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Current Functional Foods, XXXX, XX, eXXXXXXX

REVIEW ARTICLE

A Review on Functional Foods and Nutraceuticals in the Management of

Epilepsy

Opeyemi B. Ogunsuyi1,2,*

1
Department of Biomedical Technology, School of Basic Medical Sciences, The Federal University of Technology,
Akure P.M.B. 704, Nigeria; 2Drosophila Research Lab, Functional Foods and Nutraceuticals Unit, Department of
Biochemistry, The Federal University of Technology, Akure P.M.B. 704, Nigeria

Abstract: Epilepsy is a persistent neurological disorder distinguished by repetitive episodes of

seizures that presents notable complexities for patients and healthcare providers. While phar-
macotherapy remains fundamental in its management, the emergence of functional foods and
nutraceuticals has garnered attention as adjunctive therapeutic options. This review examines
the role of functional foods and nutraceuticals in epilepsy management, examining their mech-
ARTICLEHISTORY anisms of action, evidence-based efficacy, and safety profiles. The review delineates various
functional foods and nutraceuticals exhibiting promise in epilepsy management, encompassing
Received: May 10, 2024
Revised: September 12, 2024
omega-3 fatty acids, the ketogenic diet, flavonoids, vitamins, and minerals. Mechanically,
Accepted: September 13, 2024 these substances modulate neuronal excitability, neurotransmitter release, and neuroinflamma-
DOI: tion, thus exerting anticonvulsant effects. Furthermore, they may augment the efficacy of con-
10.2174/0126668629329853241028081157 ventional antiepileptic drugs while mitigating their adverse effects. Clinical investigations as-
sessing the efficacy of functional foods and nutraceuticals in epilepsy management have yield-
ed encouraging findings, albeit necessitating further inquiry to ascertain optimal dosing proto-
cols and long-term safety considerations. Additionally, challenges such as bioavailability,
formulation standardization, and patient adherence warrant attention to optimize therapeutic
outcomes.
Keywords: Status epilepticus, food bioactives, dietary therapy, epilepsy management, human health, neurodegeneration.
1. INTRODUCTION In addition to the direct health impact, epilepsy carries
significant social and economic consequences. In the United
Epilepsy, a persistent neurological disorder, imposes
States, the annual direct and indirect costs associated with
significant emotional burdens on afflicted individuals and
epilepsy are estimated to be $15.5 billion, while in Europe,
their families. According to the World Health Organization these costs range between €15.5 billion and €20.2 billion
(WHO), nearly 80% of people with epilepsy are living in
annually [5]. In addition, this condition also leads to stigma
low- and middle-income countries, with an estimated 50
and discrimination, further exacerbating the challenges
million people living with epilepsy globally [1]. In high- faced by those living with epilepsy [6]. Research indicates
income countries, the annual incidence of epilepsy is esti-
that epileptic seizures can be effectively addressed through
mated to be 49 cases per 100,000 individuals. In nations
pharmacological, behavioral, and nutritional interventions
with low and moderate incomes, this percentage can reach [7]. Conventional epilepsy treatment typically involves the
up to 139 per 100,000 [1]. Africa alone has been reported to
administration of Antiepileptic Drugs (AEDs), yet these
account for 25 million cases [2]. Despite this staggering
medications are often linked with various adverse effects. In
data, it is believed that up to 70% of people living with epi- recent years, there has been a growing focus on functional
lepsy can live seizure-free if properly diagnosed and treated
foods and nutraceuticals as potential alternative or adjunc-
[1]. Furthermore, epilepsy contributes significantly to the
tive therapies for epilepsy [8].
global burden of disease, with an estimated 7.8 million disa-
bility-adjusted life years (DALYs) lost annually due to the Functional foods are characterized as food items offering
condition. This burden is particularly pronounced in regions health advantages beyond basic nutrition, whereas nutraceu-
with limited access to medical care, where epilepsy often ticals comprise bioactive compounds derived from foods
goes untreated [3, 4]. with medicinal properties [9, 10]. The therapeutic efficacy
of functional foods and nutraceuticals in managing epilepsy
*Address correspondence to this author at the Department of Biomedical has been extensively investigated in contemporary research.
Technology, School of Basic Medical Sciences, The Federal University of The initial strategy for epilepsy management through func-
Technology, Akure P.M.B. 704, Nigeria and Drosophila Research Lab, tional foods and nutraceuticals encompasses the utilization
Functional Foods and Nutraceuticals Unit, Department of Biochemistry,
The Federal University of Technology, Akure P.M.B. 704, Nigeria;
of immunomodulatory substances. Kim et al. (2022) eluci-
E-mails: [email protected]; [email protected] dated the immunomodulatory impacts of functional foods in

