To cite this article: Christopher M DeGiorgio & Ameer Taha (2016): Omega-3 fatty acids
(ῳ-3 fatty acids) in epilepsy: animal models and human clinical trials, Expert Review of
Neurotherapeutics, DOI: 10.1080/14737175.2016.1226135
Download by: [Cornell University Library] Date: 21 August 2016, At: 03:48
Publisher: Taylor & Francis
DOI: 10.1080/14737175.2016.1226135
Special report
Omega-3 fatty acids ( -3 fatty acids) in epilepsy: animal models and human
clinical trials
DeGiorgio, Christopher M
University of California Los Angeles David Geffen School of Medicine Ringgold standard
institution - Neurology
United States
Taha, Ameer
Davis, Connecticut
United States
1
Key words: Fish Oil, -3 fatty acids, omega-3 fatty acids, Epilepsy, Seizures, Animal
2
Abstract
Introduction: There is growing interest in alternative and nutritional therapies for drug
resistant epilepsy. -3 fatty acids as fish or krill oil are widely available supplements
used to lower triglycerides and enhance cardiovascular health. -3 fatty acids have
been studied extensively in animal models of epilepsy. Yet, evidence from randomized
Areas covered: This report focuses on the key -3 fatty acids DHA and EP, their
incorporation into the lipid bilayer, modulation of ion channels, and mechanisms of
action in reducing excitability within the central nervous system. This paper presents
pre-clinical evidence from mouse, rat, and canine models, and reports the efficacy of n-3
PubMed and Google scholar for the years 1981-2016 was performed for animal studies
Expert commentary: Basic science and animal models provide a cogent rationale and
substantial evidence for a role of -3 fatty acids in reducing seizures. Results in humans
are limited. Recent Phase II RCT evidence suggests that low to moderate dose -3 fatty
acids reduce seizures; however, larger multicenter randomized trials are needed to
confirm or refute the evidence. The safety, health effects, low cost, and ease of use
make -3 fatty acids an intriguing alternative therapy for drug resistant epilepsy. Though
safety of profile is excellent, the human data is not yet sufficient to support efficacy in
3
1. Introduction
Interest in dietary and alternative interventions for epilepsy (i.e. ketogenic diet,
modified Atkins diet, cannabinoids, and n-3 fatty acids) is exploding. To date, four
randomized controlled trials (RCTs) for the ketogenic diet and one RCT for the modified
Atkins diet have been published [1]. Efficacy is promising, with reductions of up to 85%
for the ketogenic diet, and 60% for the modified Atkins diet [1]. Cannabinoids have also
received significant attention [2]. The evidence is still limited pending completion of
multiple ongoing clinical trials [2]. Interest in -3 fatty acids is also growing. The primary
goal of this review is to present the basic science data supporting or refuting the role of
-3 fatty acids in mechanistic and animal models of epilepsy. A second goal is to review
results from randomized human clinical trials of -3 fatty acids for epilepsy.
2. Methods
The PubMed and Google scholar English language databases were searched for
publications with the following keywords: -3 fatty acids, omega-3 fatty acids, EPA,
DHA, PUFA, seizures, epilepsy. Preclinical studies (including basic science and animal
publications were included. For human studies, non-randomized or open label human
studies were excluded. For background, basic science and clinical data for heart
disease, infant development, and aging were also included. The database search
4
3. Overview Of Omega-3 ( -3) Fatty Acids
-3 fatty acids are essential long-chain polyunsaturated fatty acids which play an
important role in health and disease prevention. -3 fatty acids are incorporated into
lipids and cell membranes, modulate ion flux across myocytes and neurons, reduce
excitability, and lower the risk of cardiovascular disease [3-9]. The term “Omega-3” or
“ -3” refers to the presence of a double-bond at the third carbon from the methyl
terminus of the molecule [19]. Humans and other mammals cannot synthesize -3 fatty
acids, because they lack delta-12 and delta-15 desaturase enzymes, which remove
hydrogen atoms and create double bonds, necessary to create polyunsaturated fatty
acids [20].
