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1496 Current Neuropharmacology, 2021, 19, 1496-1518
SYSTEMATIC REVIEW ARTICLE
1570-159X/21 $65.00+.00 ©2021 Bentham Science Publishers
Mechanism of Curcuma longa and Its Neuroactive Components for the
Management of Epileptic Seizures: A Systematic Review
Brandon Kar Meng Choo1 and Mohd. Farooq Shaikh1,2,*
1Neuropharmacology Research Laboratory, Jeffrey Cheah S chool of Medicine and Health Sciences, Monash University
Malaysia, Selangor, Malaysia; 2The Monash Tropical Medicine and Biology Multidisciplinary Research Platform
(TMB), Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia
Abstract: Curcuma longa (Turmeric) is a tropical herbaceous perennial plant of the family Zingib-
eraceae and contains curcuminoids, sesquiterpenoids and monoterpenoids as its major components.
Given the broad range of activities that Curcuma longa possesses and also its use as a traditional
epilepsy remedy, this review attempts to systematically review the experimentally proven activities
of Curcuma longa and its bioactive components, which are related to the management of epileptic
seizures. Using the PRISMA model, five databases (Google Scholar, PubMed, ScienceDirect,
SCOPUS and SpringerLink) were searched using the keywords [“Curcuma longa” AND
“Epilepsy”] and [“Curcuma longa” AND “Seizures”], leaving 34 articles that met the inclusion
criteria. The present systematic review elaborated on the experimentally proven potential of Cur-
cuma longa components, such as an aqueous extract of Curcuma longa itself, Curcuma longa oil
and active con stituents lik e curcuminoids and bisabolene sesquiterpenoids found in Curcuma longa
with anti-seizure potential. Using human equivalent dose calculations, human treatment parameters
were suggested for each component by analysing the various studies in this review. This review
also determined that the principal components possibly exert their anti-seizure effect via the
reduction of corticosterone, modulation of neurotransmitters signalling, modulation of sodium ion
channels, reduction of oxidative DNA damage, reduction of lipid peroxidation, upgregulation of
brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA) mediated inhibition. It
is anticipated that this review will help pave th e way for future research into the development of
Curcuma longa and its neuroactive constituents as potential drug candidates for the management of
epilepsy.
Keywords: Turmeric, Curcuma longa, Epilepsy, Seizures, Curcumin, α-tumerone, β-turmerone, ar-turmerone, α-atlantone.
1. INTRODUCTION
The human Central Nervous System (CNS) is critical to
our body’s functions but is continuously assaulted by a host
of different CNS disorders. An example of such a condition
is epileptic seizures, typically termed as a short-lived occur-
rence of signs and/or symptoms due to aberrant, excessive or
synchronous brain neuronal activity [1]. In comparison, epi-
lepsy occurs when there is a high recurrence risk of another
seizure after an unprovoked seizure; when two unprovoked
seizures occur over 24 hours apart, the diagnosis of an
epilepsy syndrome is made [2]. While epilepsy itself is
currently incurable, anti-seizure medications (ASMs) can be
used for symptomatic treatment by providing seizure control
through methods such as blockading of sodium ion channels,
activating of specific receptors or modulating the release of
*Address correspondence to this author at the Neuropharmacology Research
Laboratory, Jeffrey Cheah School of Medicine and Health Sciences,
Monash University Malaysia, 47500, Bandar Sunway, Selangor, Malaysia;
Tel: +603 5514 4483; E-mail: farooq.shaikh@monash.edu
neurotransmitters [3]. Despite close to 30 ASMs have been
discovered, the seizures in around 30% of epileptic patients
cannot be satisfactorily controlled [4]. This drug resistance
issue has spurred a search for alternative ASMs, and one
possible search area could be plants.
Turmeric is the common name of Curcuma longa and
is a tropical herbaceous perennial plant that belongs to the
family Zingiberaceae and is native to South Asia [5]. The
plant is widely cultivated in the region. The plant's rhizome
functions as both a traditional food ingredient and a
traditional remedy for ailments, such as biliary and hepatic
disorders, abdominal pains [6] and even epilepsy [7]. The
use of Curcuma Longa has also spread to the field of manu-
facturing, and it is used in perfumes, as a flavour additive for
curries and mustards and a natural colouring agent due to the
vibrant yellow powder obtained from crushing the rhizomes
of the plant [8]. Given Curcuma Longa's popularity, it is
hardly surprising that a substantial number of scientific stud-
ies have been conducted to determine its biological activi-
ties, which include anti-fungal [9], anti-cancer [10], anti-
A R T I C L E H I S T O R Y
Received: August 07, 2020
Revised: April 21, 2021
Accepted: May 05, 2021
DOI:
10.2174/1570159X19666210517120413
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1497
bacterial [11] and others, as well as therapeutic activities,
such as wound healing and anti-lithogenic among many
others [12].