2666-8629/XX $65.00+.00 © XXXX Bentham Science Publishers 1

Current Functional Foods, XXXX, Vol. XX, No. XX eXXXXXXXX Opeyemi B. Ogunsuyi

epilepsy management, highlighting their potential to regu- mechanisms of action in reducing seizure frequency
late the immune system, diminish inflammation, and miti- and improving neurological health are discussed.
gate neuronal harm, consequently lowering the frequency  It also presents underlying mechanisms through
and severity of epileptic seizures. Additionally, Venkata-
which these functional foods exert their anticonvul-
krishnan et al. (2020) noted that antioxidant-rich functional
sant effects, such as modulation of ion channels, an-
foods can mitigate oxidative stress-induced neuronal dam- tioxidant properties, and anti-inflammatory actions.
age and avert seizures in animal epilepsy models. The sec-
ond approach entails employing liposome delivery systems  The review also includes practical recommendations
to augment the bioavailability and effectiveness of nutraceu- for integrating functional foods and nutraceuticals
ticals. Ajeeshkumar et al. (2021) observed that liposomes into current epilepsy management strategies, con-
can shield nutraceuticals from degradation, ensuring target- sidering their safety profiles and potential benefits.
ed delivery to the brain and thereby enhancing their thera-
peutic efficacy in epilepsy management [11-13]. 1.2. Types of Epilepsy
Furthermore, liposomes can enhance the absorption of The categorization of epilepsy is grounded in the classi-
hydrophobic nutraceuticals while minimizing their toxicity. fication established by the International League Against
The third strategy involves leveraging postbiotics and para- Epilepsy (ILAE), which was introduced in 2017 to update
biotics as functional foods for epilepsy management. Nata- and clarify the terminology used to describe seizures and
raj et al. (2020) highlighted that postbiotics and parabiotics, epilepsies [16]. This classification system is predicated on
derived from probiotic bacteria, exhibit similar therapeutic the seizure subtype, the cerebral region where the seizure
effects to probiotics, showcasing antimicrobial, anti- initiates, and any underlying etiologies of the seizures. Pre-
inflammatory, and neuroprotective properties that can miti- dominant categories of epilepsy include focal epilepsy, gen-
gate the frequency and severity of epileptic seizures [14]. eralized epilepsy, and indeterminate (unknown) epilepsy, as
Despite the promising outcomes of employing functional outlined by Sarmast et al. (2020). Previously, seizures were
foods and nutraceuticals in epilepsy management, further classified as "partial" or "generalized." Partial seizures, now
clinical investigations are imperative to validate these find- referred to as "focal seizures," were further divided into
ings. Granato et al. (2020) emphasized the necessity of "simple partial" (where consciousness was preserved) and
evaluating the efficacy and safety of functional foods and "complex partial" (where consciousness was impaired) [17].
nutraceuticals through clinical trials before recommending
their routine use in epilepsy management. Additionally, ex- These terms have been replaced with "focal aware sei-
ploring the interaction between functional foods and An- zures" and "focal impaired awareness seizures," respective-
tiepileptic Drugs (AEDs) is crucial to avoid potential drug ly, to better reflect the patient's level of awareness during
interactions and adverse effects [15]. the seizure. The term "secondarily generalized seizures,"
which described seizures that started as focal but spread to
involve both hemispheres, has been replaced by "focal to
1.1. Highlights bilateral tonic-clonic seizures." This change emphasizes the
This review focuses on the potential role of functional spread of seizure activity from one hemisphere to both sides
foods and nutraceuticals in the management of epilepsy, of the brain [18]. Epilepsy, as shown in Fig. (1), can be clas-
highlighting both preclinical and clinical evidence. sified based on the seizure types and the areas of the brain
involved into four classes: focal epilepsy, generalized epi-
 Bioactive compounds, including omega-3 fatty ac- lepsy, combined generalized & focal epilepsy, and unknown
ids, vitamins, flavonoids, and terpenoids, and their
epilepsy [16].

Fig. (1). Types of epilepsy. (A higher resolution/colour version of this figure is available in the electronic copy of the article).

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1.2.1. Focal Epilepsy Unlike focal epilepsy, where seizures begin in a localized
area of the brain, generalized epilepsy involves widespread
Focal epilepsy, also recognized as partial epilepsy, mani-
neural activity that engages the entire brain (shown in Fig.
fests with seizures originating from a specific brain locus 2). This type of epilepsy typically results in a loss of con-
(shown in Fig. 2). Unlike other epilepsy types, focal epilep-
sciousness and can involve various motor and non-motor
sy originates from a specific area of the brain rather than
symptoms [28]. Generalized epilepsy is often associated
involving the entire brain simultaneously, and the symptoms with genetic factors and can present in different forms, each
of focal seizures can vary widely depending on the location
with distinct clinical features and challenges. The mecha-
of the seizure focus, making them more diverse in presenta-
nism underlying generalized epilepsy involves the synchro-
tion compared to generalized seizures [19]. Symptoms are nous, bilateral activation of neural networks across the brain
highly variable and localized to the affected brain region
[29]. This widespread activation is often due to a disruption
[20]. It stands as the prevailing form, encompassing approx-
in the balance between excitatory and inhibitory signals
imately 60% of cases. Within focal seizures, there exist two within the brain, leading to the simultaneous firing of neu-
subtypes: simple partial seizures, which do not impede con-
rons across both hemispheres. Unlike focal epilepsy, where
sciousness, and complex partial seizures, which may induce
the abnormal activity is localized, generalized epilepsy in-
unconsciousness or altered awareness, as explicated by volves large-scale brain networks, particularly those involv-
Sarmast et al. (2020).
ing the thalamus and cortex [30].
The mechanism underlying focal epilepsy involves ab- The primary neurotransmitter systems implicated in gen-
normal hyperexcitability and hypersynchrony of neurons in a
eralized epilepsy include GABA (gamma-aminobutyric ac-
localized brain region. This hyperexcitability can result from
id), which is the main inhibitory neurotransmitter in the
various factors, including structural abnormalities, genetic brain. In generalized epilepsy, a dysfunction in GABAergic
mutations, or acquired conditions [21]. When these neurons
inhibition can lead to excessive neuronal firing and the
become overly excitable, they start to fire excessively and
propagation of seizure activity throughout the brain. Gluta-
synchronously, leading to the generation of a seizure. The mate, which serves as the primary excitatory neurotransmit-
specific brain region involved in focal epilepsy determines the
ter, excessive glutamate activity can contribute to the hyper-
symptoms that a person will experience during a seizure [22].
excitability seen in generalized seizures [31]. An imbalance
For example, if the seizure originates in the motor cortex, the between glutamate and GABA is often a critical factor in
person may experience jerking movements of the limbs. If it
the development of generalized epilepsy and ion channels
starts in the temporal lobe, symptoms might include auditory
(genetic mutations affecting ion channels, such as sodium,
hallucinations or déjà vu. Focal seizures can remain localized potassium, or calcium channels, can disrupt the normal elec-
or spread to adjacent areas, potentially leading to more com-
trical balance in neurons, leading to widespread synchro-
plex and widespread symptoms [23]. Focal seizures are often
nous firing and the onset of generalized seizures) [32]. Gen-
classified into two subtypes: eralized epilepsy is categorized based on the type of seizures
1.2.1.1. Focal Aware Seizures it produces, which can be broadly divided into motor and
non-motor seizures:
In focal-aware seizures, the person remains fully con-
scious and aware throughout the seizure. They are aware of 1.2.2.1. Generalized Motor Seizures:
their surroundings and can often describe their symptoms
Tonic-clonic seizures, also known as grand mal seizures,
after the event [24]. Symptoms can include sensory experi- are the most recognizable type of generalized seizures. They
ences (like seeing flashes of light or hearing sounds), motor
involve two distinct phases: the tonic phase, characterized
symptoms (like jerking of a limb), or autonomic symptoms
by muscle stiffening, and the clonic phase, characterized by
(like a rising feeling in the stomach). These seizures, previ- rhythmic jerking [33]. The seizure begins with the tonic
ously known as "simple partial seizures," are significant
phase, where the person’s muscles stiffen, often causing
because they provide clues about the specific area of the
them to fall if standing. This is followed by the clonic phase,
brain where the seizure originates [25]. where the muscles jerk rhythmically. The seizure typically
1.2.1.2. Focal Impaired Awareness Seizures lasts 1-3 minutes, and the person may be confused or fa-
tigued after it ends. Tonic-clonic seizures are the most se-
In focal impaired awareness seizures, the person experi- vere form of generalized seizures and can be associated with
ences a loss or alteration of consciousness. They may appear
significant injury risks during the event [34]. Myoclonic
confused, be unresponsive, or engage in repetitive move-
seizures involve sudden, brief jerks of muscles, typically
ments (automatisms) without awareness [26]. Symptoms affecting the arms, legs, or upper body. These seizures are
might include automatisms (e.g., lip-smacking, hand-
usually very short, often lasting only a fraction of a second.
wringing), changes in behavior, or a sense of déjà vu. After
The person may experience sudden, involuntary muscle
the seizure, the person may have no memory of the event. twitches that can occur singly or in clusters. Consciousness
Previously referred to as "complex partial seizures," these
is usually preserved during these events [35].
seizures can have a significant impact on daily life and safe-
ty, as the person may be unaware of their surroundings and Myoclonic seizures are common in specific epilepsy
unable to respond appropriately [27]. syndromes, such as juvenile myoclonic epilepsy, and while
they are brief, they can occur in clusters and impact daily
1.2.2. Generalized Epilepsy activities. Atonic seizures: Also known as "drop attacks,"
Generalized epilepsy encompasses seizures that impact atonic seizures involve a sudden loss of muscle tone, lead-
the entire brain, often leading to loss of consciousness [16]. ing to a collapse or fall. The person may suddenly go limp
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Current Functional Foods, XXXX, Vol. XX, No. XX eXXXXXXXX Opeyemi B. Ogunsuyi