The three major -3 fatty acids are linolenic acid (ALA), eicosopentaenoic acid
(EPA), and docosohexaenoic acid (DHA). ALA is an essential 18-carbon fatty acid found
in walnuts, flaxseed, soybean oil and canola oil. EPA and DHA are essential -3 fatty
acids found in marine sources, including salmon, tuna, mackerel, anchovies, and krill.
EPA and DHA are the primary ingredients in Fish oil or Krill oil.
DHA, a 22 carbon -3 fatty acid is the principle fatty acid in the brain. DHA
accumulates in lipid and synaptic membranes in cortex and retina, accounting for up to
35% of synaptic membrane content [20]. DHA is critical for brain maturation,
development, and aging. [20, 21] DHA regulates the neurogenesis of stem cells to
neurons, and promotes cell growth and differentiation. [20, 21]. Maternal DHA deficiency
5
may have a negative effect on infant brain development. Since -3 fatty acids are
transferred from mother to infant via the placenta, infants are solely dependent on
maternal dietary intake. Higher DHA concentrations in infants are positively correlated
with better visual acuity, cognition, and motor development in infants. [20] As a result,
impairment has not been proven to slow disease progression, but high levels of w-3 fatty
acids are associated with reduced rates of cerebral atrophy [12, 13]. Interventional
studies have demonstrated that -3 fatty acid supplementation reduces the rate of grey
matter atrophy. In one longitudinal study, healthy elderly subjects randomized to 2.2
grams of -3 fatty acids over a 26 week period demonstrated significantly better grey
matter volumes than controls n hippocampus, temporal, and parietal cortex [22]. In
with improved brain volumes only when -3 fatty acid levels were normal, indicating a
excitability is heavily dependent on sodium and calcium ion channels, which can be
modulated by EPA and DHA. Xiao et el made the seminal observation that EPA
suppresses voltage-activated Na+ currents in cultured rat myocytes, and found that both
EPA and DHA reduce inward calcium currents, prolonging the inactivation state
[23,24,25]. Leaf and el proposed that inhibition of sodium and calcium channels may
occur via juxtaposition of essential fatty acids adjacent to trans-membrane sodium and
calcium channels [26]. It is hypothesized that EPA and DHA are incorporated into the
6
lipid bi-layer, and the negatively-charged carboxyl terminal of EPA and DHA come into
proximity with the positively-charged region of the alpha subunit of the ion channel [26].
This leads to de-activation and stabilization. In the brain, EPA inhibits action potentials in
mouse hippocampus, while EPA and DHA reduce firing rates of CA1 pyramidal neurons
by 40-50% [27].
In animal models of epilepsy, the experience with -3 fatty acids has been highly
variable. Several animal studies reported that -3 fatty acids reduce seizure frequency
or prolong the latency to the onset of seizures, while some have found no effect. In a
mouse model of epilepsy, Taha et al. reported a 45% non-significant increase in time to
the onset of seizures (prolonged seizure latency) in fat-1 mice, which synthesize EPA
and DHA endogenously from Arachidonic Acid [28]. Willis et al. found no anticonvulsant
effect of EPA or DHA administration for 1-month at a low dose of 6 mg/kg. [29] However,
El-Mowafy et al. and Abdel-Dayem et al. found that high dose EPA (125-200 mg/kg) or
DHA (120-250 mg/kg) administration delayed the onset of seizures by 49%, and
than 50% when given intra-peritoneal to mice for 5 days at 0.57 mg/kg [32]. This
suggests that the anticonvulsant effects of DHA may be mediated by one of its
frequency > 50% in the electroconvulsive shock seizure model, but decreases latency to
7
5. Rat models of -3 fatty acids in epilepsy
In rat studies, fish oil containing EPA and DHA was reported to raise seizure
threshold in most studies when given over a longer term of at least 3 months [34-36].