The idea of plant-derived ASMs is not entirely novel as
cannabidiol (CBD)-enriched cannabis oil from the infamous
Cannabis sativa plant has been found to work well to treat
refractory epilepsy [13]. The ASM losigamone derived from
the kava-kava plant can also reduce seizure frequency [14].
Thus, given the broad range of activities that Curcuma
Longa possesses and its use as a traditional epilepsy remedy,
this review attempts to systematically review the experimen-
tally proven activities of Curcuma longa and its bioactive
components and the management of epileptic seizures to
determine the possible mechanisms of action.
2. METHODS
2.1. Search Method
Five databases (Google Scholar, PubMed, ScienceDirect,
SCOPUS and SpringerLink) were searched using the key-
words [“Curcuma longa” AND “Epilepsy”] and [“Curcuma
longa” AND “Seizures”]. The results were limited to articles
published between January 2010 and April 2020 to allow for
more recent articles while limiting the likelihood of inadver-
tently excluding older articles.
2.2. Study Selection and Inclusion Criteria
This systematic review has only considered original re-
search articles' content as other publication types might not
provide sufficient information for evaluation and comparison
between the articles. Duplicated results were also removed as
well as those irrelevant to Curcuma Longa or the field of
neuroscience. The selection process was conducted accord-
ing to the guidelines underlined by the PRISMA protocol
[15]. The quality of the included articles was assessed using
the Risk of Bias (RoB) tool developed by the SYstematic
Review Center for Laboratory an imal Experimentation
(SYRCLE) [16]. Articles with both positive and negative
outcomes were considered to reduce the possibility of publi-
cation bias.
3. RESULTS
Using the chosen keywords to search the aforementioned
databases resulted in a total of 2770 results. Of the 2770 re-
sults, 2000 were from Google Scholar (out of 3710 results as
Google Scholar only allows the retrieval of the first 1000 results
for each search), 8 from PubMed, 491 from ScienceDirect,
44 from SCOPUS and 227 from SpringerLink. After apply-
ing the exclusion criteria, 2727 results were removed, which
included 631 duplicates and 2096 results not related to the
scope of the review (Fig. 1). The remaining 43 results
Fig. (1). Flow chart of the article selection and exclusion criteria based on the Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) guidelines. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
1498 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
Table 1. A summarized table of studies focused on active constituents of turmeric in experimental epilepsy models.
Principal Component
Treatment Regimen
Seizure Model
Major Relevant Outcome/s
Refs.
Curcumin (20 mg/kg)
Intraperitoneal
14 days daily pre-
treatment
30 minutes pre-
treatment
Wistar Rats
PTZ
(60 mg/kg, ip)
• Curcumin pre-treatment for 14 days alleviated PTZ-induced seizure
activity, increased myoclonic jerk latency as well as decreased the
duration and severity of generalized tonic-clonic seizures under
stressful conditions.
• Curcumin pre-treatment for 30 minutes before PTZ administration
did not affect the seizures under stressful conditions.
[19]
Curcumin (50, 100, 200
mg/kg)
Oral, three days daily
pre-treatment
Sprague-Dawley
Rats
Lithium
(3 mEq/ml/kg, ip)
+ Pilocarpine (20
mg/ml/kg, sc)
• Curcumin dose-dependently increased seizure and status epilepticus
latency, decreased the percentage of seizures and status epilepticus
in a dose-dependent manner as well as reduced the intensity and
frequency of seizures and their resulting behavioral changes.
• Curcumin significantly ameliorated status epilepticus induced cog-
nitive dysfunction and oxidative damage in the hippocampus and
striatum areas of the brain.
[20]
Curcumin
Molecular docking
against human 4-
aminobutyrate-
aminotransferase
-
• Curcumin binds to 4-aminobutyrate-aminotransferase with Leu299,
Leu301, Ala135, Gln267, Arg164 and Tyr161 being the contact
points.