and drop to the ground, which can lead to injuries, particu- with slower, less rhythmic eye blinking or subtle move-
larly to the head. These seizures are brief but can be very ments. The seizure may last longer than a typical absence
disabling due to the risk of falls. Atonic seizures are particu- seizure and can be more challenging to recognize. Atypical
larly challenging because of the injury risk, and they often absence seizures are usually associated with more severe
occur in individuals with severe epilepsy syndromes, such epilepsy syndromes, such as Lennox-Gastaut syndrome, and
as Lennox-Gastaut syndrome [36]. Clonic seizures are char- can be harder to control with medication [42].
acterized by sustained rhythmic jerking of muscles, typical-
Myoclonic absence seizures combine features of both
ly involving both sides of the body. The person experiences
myoclonic and absence seizures, involving brief, rhythmic
repeated, rhythmic muscle contractions, which can last sev- jerks of the muscles along with a lapse in consciousness.
eral seconds to minutes [37].
The person may experience rhythmic jerking of the upper
Consciousness is usually impaired during the seizure. body or limbs, along with a blank stare or loss of awareness
Clonic seizures are less common than tonic-clonic seizures [43]. These seizures are typically brief but can occur in clus-
but still represent a significant challenge in managing gen- ters. Myoclonic absence seizures are relatively rare and may
eralized epilepsy. Tonic seizures involve a sustained in- be difficult to diagnose, as they can resemble other types of
crease in muscle tone, leading to stiffness and rigidity of the seizures. Eyelid myoclonia involves rapid, rhythmic jerking
muscles, particularly in the arms, legs, and back. The per- of the eyelids, often associated with brief lapses in con-
son’s muscles suddenly stiffen, which can cause the body to sciousness. The person’s eyelids may flutter rapidly, often
assume unusual postures or lead to falls if standing [38]. triggered by closing the eyes or exposure to bright light.
These seizures are brief, usually lasting less than 20 sec- There may be an associated brief loss of awareness [44].
onds. Tonic seizures are common in severe epilepsy syn- Eyelid myoclonia is often seen in conditions like Jeavons
dromes, and like atonic seizures, they carry a high risk of syndrome and can be a specific diagnostic clue when evalu-
injury [39]. ating generalized epilepsy [45].
1.2.2.2. Generalized Non-Motor Seizures 1.2.3. Combined Generalized and Focal Epilepsy
Absence seizures, previously known as petit mal sei- Combined generalized and focal epilepsy is a category
zures, are characterized by brief lapses in consciousness, of epilepsy in which an individual experiences both general-
often lasting only a few seconds. The person suddenly stops ized and focal seizures (as shown in Fig. 2). This type of
what they are doing and stares blankly into space. They may epilepsy acknowledges that some patients exhibit seizure
blink their eyes or make small movements, but they are un- types and patterns that do not fit neatly into either purely
responsive during the seizure [40]. Absence seizures often generalized or purely focal categories [46]. Instead, they
go unnoticed because they are so brief and may be mistaken have features of both, reflecting a more complex form of
for daydreaming. Absence seizures are most common in epilepsy that involves both localized and widespread brain
children and are often the primary seizure type in conditions activity. This category is relatively newer in the classifica-
like childhood absence epilepsy. They can occur frequently tion of epilepsy, introduced to better capture the diversity of
throughout the day, interfering with learning and daily activ- seizure presentations that some patients experience. The
ities [41]. Atypical absence seizures are similar to typical underlying mechanisms of combined generalized and focal
absence seizures but have a slower onset and resolution, and epilepsy are complex and not fully understood, largely be-
they are often associated with more pronounced changes in cause they involve both focal and generalized processes
muscle tone. The person may exhibit a blank stare, along within the brain [47].