When administered for only one month, two studies did not find an anticonvulsant effect
[37, 38]. However, a time-course study by Taha et al. showed that at least 3 months are
required for fish oil to raise seizure threshold in rats [39]. The delayed effect of dietary
fish oil may be due to the delay in formation of unesterifed EPA and DHA or their
bioactive metabolites (such as NPD1) within the brain. Since fish oil high in EPA and
DHA raises seizure thresholds in rats, studies have tested the anticonvulsant effects of
injected unesterified EPA or DHA. Voskuyl et al. reported that EPA or DHA injected
intravenously (IV) at 60-69 mg/kg over 30 minutes increased focal and generalized
seizure thresholds up to 6-16 fold in a cortical stimulation model [40]. Taha et al. found
that high dose (400 mg/kg), but not low dose, DHA administered subcutaneously
delayed the onset of seizures using a PTZ-induced seizure model [41]. DHA at 300-400
administration and within minutes after 25-200 mg/kg IV administration [41]. The
Interestingly, Taha et al. and Trepanier et al both found that high doses of DHA were not
as effective as lower doses, an interesting finding that is consistent with recent clinical
trials in epilepsy indicating lower dose w-3 fatty acids may be more effective than higher
8
In canines, two studies tested the anticonvulsant effects of -3 fatty acids in
dogs. Scorza et al. reported a reduction in seizure incidence from 3 per month to 1 per 3
months in a dog supplemented with 2 g/ day of -3 fatty acids for at least 18 months
et al found no effect of EPA (40 mg/kg) and DHA (25 mg/kg) supplementation for 12
weeks, except in one German shepherd dog which showed a 10-fold reduction in
seizure frequency during fish oil supplementation phase [45]. Overall, the data in canine
models is incomplete, and more evidence is needed. We can conclude that efficacy of
EPA and DHA on seizures is species specific, and dependent on dose and duration of
exposure. The greatest efficacy has been identified in mouse and rat models, with little
evidence in canine models. The evidence supports that acute administration of -3 fatty
acids requires high doses for acute efficacy. Chronic dosing for 3-months or longer is
Other -3 fatty acids like ALA acid have anti-seizure effects, and are synergistic
when administered with antiepileptic drugs. This synergistic effect of ALA has been
reported by multiple authors [46-48]. ALA from flaxseed or canola oil decreases
of audiogenic seizures [46]. By itself, EPA 300 mg/kg increased latency to PTZ-induced
mg/kg), EPA further increased latency by more than 300% compared with EPA alone
[47]. EPA did not increase seizure latency in a PTZ model of tonic-clonic seizures,
9
latency and decreased severity up to 59% compared to -3 fatty acids alone [48]. This
animal data suggests that -3 fatty acids are best administered as adjunctive therapy to
standard anti-epileptic drugs, rather than as a stand-alone therapy. This would need to
Fish Oil is safe and well tolerated. Mild gastrointestinal side effects such as
burping, fishy after-taste or diarrhea may occur [18, 49, and 50]. Independent laboratory
tests found that most brands of Fish Oil contained little or no heavy metals or PCB [51].
In preparation for one of the author’s recent clinical trial, independent testing of fish oil
Three major randomized controlled trials (RCT) of -3 fatty acids in epilepsy have
been reported to date [15-17]. All have been performed in subjects with severe drug
resistant focal-onset (partial) epilepsy with or without tonic-clonic seizures. The first and
largest was reported by Yuen et al in 2005. The primary intervention was 6 capsules of
measure was 50% or greater reduction in seizures during the 12-week treatment period.
58 subjects with drug resistant epilepsy were randomized to fish oil or placebo. Fish oil
was well tolerated. Side effects were few, and diarrhea was reported in only 1/30 (3%) of
patients on active treatment. Within the first 6-weeks of treatment, seizure frequency
was significantly reduced in the active treatment fish-oil group. At 6-weeks, 17% of fish
oil group experienced a 50% reduction in seizures, versus none (0%) in the control
10
group. [15]. Five of twenty-nine had at least a 50% reduction in seizures (compared with
0/27) [15]. However, at 12-weeks, there was no difference in efficacy between the fish
oil group and controls [15]. Though this study did not demonstrate sustained efficacy
over the 12-month treatment period, it did establish the overall safety of fish oil in people
The dose of -3 fatty acids was higher than the Yuen et al study, at 2200 mg/day
EPA+DHA. The primary outcome was similar, a > 50% reduction in seizure frequency.
the trial [16]. The study cohort was highly drug resistant, averaging 14.9/month
(treatment) versus 21.4/month (control). After a 4-week baseline, active subjects were
titrated to 2200 mg/day, and no changes in AED’s were allowed. EPA+DHA 2200 m/day
increase in seizures, versus a 12% reduction for controls. (Not significant, p =0.17) [16].