[21]
Curcumin (100 mg/kg)
Intraperitoneal, seven
days daily pre-
treatment
Wistar Rats
Kainic Acid (10
mg/kg, ip)
• Curcumin upregulated genes related to anti-inflammatory cytokines
(Il10rb, Cxcl16, and Cxcl17) to modulate the epilepto genic p rocess
and protected against hippocampal cell loss by upregulating nicas-
trin.
• It likely also exerted neuroprotective effects by upregulating Cx3cl1
and Cxcl16.
[22]
Curcuma longa aque-
ous extract (50, 100,
200 mg/kg)
Oral, 21 days daily
pre-treatment
Albino Mice
PTZ (80 mg/kg ,
ip)
MES (150 mA
for 0.2 seconds)
• A 100 and 200 mg/kg dose of the extract delayed the onset of PTZ
induced convulsions.
• Only 200 mg/kg decreased the duration of MES induced convul-
sions.
• No extract dose completely prevented the occurrence of convulsions.
[23]
Curcumin (20 mg/kg)
Intraperitoneal
14 days daily pre-
treatment
30 minutes pre-
treatment
Wistar Rats
PTZ
(60 mg/kg, ip)
• The latency to the onset of myoclonic jerks and the latency to stage
3 seizures were increased by the 14-day pre-treatment.
• The rate of myoclonic seizure occurrence and the seizure severity
score were both reduced by the 14-day curcumin pre-treatment in
both stress and non-stress conditions.
• The 14-day curcumin pre-treatment also improved learning ability.
• The 30 minutes pre-treatment dose had no significant effect.
[24]
Curcumin (50, 100
mg/kg)
Oral, 14 days daily
pre-treatment
Swiss Albino
Mice
PTZ (95 mg/kg ,
ip)
MES (36 mA for
0.2 seconds)
• Neither dose had a significant effect on MES induced tonic exten-
sion, but the 100 mg/kg dose significantly reduced the clonic phase.
• The 100 mg/kg dose inhibited PTZ induced seizures.
• Curcumin pre-treatment had no effect on memory retention.
[25]
Curcumin (80 mg/kg)
Oral, 21 days daily
pre-treatment
Wistar Albino
Rats
Pilocarp ine (380
mg/kg, ip)
• Curcumin pre-treatment ameliorated the pilocarpine-induced in-
crease in nitric oxide levels, decrease in glutathione levels, decrease
in catalase activity, and decrease in Na+, K+-ATPase activity.
• Curcumin had no effect on acetylcholinesterase levels.
• Curcumin worsened the pilocarpine-induced decline in catalase.
[26]
(Table 1) contd….
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1499
Principal Component
Treatment Regimen
Seizure Model
Major Relevant Outcome/s
Refs.
Liposomal Curcumin
(25, 50 mg/kg)
Oral for PTZ induced
seizures and ICES,
treatment duration
and the number of
doses were not given
Intravenous for PTZ
induced status epi-
lepticus, and treat-
ment duration were
not given
Swiss Albino Inbred
Mice
ICES
(starting current of
2 mA for
0.2 seconds with a
linear increase of
2mA/2 seconds
PTZ (60 mg/kg , ip)
PTZ Induced Status
Epilepticus
(80 mg/kg, sc)
• Liposomal curcumin dose-dependently increased the seizure
threshold current in the ICES model.
• Liposomal curcumin at both doses increased the latency to PTZ
induced myoclonic jerks and generalised seizures.
• Liposomal curcumin dose-dependently increased the latency and
decreased the duration of clonic seizures in PTZ induced status
epilepticus.
[27]
Curcumin
(50, 100, 200 mg/kg)
Oral, one-hour pre-
treatment, daily for
seven days up to 35
days
Swiss Albino
Inbred Mice
PTZ kindling
(25 mg/kg, ip),
every alternate day,
one hour after daily
curcumin pre-
treatment
• Curcumin administration dose-dependently decreased the seizure
score from PTZ kindling from seven days onwards.
• Curcumin dose-dependently decreased whole brain malondialde-
hyde levels.
• All doses of curcumin increased whole brain glutathione levels.