Fig. (2). Illustration describing the four types of epilepsy. (A higher resolution/colour version of this figure is available in the electronic
copy of the article).

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Table 1. Comparison of the Four Major Epilepsy Categories: Focal, Generalized, Combined Generalized and Focal, and Unknown
Epilepsy.

Combined Generalized
Features Focal Epilepsy Generalized Epilepsy Unknown Epilepsy References
and Focal Epilepsy

Seizures that cannot be

Seizures originate in a spe- Seizures affect both hemi- Involves both focal and
definitively classified as
Definition cific area of one hemisphere spheres of the brain simul- generalized seizures in the [20]
either focal or generalized
of the brain. taneously from the onset. same individual.
due to insufficient data.

It can begin as focal or

Begins with widespread,
Begins in a localized region, generalized, with some Onset is unclear, and the
synchronous neuronal dis-
Onset such as the temporal or seizures potentially spread- type of seizure cannot be [20]
charges across both hemi-
frontal lobe. ing from focal to general- determined.
spheres.
ized.

Generalized motor seizures

Combination of focal and Seizures with motor symp-
- Focal aware seizures - (e.g., tonic-clonic, myo-
Types of generalized seizure types, toms
Focal impaired awareness clonic, atonic) [48, 49]
seizures including focal to bilateral - Seizures without motor
seizures - Generalized non-motor tonic-clonic seizures symptoms
seizures (e.g., absence)

Synchronous bilateral acti- Complex interaction be-

Abnormal hyperexcitability
vation of neural networks, tween focal and generalized
and hypersynchrony in Mechanisms are not well
often linked to genetic mu- seizure mechanisms, possi-
Mechanism localized brain regions, understood due to the un- [50]
tations affecting ion chan- bly involving both localized
often due to structural, clear nature of the seizures
nels and neurotransmitter and widespread brain activi-
genetic, or acquired factors
systems ty

- Structural abnormalities
- Genetic predispositions - Genetic syndromes (e.g.,
(e.g., tumors, cortical dys-
Dravet syndrome) Etiology is often unclear,
plasia) - Metabolic or mitochondri-
Etiology requiring further investiga- [51, 52]
al disorders - Structural lesions
- Genetic mutations tion
- Unknown (idiopathic) - Metabolic conditions
- Brain injuries

