 2003; Pierre and Pellerin, 2005).
Controlled clinical trials are required to confirm the
utility of the diet as a disease-modifying
approach in any of the conditions in which it has been
proposed to be effective. A greater
Gasior et al. Page 8
Behav Pharmacol. Author manuscript; available in PMC 2008
May 5.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA
Author Manuscriptunderstanding of the underlying mechanisms, however, should
allow the diet to be more
appropriately studied. Indeed, there are many as yet
unanswered questions about the use of the
diet. For example, in epilepsy, how long an exposure to the
diet is necessary? Do short periods
of exposure to the diet confer long-term benefit? Why can
the protective effects of the diet be
readily reversed by exposure to carbohydrates in some but
not all patients? In situations of
acute neuronal injury, can the diet be administered after
the neuronal injury, and if so, what
time window is available? Does monitoring the diet through
measurements of biochemical
parameters improve efficacy and, if so, what is the best
marker to monitor? Finally, the most
fundamental research questions are what role ketosis plays,
if any, in the therapeutic effects of
the diet, and whether low glucose levels contribute to or
are necessary for its symptomatic or
proposed disease-modifying activity.
Moreover, a better understanding of the mechanisms may
provide insights into ketogenic dietinspired
therapeutic approaches that eliminate the need for strict
adherence to the diet, which
is unpalatable, difficult to maintain, and is associated
with side effects such as hyperuricemia
and nephrolithiasis, and adverse effects on bone health and
the liver (Freeman et al., 2006). A
variety of approaches have been devised that allow ketosis
to be obtained without the need to
consume a high fat, low carbohydrate diet. The simplest is
the direct administration of ketone
bodies, such as through the use of the sodium salt form of
β-hydroxybutyrate. Toxicological
studies in animals have demonstrated that β-hydroxybutyrate
sodium is well tolerated, and that
theoretical risks such as acidosis and sodium and osmotic
overload can be avoided by careful
monitoring of blood parameters (Smith et al., 2005).
Intravenous β-hydroxybutyrate has the
potential to provide neuroprotection against ischemia during
some surgical procedures, such
as cardiopulmonary bypass. Owing to its short half-life,
β-hydroxybutyrate sodium is,
however, not suitable for long-term therapy in the treatment
of chronic neurodegenerative
disorders. In these circumstances, orally bioavailable
polymers of β-hydroxybutyrate and its
derivatives with improved pharmacokinetic properties may be
of utility (Veech, 2004; Smith
et al., 2005). Another interesting alternative to the
ketogenic diet is the administration of
metabolic precursors of ketone bodies. Among potential
precursor molecules, 1,3-butanediol
and 1,3-butanediol acetoacetate esters have been most
extensively studied. These compounds
are metabolized in a chain of enzymatic reactions in the
plasma and liver to the same ketone
bodies that are produced during the ketogenic diet
(Desrochers et al., 1992, 1995; Ciraolo et
al., 1995). Although each of the aforementioned alternatives
is still early in development, the
idea of developing the ketogenic diet in a ‘pill’ is very
attractive and may be approachable.
Acknowledgements
We thank Amy French and Jessica Yankura for their helpful
comments.
Sponsorship: This work was supported by the Intramural
Research Program of the NINDS, NIH.
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