[28]
Curcumin
(50, 100, 200 mg/kg)
Curcumin (50 mg/kg) +
Diazepam (5 µg)
Intraperitoneal,
10 minutes
after penicillin ad-
ministration
Wistar Rats
Penicillin
(200 IU, 1 µl, ic)
• Curcumin at doses of 100 and 200 mg/kg significantly reduced
the frequency and amplitude of spike waves.
• Co-administration of sub-therapeutic dose of curcumin with
diazepam enhanced the anti-epileptic effect of diazepam.
[29]
Curcumin
(20, 40, 80, 120 mg/kg)
Oral, multiple
15-minute treatment
timepoints up to
60 minutes
Albino Mice
(Laka Strain)
PTZ
(0.5%, iv infusion)
• Curcumin had a maximal anti-convulsive effect 45 minutes after
administration.
• The optimal curcumin dose was 80 mg/kg, with neither higher
nor lower doses having a significant effect on the convulsive
phases.
• The PTZ dose threshold required for the onset of the tonic exten-
sion was increased by PTZ.
• Using a combination of A1 and A2 adenosine receptor agonists
and antagonists, curcumin was found to exert its effect via a di-
rect or indirect activation of the adenosine A1 receptor but not
A2.
• Piperine coadministration (to inhibit curcumin metabolism) did
not change the curcumin bell-shaped dose-response curve seen
against the PTZ induced tonic extensor phase.
[30]
Curcumin C3 Complex
(mixture of curcumin,
demethoxycurcumin
and
bisdemethoxycurcu-
min) Nanoparticles (1,
5, 10, 20, 40, 80 mg/kg)
Curcumin
(40, 80 mg/kg)
Nanoparticles -
Intraperitoneal,
multiple timepoints
up to 120 minutes
Curcumin -
intraperitoneal,
75 minutes pre-
treatment
NMRI Albino Mice
PTZ
(0.5%, iv infusion)
• Curcumin C3 Complex Nanoparticles had significant anti-
convulsant properties in a dose-dependent manner at 2 0, 40 and
80 mg/kg.
• The nanoparticles had a significant anticonvulsive effect at 45,
60 and 120 minutes after administration.
• The nitric oxide donor dose--dependently reversed the anti-
convulsant effect of the nanoparticles.
• Both the non-selective nitric oxide synthase inhibitor and the
selective inducible nitric oxide synthase inhibitor increased the
seizure thresholds and potentiated a sub-effective dose of the
nanoparticles in a synergistic manner.
• Neither dose of curcumin had any effect on seizure thresholds.
[31]
(Table 1) contd….
1500 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
Principal Component
Treatment Regimen
Seizure Model
Major Relevant Outcome/s
Refs.
Curcumin (150 mg/kg)
Intraperitoneal, 25
minutes pre-
treatment
Mice
PTZ (80 mg/kg , ip)
• Curcumin increased the seizure and tonic-clonic stage latency as
well as reduced the duration of tonic-clonic seizures.
• When brain serotonin levels were depleted, the anti-convulsant
effect of curcumin was partially reversed.
• Antagonising the serotonin 5-HT1A, 5-HT2C or 5-HT4 receptors
individually diminished the anti-convulsant effect of curcumin
but antagonising 5-HT7 potentiated it.
• Antagonising 5-HT1A, 5-HT2C,5-HT4 and 5-HT7 together pre-
vented the anticonvulsant effect of curcumin.
• In hippocampal tissue, only 5-HT7 gene expression was reduced
after administration of curcumin.
[32]
Curcumin (50, 100, 200
mg/kg)
Intraperitoneal, 20
minutes pre-
treatment, daily for
24 days
Wistar Rats
PTZ (35 mg/kg , ip),
every alternate day,
20 minutes after daily
curcumin treatment
• A 200 mg/kg curcumin dose most effectively decreased the
mean frequency of PTZ-induced epileptiform activity, followed
by 100 mg/kg, whereas 50 mg/kg was found ineffective.
• Co-administering a non-selective nitric oxide synthase inhibitor
with curcumin augmented the anti-epileptic activity of curcumin.
• A selective neuronal nitric oxide synthase potentiated the anti-
epileptic activity of curcumin, whereas a selective inducible ni-
tric oxide synthase inhibitor did not have an effect.