1.2.4. Unknown Epilepsy convulsant abilities and can augment the effectiveness of
antiepileptic drugs. For instance, quercetin, a flavonoid
As shown in Fig. 2, unknown epilepsy describes seizures
found in onions and green tea, possesses anticonvulsant
that do not align with focal or generalized distinctions, properties. These compounds share structural similarities
sometimes termed idiopathic epilepsy, typically diagnosed
with benzodiazepines, which are commonly used in epilepsy
during childhood. The etiology of idiopathic epilepsy re-
treatment, and they exert their effects through the regulation
mains obscure but is often attributed to genetic factors, as of the GABAA-Cl-channel complex, a key pathway in con-
posited in a previous study [16]. Table 1 below provides a
trolling neuronal excitability [54, 55].
summary of the comparison between the four major catego-
ries of epilepsy. Similarly, curcumin, a polyphenol found in turmeric
commonly used in Indian cuisine, exhibits anticonvulsant
effects both individually [56] and in combination with
2. FUNCTIONAL FOODS AND NUTRACEUTICALS
treadmill exercise [7, 57]. Mushrooms also harbor bioactive
IN EPILEPSY MANAGEMENT
compounds with anticonvulsant effects, such as polysaccha-
Functional foods refer to whole or fortified foods that rides known for their neuroprotective and antioxidant prop-
offer specific health benefits beyond basic nutritional values erties, mitigating seizure-related oxidative stress [50].
[9]. On the other hand, nutraceuticals are bioactive com- Tanshinone IIA, a hydrophobic ketone extracted from Sal-
pounds sourced from foods or plants, possessing medicinal via miltiorrhiza, has been demonstrated to reduce c-fos ex-
attributes that enhance health outcomes [15]. Research indi- pression in the brains of PTZ-exposed zebrafish larvae,
cates that both functional foods and nutraceuticals exhibit which plays a therapeutic role in epilepsy through the acti-
anticonvulsant properties, making them viable adjunct ther- vation of the GABA signaling pathway [58]. It also acti-
apies in epilepsy management [53]. The therapeutic effects vates potassium channels by increasing presynaptic Ca2+
of functional foods and nutraceuticals stem from their bioac- influx, thereby improving cognitive function in epileptic rats
tive compounds, which encompass polyphenols, flavonoids, [59, 60]. Similarly, compounds like ginsenoside Rg3, a gly-
terpenoids, alkaloids, and others [10]. Certain bioactive coside, inhibit seizure-induced Ca2+ influx and attenuate
compounds found in these foods have demonstrated anti- spontaneous recurrent epileptiform discharges, highlighting
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their role in reducing neuronal death associated with epilep- 3 PUFAs) have been widely studied, with preclinical re-
sy [61]. search suggesting their potential to modulate ion channels
The main isolate of resveratrol, luteolin, has been found and exert antioxidant and anti-inflammatory effects, thus
stabilizing neuronal excitability [71]. Despite promising
to increase the seizure threshold, possibly by enhancing the
results in animal models, clinical outcomes have been in-
activation of GABAA receptors and promoting the opening
of GABA-mediated chloride channels [62, 63]. Terpenoids, consistent. Some randomized controlled trials reported that
fish oil supplementation, rich in n-3 PUFAs, reduced seizure
another class of compounds, exert their effects by modulat-
frequency, and duration [72], while other studies found no
ing ion channels. Triptolide, for example, has neuroprotec-
tive effects in epileptic models by increasing the expression significant effect on seizure control [73, 74]. Vitamin D3
has also shown promise in both preclinical and clinical set-
of Kv1.1 in the hippocampus, while eugenol influences ion-
tings.
ic currents by enhancing the inactivation of voltage-gated
Na+ channels [64, 65]. Alkaloids such as rhynchophylline Preclinical studies have demonstrated that vitamin D3
(RIN) have been reported to decrease neuronal hyperexcita- reduces neuronal calcium overload and oxidative stress,
bility by inhibiting continuous sodium current (INaP) and which are critical in seizure pathophysiology [75]. The cor-
reducing Ca2+ influx in the central nervous system, thereby rection of vitamin D deficiency has been clinically associat-
mitigating seizure severity [66]. Similarly, aconitine acts on ed with a significant reduction in seizure frequency in pa-
sodium ion channels to modulate their voltage sensitivity tients with drug-resistant epilepsy [76]. Vitamin E, known
and reduce hyperpolarization potential, further contributing for its antioxidant properties, has shown neuroprotective
to its anti-epileptic effects [46]. effects in preclinical studies by reducing reactive oxygen
Beyond their effects on ion channels, these compounds species (ROS) accumulation and mitigating excitotoxicity,
which are factors that exacerbate seizures [77]. Clinically,
also exhibit significant anti-inflammatory and neuroprotec-
some studies have reported that chronic vitamin E supple-
tive properties. Carbenoxolone (CBX), a flavonoid, has
shown anti-inflammatory effects by stimulating adrenal mentation reduces seizure frequency, particularly in patients
with refractory epilepsy, while other trials have not ob-
glands or enhancing the effects of endogenous corticoster-
served significant improvements [75]. Preclinical studies
oids, which in turn reduced seizure severity in epileptic
models [67]. Saponins and glycosides, such as saikosaponin underscore its importance in neurotransmitter synthesis,
particularly GABA, and have linked its deficiency to in-
A, play an indirect therapeutic role by inhibiting inflamma-
creased neuronal excitability. Clinically, some studies have
tory factors, leading to a reduction in refractory epilepsy
symptoms [68]. reported significant reductions in seizure frequency with
vitamin B6 supplementation. Two clinical studies examined
Moreover, compounds like β-asarone and morin have the impact of vitamin B6 administration on seizure reduc-
been demonstrated to decrease oxidative stress and reduce tion. The researchers observed that while some patients ex-
the activity of inflammatory cytokines, further highlighting perienced significant clinical improvement with vitamin B6
their neuroprotective potential in epilepsy [69, 70]. Clinical treatment, this effect was not consistent across all patients
and preclinical studies have provided varying levels of evi- [75]. A more detailed outline of functional foods and
dence for the efficacy of functional foods and nutrients in nutraceuticals with neuroprotective properties is presented
managing epilepsy. Omega-3 polyunsaturated fatty acids (n- in Tables 2 and 3.

Table 2. Functional foods with neuroprotective properties.

Functional Foods Examples Functions Citation

It has anti-inflammatory properties,

which might be beneficial in managing
Turmeric Curcumin [7]
chronic inflammation associated with
some types of epilepsy.

Induces a diverse array of cellular and

pharmacological effects, including CNS
Coffee, cocoa, tea, cola drinks, and
Caffeine, caffeic acid stimulation, potential cognitive en- [78]
chocolate
hancement properties, and antioxidant
activity.

Enhances cognitive function and dimin-

Ginkgo biloba [79]
ishes seizure frequency.

Exhibits sedative and anticonvulsant

Withaniasomnifera [79]
properties. Reduces seizure severity.

Antiepileptic effects owing to its antiox-

Bacopa monnieri [79]
idative and anti-inflammatory attributes.

(Table 2) contd....

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Functional Foods Examples Functions Citation

Displays antiepileptic effects due to its

Onions Quercetin [80]
antioxidant properties.

Treatment of Parkinson’s disease,

African eggplant (AE) memory impairment, angina, cancerous [81]
tumor, and inflammation.

It can be used in the treatment of Par-

Black nightshade (BN) [81]
kinson’s

It may protect brain cells from oxidative

Berries Antioxidants [82]
stress.

Provide steady energy supply to the

Complex carbohydrates, B-
Whole Grains brain, supporting overall neurological [83]
vitamins
health.

Support nerve function and brain health.

Healthy fats, Magnesium, B-
Avocados (Lauraceae) Healthy fats contribute to overall cell [84]
vitamins
integrity.

Folate can support overall brain func-

Spinach and Greens Folate, Magnesium tion, while magnesium might help con- [85]
trol the spread of seizure activity.

Supportive in reducing inflammation

Nuts and Seeds (flaxseed, walnuts) Omega-3 fatty acids, Magnesium [75]
and potentially

Fatty Fish (cod, swordfish, salmon, Omega-3 fatty acids (EPA and Decreases neuronal excitability and
[75]
tuna, and sardines etc) DHA) inflammation.

Anticonvulsive effect
Omega -3- fatty acid (Omega-3
Marine fish (salmon, tuna, and macke- It modulates neuronal membranes and
polyunsaturated fatty acids (n-3 [75]
rel etc.) mitigates inflammation.
PUFAs)
Reduces seizures after intervention.

Flavonoids have neuroprotective ef-

Dark Chocolate Flavonoids, Magnesium fects, and magnesium is important for [86]
preventing excessive neuronal firing.