However, during un-blinded long-term follow-up, all subjects were crossed over to active
treatment with fish oil, and 5/19 (26%) had > 50% reduction in seizures [16].
A third RCT trial was reported by DeGiorgio et al. in 2015 [17]. The study design
was a phase II 3-period crossover study. This trial compared 2160 mg EPA+DHA (six
1200 mg fish oil capsules/day) to 1200 mg EPA +DHA (three 1200 mg fish oil
seizure frequency compared with placebo. Twenty-four highly drug-resistant subjects (>
AED’s were allowed. Low dose fish-oil (1080 mg EPA+DHA total) was associated with a
11
33.6% reduction in seizures (12.18 SE 2.72 seizures/day) compared with placebo [17].
High dose fish-oil (2160 mg EPA+DHA) was no different from placebo (-3.6%, 17.67 SE
4.56 versus placebo) [17]. In addition, low dose fish-oil was associated with twenty-five
percent of subjects experiencing a > 50% reduction in seizures during the treatment
period [17]. With these results, this phase II study met its primary endpoint, i.e., a
Of interest, low dose fish-oil was also associated with a reduction in blood
pressure, (-1.95 mmHg) [17]. Reasons for the positive study may include the crossover
design, which provides greater statistical power with a smaller cohort. Since all
comparisons are within group, variability is reduced compared with parallel designs. This
fish oil per day), and to demonstrate the superiority of low dose versus high dose.
Limitations include the small size of the cohort, indicating a large phase III trial will be
9. Summary
The weight of evidence from animal studies in rodents indicates that -3 fatty
acids have an anticonvulsant effect. This effect may be maximal when administered
over the long-term and in conjunction with standard antiepileptic drugs. Human phase II
studies of -3 fatty acids have shown mixed results. Most recently, lower dose -3 fatty
acids (i.e. 1080 mg EPA+DHA/day), equivalent to three fish oil capsules/day were
effective in a phase II randomized controlled trial [17]. -3 fatty acids may have other
health benefits in people with epilepsy, including reductions in blood pressure and
improvements in cardiovascular risk which one can extrapolate from large trials in heart
12
disease [7, 17]. Based on the phase II data, a large multicenter Phase III randomized
-3 fatty acids have significant health benefits. These include lowering serum
triglyceride levels, reducing mortality and sudden death after myocardial infarction,
In contrast, the data supporting human clinical use is limited to three small to
medium size randomized controlled trials with mixed results. Most recently, a phase
II RCT found that low to moderate dose -3 fatty acids (1080 mg/day EPA+DHA)
reduce seizures by 33% in patients with drug resistant epilepsy. However, a large,
The safety, health effects, low cost, and ease of use make -3 fatty acids an
intriguing alternative therapy for drug resistant epilepsy. At this time, clinical trial data
A multi-center randomized controlled trial, likely in the range of 100-200 subjects, will
require involvement of 10-20 centers, and will take 2-4 years to be completed.
Though safety data indicates the risk of supplementation with -3 fatty acids is low,
phase III pivotal data will be needed to demonstrate efficacy. If this trial is positive, it
13
will provide important evidence to justify supplementation with -3 fatty acids in
• -3 fatty acids are essential fatty acids (DHA and EPA) which lower triglyceride
levels, reduce the risk of death after myocardial infarction, and improve
• -3 fatty acids (with B-vitamins) may reduce the rate of cerebral atrophy in elderly
subjects.
• -3 fatty acids are incorporated into lipid membranes, where they modulate
sodium and calcium flux, and reduce neuronal and hippocampal excitability.
anticonvulsant effect.
• Human clinical trial data is conflicting, with two small to medium sized trials
found that 1080 mg of DHA+ EPA as fish oil reduced seizures compared to
placebo by 33.6%.
Funding
This paper was supported by a research grant from the NIH National Center for
14
unrestricted research support to UCLA by Beverly and James Peters, and Linda and
Robert Brill.
Declaration of Interest
The authors have no relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject matter or
pending, or royalties.
15
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