• Giving a nitric oxide precursor reversed the anti-epileptic activ-
ity of curcumin in the early stage and aggravated interictal ac-
tivity but augmented the activity of curcumin in the late stage
and also relieved interictal activity.
[33]
Curcumin (50, 100, 200
mg/kg)
Intraperitoneal, 5, 10
or 15 days daily pre-
treatment in kindled
animals
Swiss Albino Mice
PTZ (35 mg/kg , ip),
considered kindled
after two administra-
tions 48 hours apart
• Curcumin attenuated seizure severity as well as depression-
like behaviour and memory impairment in a dose-dependent
manner.
• Curcumin increased whole brain serotonin and norepinephrine
levels as well as reduced nitrite levels and acetylcholinesterase
activity.
[34]
Curcumin (300 mg/kg)
Intraperitoneal, 15,
30, 60 or 120 min-
utes pre-treatment
Swiss Mice
MES (25 mA for 0.2
seconds, 50 Hz, 500 V)
• No anti-convulsant effect of curcumin was found at any pre-
treatment time.
[35]
Curcumin Loaded
Nanoparticles (12.5,
25.0 mg/kg)
Free Curcumin (12.5,
25 mg/kg)
Intraperitoneal, one-
hour pre-treatment,
daily for 10 days
NMRI Mice
PTZ (36.5 mg/k g, ip),
every alternate day,
one hour after
daily curcumin ad-
ministration
• Free curcumin was found to not h ave an anti-seizure effect or
memory improving ability.
• The curcumin loaded nanoparticles at a dose of 25 mg/kg re-
duced the seizure-induced behavioural signs as well as im-
proved spatial learning and memory.
• Free curcumin slightly redu ced the level of PTZ induced hippo-
campal cell death and glial activation, whereas the curcumin
loaded nanoparticles greatly reduced both.
[36]
Curcumin (100, 200,
300 mg/kg)
Oral, one-hour pre-
treatment, daily for
up to 10 weeks
Wistar Rats
PTZ (35 mg/kg , ip),
every alternate day,
one hour after daily
curcumin
administration
• All curcumin doses decreased seizure score in a dose-dependent
manner and protected against PTZ kindling.
• Curcumin at a 300 mg/kg dose increased the latency to myoclo-
nic jerks, clonic seizures, generalised tonic-clonic seizures as
well as improved the seizure score and decreased the number of
myoclonic jerks.
• Curcumin reversed the PTZ kindling induced hippocampal
injury, oxidative stress and apoptosis in a dose-dependent
manner.
[37]
(Table 1) contd….
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1501
Principal Component
Treatment Regimen
Seizure Model
Major Relevant Outcome/s
Refs.
Curcumin (100 mg/kg)
Intraperitoneal, 14
days daily pre-
treatment after cessa-
tion of kainic acid-
induced status epi-
lepticus
Wistar Rats
Kainic Acid (0.8 µg,
ihc)
• Kainic acid-induced elevation of Il-1β and Tnf-α was reduced
by curcumin.
• Kainic acid-induced astrocyte activation was reduced by
curcumin.
• Kainic acid-induced neuronal loss in the dentate hilus and CA3
regions was reduced by curcumin.
• Kainic acid-induced mossy fibre sprouting was reduced by
curcumin.
• Kainic acid-induced abnormal EEG spike frequency and the rate
of spontaneous recurrent seizure occurrence were reduced by
curcumin.
• Kainic acid-induced learning and memory deficit were reduced
by curcumin.
[38]
Curcumin (100 mg/kg)
Oral, 30 minutes pre-
treatment, daily for
40 days
Wistar Rats
PTZ (40 mg/kg , ip),
every alternate day
for 30 days, 30 min-
utes after daily cur-
cumin administration
• Curcumin did not affect the seizure score.
• Curcumin restored the activities of the mitochondrial complexes
in both the hippocampus and the cerebral cortex.
• Curcumin decreased reactive oxygen species, protein carbonyl
and lipid peroxidation levels and restored the level of glu-
tathione.
• Curcumin prevented PTZ induced mitochondrial swelling and
restored other mitochondrial functions.
• Curcumin attenuated PTZ induced neuronal cell death in both
the hippocampus and the cerebral cortex.
• Curcumin ameliorated PTZ induced impaired memory functions.