Calcium plays a role in neurotransmis-

Yogurt Calcium, Probiotics sion. Probiotics may influence the gut- [75]
brain axis, affecting brain health.

Table 3. Nutraceuticals with neuroprotective properties.

Nutraceuticals Sources Potential Benefits of Epilepsy Citation

It may reduce seizure susceptibility.

Magnesium Oily fish, flax seeds [75]
It may decrease seizure susceptibility.

Nuts, seeds, green leafy vege- Antioxidant properties, potential to reduce seizure frequency.
Vitamin E [87]
tables Antioxidant protects cells from oxidative stress.

It may reduce seizure frequency; anti-inflammatory effects.

Omega-3 Fatty Acids Fish oil, flax seeds [75]
Modulation of neurotransmitter systems.

Vitamin B6 Bananas, potatoes, turkey Important for brain health and function; deficiency linked with seizures. [88]

Supports brain function and may reduce homocysteine levels linked with epilepsy.
Folic Acid Leafy greens, fortified foods [89]
Involved in the production of DNA and healthy cell function.

(Table 3) contd....

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Nutraceuticals Sources Potential Benefits of Epilepsy Citation

Cannabidiol (CBD) Hemp, CBD oil It has been shown to reduce seizure frequency in some types of epilepsy. [90]

Synthesized naturally; availa- It may improve sleep quality and reduce nighttime seizures.
Melatonin [91]
ble as a supplement Regulates sleep-wake cycles and antioxidant properties.

Curcumin Turmeric Anti-inflammatory, antioxidant, and potentially anticonvulsant effects. [7]

Supports neurotransmitter function and brain health.

Zinc Meat, shellfish, legumes [92]
Modulates neurotransmitter action.

Fig. (3). The mechanism of action of functional foods in the management of epilepsy. (A higher resolution/colour version of this figure is
available in the electronic copy of the article).
3. POTENTIAL MECHANISMS OF ACTION OF cals in improving DNA methylation and reducing inflamma-
FUNCTIONAL FOODS AND NUTRACEUTICALS tion in chronic diseases. Despite these potential therapeutic
benefits, further investigations are necessary to determine
There has been an increasing focus on utilizing function- the efficacy and optimal dosages of functional foods and
al foods and nutraceuticals as adjunctive treatments for
nutraceuticals in epilepsy management. Nonetheless, given
managing epilepsy. These substances contain bioactive con-
their potential advantages, these substances could serve as
stituents capable of altering both physiological and patho- complementary therapies alongside conventional medica-
logical brain functions, as shown in Fig. (3). Numerous
tions, enhancing the quality of life for individuals with epi-
studies have elucidated potential mechanisms by which
lepsy [93].
functional foods and nutraceuticals contribute to epilepsy
management. Emerging evidence suggests that addressing inflamma-
tion is pivotal in managing epilepsy. Functional foods and
nutraceuticals are recognized for their anti-inflammatory
3.1. Anti-inflammatory Properties
properties, potentially offering therapeutic benefits for epi-
Furthermore, functional foods and nutraceuticals exhibit lepsy. Research indicates that omega-3 fatty acids, abundant
potential anti-inflammatory properties, which are beneficial in fish oil, exhibit anti-inflammatory effects that are benefi-
in epilepsy management. Inflammation often exacerbates cial for epilepsy management, as demonstratedin Figs. 3 and
seizure severity and frequency, as demonstrated in Fig. (4). 4) [75]. Similarly, curcumin, a polyphenol from turmeric,
Research by Wal et al. (2024) demonstrated the anti- demonstrates anti-inflammatory properties, holding promise
inflammatory effects of probiotic-containing nutraceuticals for epilepsy management. Beyond omega-3 fatty acids and
in alleviating irritable bowel syndrome symptoms. Addi- curcumin, various other functional foods and nutraceuticals
tionally, she emphasized the role of vitamins as nutraceuti- exhibit anti-inflammatory effects, presenting potential ave-

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A Review on Functional Foods eXXXXXXXX Current Functional Foods, XXXX, Vol. XX, No. XX

nues for epilepsy management. For instance, quercetin, a compounds present in specific foods, offer health benefits
flavonol found in fruits and vegetables, displays anti- beyond basic nutrition. Among these, antioxidants like vit-
inflammatory properties relevant to epilepsy management amins E and C, flavonoids, and carotenoids play a crucial
[94]. Additionally, resveratrol, a polyphenol in grapes, has role in neutralizing free radicals and safeguarding brain cells
anti-inflammatory potential and is beneficial for epilepsy (Fig. 4) from oxidative damage [96]. Research has delved
[95]. It is crucial to note that while these anti-inflammatory into the efficacy of antioxidants in epilepsy management.
effects of functional foods and nutraceuticals hold promise Aqil and Batra, in 2020, highlighted their potential in cos-
for epilepsy management, further research is imperative for meceuticals and cosme-nutraceuticals, showcasing anti-
a comprehensive understanding of their therapeutic benefits. inflammatory and antioxidant properties that alleviate skin
inflammation and oxidative stress [97]. A study by Seo et
3.2. Antioxidant Effects al. in2012 demonstrated the positive impact of alpha-lipoic
acid, a potent antioxidant, in enhancing serum lipid profiles
The antioxidant effects of nutraceuticals have garnered and curbing weight gain in rat models, suggesting a poten-
attention in the context of epilepsy pathogenesis and man- tial benefit in epilepsy symptom management [98].
agement. Nutraceuticals, defined as natural or bioactive

Fig. (4). Key outcomes of the effects of functional foods in epilepsy management. (A higher resolution/colour version of this figure is avail-
able in the electronic copy of the article).

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Current Functional Foods, XXXX, Vol. XX, No. XX eXXXXXXXX Opeyemi B. Ogunsuyi

Moreover, compounds like glucosinolates found in foods and nutraceuticals to modulate neurotransmitters
oilseed Brassica exhibit antioxidant capabilities, as evi- (demonstrated in Fig. 4) like Gamma-Aminobutyric Acid
denced by Shaheen and Alsenosy in 2019, who observed (GABA) and glutamate, which are pivotal in epilepsy's
reduced oxidative stress and inflammation in animal models pathophysiology. GABA serves as the principal inhibitory
[99]. Isoflavones, a type of flavonoid present in soy prod- neurotransmitter in the brain, and its insufficiency or dys-
ucts, have also demonstrated antioxidant and anti- function correlates with epileptic seizures.
inflammatory effects, as reported by Muscolo et al. in 2024,
Noteworthy research indicates that certain functional
who noted their role in enhancing immunity and growth in
foods and nutraceuticals, such as omega-3 fatty acids, fla-
Nile tilapia. While these studies underscore the potential of vonoids, and magnesium, can augment GABAergic neuro-
antioxidants in epilepsy management, further investigations
transmission, consequently mitigating seizure activity. For
are warranted to validate their safety and efficacy [100].
instance, Nasopoulou et al. (2014) highlighted the anti-
(Bega and Malkani, 2016) highlighted the promising out- inflammatory attributes of olive oil, which is rich in poly-
comes of multidisciplinary approaches involving nutraceuti-
phenols and flavonoids and modulates GABAergic neuro-
cals, lifestyle modifications, and mind-body interventions in
transmission, thus manifesting antiepileptic effects. Similar-
managing neurological disorders akin to epilepsy, emphasiz- ly, it showcased the capacity of neoagarooligosaccharides, a
ing the need for comprehensive strategies for effective epi-
novel bio-functional compound from seaweed, to enhance
lepsy management [101].
GABAergic neurotransmission and diminish seizure suscep-
Compounds like isoflavones and alpha-lipoic acid, with tibility [105]. On the other hand, glutamate serves as the
their antioxidant properties, hold promise in mitigating oxi- primary excitatory neurotransmitter in the brain, and its ex-
dative stress and inflammation in epilepsy. However, ongo- cessive release is implicated in seizures and neuronal harm.
ing research is essential to ascertain their safety and effec- Several functional foods and nutraceuticals, such as curcu-
tiveness, advocating for a holistic treatment approach en- min, resveratrol, and caffeine, have demonstrated the ability
compassing nutraceuticals, lifestyle adjustments, and com- to modulate glutamatergic neurotransmission, thereby ex-
plementary interventions for optimal epilepsy management. hibiting antiepileptic effects. The seizure-reducing potential
of ketogenic diets (shown in Fig. 4) is also noted, character-
3.3. Food-Drug Interaction ized by high fat and low carbohydrate content, which is at-
tributed to their ability to curtail glutamate release while
Combining nutraceuticals with conventional antiepilep- augmenting GABAergic neurotransmission. Furthermore,
tic drugs shows synergistic benefits in epilepsy manage- Wanjari and Desai (2015) highlighted the antiepileptic
ment. George et al. (2015) found that immune boosters and prowess of herbal and neutraceutical products containing cur-
nutraceuticals, alongside antiepileptic drugs, decrease sei- cumin and resveratrol due to their modulation of glutama-
zure frequency and enhance patients' quality of life [102]. tergic neurotransmission [106]. Recent studies substantiate
Gharibnaseri et al. (2012) supported this, emphasizing the that compounds such as omega-3 fatty acids, flavonoids,
cost-effectiveness of combining nutraceuticals with antiepi- olive oil, neoagarooligosaccharides, curcumin, resveratrol,
leptic medications. Therefore, supplementing antiepileptic and caffeine can confer antiepileptic effects by modulating
drugs with nutraceuticals offers a viable therapeutic ap- neurotransmitter activity. Nonetheless, further investigations
proach for epilepsy. Nanotechnology presents novel drug are imperative to delineate the mechanisms of action and
delivery avenues for epilepsy management [103]. safety profiles of these compounds in epilepsy management.
Movahedpour et al. (2023) highlighted nanotechnology's The development of novel immune-modulating bio-
success in epilepsy treatment, as demonstrated in Fig. 4. functional compounds sourced from natural reservoirs holds
Nanocarriers for neutraceutical delivery offer targeted and promise in offering new therapeutic avenues for epilepsy
controlled release, improving therapeutic outcomes. This management [107]. Hence, the integration of functional
innovative approach, alongside the neuroprotective and anti- foods and nutraceuticals as adjunctive therapy in epilepsy
inflammatory effects of compounds, provides a potential management warrants consideration, necessitating a meticu-
therapeutic strategy for epilepsy [104]. Future research lous evaluation of their potential benefits and risks.
should prioritize developing advanced delivery methods and
assessing long-term safety and efficacy.
4. CLINICAL STUDIES ON FUNCTIONAL FOODS
AND NUTRACEUTICALS IN EPILEPSY
3.4. Modulation of Neurotransmitters in Epilepsy Man- MANAGEMENT
agement
Functional foods and nutraceuticals have gained increas-
Epilepsy stands as a chronic neurological condition dis- ing attention in recent years due to their potential beneficial
tinguished by recurrent seizures stemming from aberrant effects on various health conditions. The role of functional
electrical brain activity. The primary approach to epilepsy foods and nutraceuticals in the management of epilepsy has
management revolves around Antiepileptic Drugs (AEDs), been investigated, and several studies have reported promis-
targeting the reduction and control of seizure frequency and ing results. Microorganisms in fermented foods have been
intensity. However, the undesirable side effects associated shown to possess functional properties that can positively
with AEDs and the emergence of drug resistance have impact human health, including antiepileptic effects [108].
prompted exploration into alternative therapies, notably Additionally, the development of functional foods has been
functional foods and nutraceuticals. Numerous investiga- investigated as a potential management strategy for epilepsy
tions have underscored the capacity of specific functional [109]. Consumers' awareness, acceptance, and attitudes to-