[39]
Curcumin (100 mg/kg)
Oral, 30 minutes pre-
treatment, daily for
40 days
Wistar Rats
PTZ (40 mg/kg , ip),
every alternate day
for 30 days, 30 min-
utes after daily cur-
cumin administration
• Curcumin at 100 mg/kg had no anti-convulsant potential against
a PTZ induced model of chronic epilepsy but prevented cogni-
tive deficits.
• Curcumin decreased pro-inflammatory cytokines and
chemokine activation in the hippocampus and cortex.
• Gfap and Iba-1 upregulation by PTZ was also attenuated by
curcumin.
• Curcumin also reduced the number of activated glial cells.
[40]
Curcumin
(approximately
equivalent to
100 mg/kg)
Curcumin supple-
mented food pellets,
six months daily
feeding
Wistar Rats
FeCl3 (100 mM, ic),
administered five
months after the start
of curcumin feeding
• Curcumin reduced the development and occurrence of seizures
but did not completely suppress it.
• Curcumin reduced an epilepsy-related increase in multiple-unit
activity (electrocorticography) but did not alter the basal
electrical activity of the brain.
• Curcumin reduced the mRNA and protein expression of Nav 1.1
in the cortex but not in the hip pocampus.
• Curcumin did not affect the mRNA expression of Nav 1.6
but reduced its protein levels in both the cortex and the
hippocampus.
[41]
Curcumin Loaded
Nanoparticles (12.5
mg/kg)
Free Curcumin (12.5
mg/kg)
Intraperitoneal, one-
hour pre-treatment,
daily for 30 days
NMRI Mice
PTZ (36.5 mg/k g, ip),
every alternate day
for 20 days after 10
days of curcumin
administration, one
hour after daily
curcumin
administration
• Curcumin loaded nanoparticles alleviated PTZ induced neuronal
cell death.
• Curcumin loaded nanoparticles upregulated the levels of
erythropoietin and klotho in mice receiving PTZ.
• Curcumin loaded nanoparticles reduced the mRNA level of
Tnf-α.
• Free curcumin generally had the same effect as the
nanoparticles, but typically to a lesser degree.
[42]
(Table 1) contd….
1502 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
Principal Component
Treatment Regimen
Seizure Model
Major Relevant Outcome/s
Refs.
Curcumin (100, 200, 300
mg/kg)
Oral, 30 minutes pre-
treatment, daily for
up to 43 days
Wistar Rats
PTZ (30 mg/kg ,
ip), every alter-
nate day until the
development of
kindling or up to
day 43, 30 min-
utes after daily
curcumin
administration
• Curcumin significantly increased the latency to myoclonic
jerks, clonic seizures as well as generalised tonic-clonic sei-
zures, improved seizure score and decreased the number of
myoclonic jerks in a dose-dependent manner.
• Curcumin reversed PTZ induced oxidative stress and cogni-
tive impairment in a dose-dependent manner.
• Curcumin at a 300 mg/kg dose did not change cognitive func-
tion in normal rats but improved cognition in kindled rats.
• Curcumin prevented PTZ induced rise in whole-brain
malondialdehyde and glutathione levels.
[43]
Curcumin Nanoparticles (50
mg/kg)
Intraperitoneal, daily
pre-treatment for four
days
Wistar Rats
Pilocarpine (380
mg/kg, ip), ad-
ministered after
the end of cur-
cumin treatment
• The nanoparticles prevented a pilocarpine-induced decrease in
cortical and hippocampal acetylcholinesterase, but not the de-
crease in Na+/K+-ATPase activity.
• The nanoparticles produced control like lipid peroxidation
values in the cortex and nonsignificant change in the hippo-
campus as compared to the control.
• The nanoparticles improved the decreased levels of cortical
and hippocampal glutathione.
• The nanoparticles prevented the decrease in hippocampal
nitric oxide levels, but not cortical levels.
• The nanoparticles reduced hippocampal Tnf-α levels to near
control levels, but not cortical levels.
• The nanoparticles attenuated the increase in cortical and hip-
pocampal caspase-3 levels.
[44]
Curcumin (80 mg/kg)
Intraperitoneal, daily
for 21 days in rats
with spontaneous
recurrent seizures
Wistar Albino
Rats
Pilocarpine (380
mg/kg, ip), sin-
gle-dose admini-
stration and left
for 22 days to
establish sponta-
neous recurrent
seizures
• Curcumin prevented the manifestation of seizures.
• Cortical aspartic acid and glycine in rats given pilocarpine
were restored to near control levels, whereas GABA levels
were increased with curcumin treatment though the decrease
in taurine levels was not prevented.
• Hippocampal glutamate and glutamine levels in rats given
pilocarpine were decreased by curcumin treatment, whereas
GABA levels were increased together with aspartic acid and
taurine co ncentrations to near normal levels.
• Overall, curcumin treatment of rats given pilocarpine produ ced a
state of inhibition in the hippocampus and cortex by altering the
balance between inhibitory and excitatory amino acids.
• Curcumin treatment reduced pilocarpine-induced pathological
abnormalities in both the hippocampus and cortex.
[45]
Curcuma longa methanolic
extract (3.1, 6.2, 12.5 µg/ml)
Curcuminoids mixture (Cur-
cumin, demethoxycurcumin
and bisdemethoxycurcumin,
2.5, 5.0, 10.0 µg/ml)
Curcuma longa oil
Zebrafish: 2.5, 5.0, 10 µg/ml
Mice: 50, 100 mg/kg)
Ar-turmerone
Zebrafish: 11.0, 23.0, 46.0
µM
Mice: 50 mg/kg
α,β-turmerone (1:1 mixture)
Zebrafish: 5.0, 11.0, 23.0 µM
Mice: 100 mg/kg
α-atlantone (11.0, 23.0, 46.0
µM)
Added into the water
for zebrafish larvae,
one-hour pre-
treatment
Intravenous infusion
for mice, 10 minutes
pre-treatment
Zebrafish Lar-
vae: Tg (fli 1a:
EGFP)y1 strain
PTZ (20 mM),
added into the
water
C57Bl/6 Mice
PTZ
(7.5 mg/ml at
150 µl/minute,
iv)
• Curcuma longa methanolic extract h ad anti-convulsant activ-
ity in larval zebrafish at a 12.5 µg/ml dose.
• The curcuminoids mixture produced an anti-convulsant effect
at all doses in a dose-dependent manner.
• Curcuma longa oil had anti-convulsant activity at 10 µg/ml.
• α,β-turmerone, ar-turmerone and α-atlantone were determined
to have anti-convulsant activity.
• All constituents slightly increased zebrafish larvae locomotor
activity despite the absence of PTZ, but EEG showed that the
oil was not pro-convulsant.
• Mice treated with the 50 mg/kg of Curcuma longa oil required
a higher PTZ dose to trigger all behavioural endpoin ts,
whereas a 100 mg/kg dose delayed seizure generation for all
parameters and also death, with the required PTZ dose for all
assessed events being increased.
• Mice treated with ar-tumerone required an increased PTZ dose
to trigger assessed events, whereas α,β-turmerone positively
affected all seizure parameters.
• α-atlantone was not tested in mice due to an insufficient
amount being collected.
[46]
(Table 1) contd….
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1503
Principal Component
Treatment Regimen
Seizure Model
Major Relevant Outcome/s
Refs.
Ar-tumerone
Zebrafish: 46 µM
C57BI/6 Mice:
50 mg/kg
NMRI Mice:
1, 20, 50 mg/kg
Added into the water
for zebrafish larvae,
one-hour pre-treatment
Intraperitoneal for
C57BI/6 mice, 30
minutes or 24 hours
pre-treatment
Intraperitoneal for
NMRI mice, 10 min-
utes pre-treatment
Zebrafish Larvae: AB
strain
PTZ (20 mM), added
into the water
C57Bl/6 Mice
PTZ (7.5 mg/ml at
150 µl/minute, iv)
NMRI Mice
Low frequency, long
duration corneal
stimulation (6 Hz, 0.2
milliseconds rectangu-
lar pulse width, 3
seconds duration, 44
mA)
• All C57BI/6 mice were protected from corneal stimulation by an
ar-tumerone dose between 0.1 and 50 mg/kg with a 30 minutes
pre-treatment time and 70% were protected after 24 hours pre-
treatment with a 50 mg/kg dose.
• A 1 mg/kg ar-tumerone dose raised the PTZ threshold required to
trigger tonic hind limb extension and death, whereas 20 mg/k g in-
creased the dose needed to cause death in the NMRI mice.