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A Review on Functional Foods eXXXXXXXX Current Functional Foods, XXXX, Vol. XX, No. XX

wards functional foods have also been studied in various Kim and Cho (2019b) reported that the interaction between
populations, including Turkey. A study conducted in Turkey functional foods and medications used to manage epilepsy
reported that the majority of participants had a positive atti- needs to be evaluated to ensure safety [75]. Therefore, indi-
tude towards functional foods and considered them to be viduals with epilepsy who are considering using functional
beneficial for health [110]. Similarly, a systematic review of foods and nutraceuticals as complementary therapy need to
functional food consumption in Europe reported a high consult with their healthcare provider before starting any
prevalence of consumption, particularly among individuals treatment. Several studies have reported the potential side
with specific health conditions [111]. effects of functional foods and nutraceuticals, including
These findings suggest that there is potential for func- gastrointestinal symptoms, allergic reactions, and drug in-
teractions. A previous study [117] reported that the use of
tional foods and nutraceuticals to be utilized in the man-
medicinal foods should be based on the principles of medi-
agement of epilepsy, given their perceived benefits by con-
sumers. Despite the potential benefits of functional foods cine food homology to ensure safety and efficacy. There-
fore, the use of functional foods and nutraceuticals should
and nutraceuticals in the management of epilepsy, variations
be based on evidence-based recommendations and should be
in their consumption have been reported. A study conducted
in Croatia reported that education and income were signifi- monitored for potential side effects.
cant predictors of functional food consumption, with higher-
educated individuals and those with higher incomes more 6. LIMITATIONS OF FUNCTIONAL FOODS AND
likely to consume functional foods [112]. These findings NUTRACEUTICALS
suggest that access to functional foods and nutraceuticals
Although the utilization of functional foods and
may be limited among certain populations, which can im- nutraceuticals in epilepsy management is a burgeoning area,
pact their potential use in the management of health condi-
more research is necessary to comprehend their full poten-
tions such as epilepsy.
tial. Galvan et al. (2021) emphasized the importance of de-
Finally, the role of diet and nutrition in general has been veloping palatable functional beverages with health benefits
investigated in relation to epilepsy management. A study to encourage epilepsy patients to incorporate these foods
conducted in older adults reported that a high-protein diet, into their diets [118]. Similarly, Tselaesele et al. (2023)
coupled with physical activity, protected against age-related stressed the need for comprehensive research on functional
muscle loss and functional decline associated with epilepsy foods and nutraceuticals to establish their safety, effective-
[113]. Additionally, strategies for promoting sleep, such as ness, and optimal dosages for epilepsy management [119].
the consumption of functional foods, have been investigated Also, consumer perception, influenced by food neophobia
as a potential management strategy for epilepsy [114]. and trust issues, also hinders product acceptance [120].
These findings highlight the potential benefits of functional
foods and nutraceuticals in the management of epilepsy and 7. CONCLUSION AND FUTURE PERSPECTIVES
suggest that further research is warranted to explore their
effectiveness and potential limitations.
7.1. Conclusion
5. SAFETY ASPECTS OF FUNCTIONAL FOODS Epilepsy, characterized by recurrent seizures, has
AND NUTRACEUTICALS IN THE MANAGEMENT prompted investigations into functional foods and nutraceu-
OF EPILEPSY ticals as complementary therapies. Their potential to de-
crease seizure frequency and enhance quality of life has
Functional foods and nutraceuticals have gained popu-
been noted. Chlorophytum borivilianum, for instance,
larity in recent years as a complementary therapy for epilep-
demonstrated anticonvulsant properties in animal trials [121,
sy, but the safety and potential side effects of these products 122], notably increasing seizure threshold without sedative
need to be evaluated. Several studies have reported the safe-
or muscle-relaxing effects, indicating a distinct mechanism
ty profile of functional foods and nutraceuticals in the man-
from traditional antiepileptic drugs. Phytosomes, a novel
agement of epilepsy. A review of prebiotics as functional delivery system enhancing bioavailability, is a noteworthy
foods by Al-Sheraji et al. (2013) reported the safety profile
consideration [123]. By improving absorption and targeting
of prebiotics in individuals with epilepsy. Prebiotics are
of active compounds, phytosomes could bolster the efficacy
non-digestible carbohydrates that selectively stimulate the of functional foods and nutraceuticals, especially those with
growth of beneficial bacteria in the gut. The authors found
limited oral bioavailability, like fatty acids from aquatic
that prebiotics were well tolerated in individuals with epi-
weeds, known for modulating neuronal activity [122]. While
lepsy, and they did not cause any adverse effects [115]. natural compounds' antimicrobial efficacy is well-studied,
Similarly, fermented milk and milk products have been re-
their potential as antiepileptic agents remains underexplored
ported to have anti-epileptic effects, but the safety of these
[124]. Compounds like pomegranate extract, green tea, and
products needs to be evaluated. Shiby and Mishra. (2013) cinnamon, exhibiting strong antimicrobial activity, may
reported that fermented milk and milk products were safe
offer neuroprotective and anti-inflammatory benefits, war-
for consumption in individuals with epilepsy [116].
ranting further investigation for epilepsy management. Die-
Functional foods and nutraceuticals are derived from tary interventions, examined as non-pharmacological ave-
natural sources and are generally considered safe. However, nues for epilepsy, echo findings from ADHD studies [125],
some of these products may interact with medications used showcasing symptom alleviation and improved quality of
to manage epilepsy, leading to potential adverse effects. life. However, understanding their mechanisms and efficacy

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Current Functional Foods, XXXX, Vol. XX, No. XX eXXXXXXXX Opeyemi B. Ogunsuyi

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CONFLICT OF INTEREST http://dx.doi.org/10.1111/1541-4337.12725 PMID: 33665991
[14] Nataraj BH, Ali SA, Behare PV, Yadav H. Postbiotics-parabiotics:
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otherwise.
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Declared None. 2020; 11(1): 93-118. a
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PMID: 31905019
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