• A 50 mg/kg dose of ar-tumerone did not produce any loss of bal-
ance in the C57Bl/6 mice.
• Ar-tumerone at a 50 mg/kg dose was detectable in the brains of
C57BI/6 mice as early as 15 minutes and as late as 24 hours after
administration.
• In zebrafish larvae, ar-tumerone downregulated C-fos expression
and upregulated Bdnf in both the presenc e and ab sence of PTZ,
whereas the expression patterns of the GABAA receptor and Il-10
were not affected.
[47]
Curcumin (20 µM)
-
Human Embryonic
Kidney cells 293
(HEK293)
Patch-Clamp Electro-
physiology, no sei-
zures induced
• Curcumin treatment did not significantly change peak current
nor deactivation and desensitisation of the AMPA receptor.
• Some derivativ es of curcumin at the same dose did demonstrate an
inhibitory effect.
[48]
Curcumin (300 mg/kg)
Oral, one-hour pre-
treatment
Wistar Rats
PTZ (60 mg/kg , ip)
MES (70 mA, 0.2
seconds)
• Curcumin alone significantly increased myoclonic latency but only
had a 50% protection rate against generalised tonic-clonic seizures
and did not affect learning and memory.
• Curcumin alone had a 33.33% protection rate against MES in-
duced seizures.
• Curcumin alone reversed the PZT/MES induced rise in malondial-
dehyde and decrease in glutathione levels.
• Co-administration of curcumin with sub-therapeutic doses of
ASMs potentiated the effect of ASMs and prevented the impair-
ment of learning and memory.
[49]
Curcumin
Larvae: 1 µM
Adult: 0.5 µM
Micronized Curcumin
Larvae: 1 µM
Adult: 0.5 µM
Larvae: Added into the
water, 30 minutes pre-
treatment
Adult: Intraperitoneal,
30 minutes pre-
treatment
Wild-Type Zebrafish
PTZ (3 mM), added
into the water
• Both curcumin and micronized curcumin treatment in zebraf ish larvae
did not alter the d istance traveled and the number of line crossings.
• In adult zebrafish, both curcumin and micronized curcumin treatment
reduced locomotion but did not alter the number of line crossings.
• Both micronized cu rcumin and curcumin administration to zebrafish
larvae reduced seizure occurrence and slowed seizure stage progression.
• Both micronized curcumin and curcumin administration to zebraf-
ish adults slowed seizure stage progression.
[50]
Curcumin
(200 mg/kg)
Oral, daily pre-
treatment fo r seven or
three day s
Swiss Albino Mice
Kainic acid
(10 mg/kg, ip), admin-
istered after the com-
pletion of curcumin
pre-treatment
• Blood samples and brain tissue biochemical parameters showed
that curcu min administration had antioxidant, anti-inflammatory
and antiapoptotic effects.
• Curcumin reduced the severity of pathological changes (mainly in
haemorrhage, oedema, neural degeneration and encephalomalacia)
in the brain to varying degrees.
[51]
Curcumin
(200, 300 mg/kg )
Oral, daily pre-
treatment fo r two
weeks
Sprague-Dawley Rats
Pilocarpine (20
mg/kg, ip), adminis-
tered after the comple-
tion of curcumin
treatment
• Curcumin pre-treatment markedly decreased the number of apop-
totic neurons and increased the number of surviving neurons in the
hippocampus (CA1, CA3, dentate gyrus, hilus) after 24 and 72
hours post pilocarpine administration.
• Upregulation of Mlkl and Rip-1 due to pilocarpine was inhibited
by curcumin in a dose-dependent manner.
• Curcumin pre-treatment upregulated the expression levels of Be-
clin-1 and LC3BII/LC3BI and increased the number of auto-
phagosomes.
[52]
ASM: Anti-Seizure Medication, AMPA: L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, Bdnf: brain-derived neurotrophic factor, Cxcl16: Chemokine (C-X-C motif)
ligand 16, EEG: Electroencephalography, GABA: γ-aminobutyric acid, Gfap: Glial fibrillary acidic protein, Iba1: Ionized calcium binding adaptor molecule 1, Il-1β: Interleukin 1
beta, Il10rb: Interleukin 10 Receptor Subunit Beta, MES: Maximal ElectroShock, ICES: Increasing Current Electroshock Seizures, Mlkl: Mixed lineage kinase domain like pseu-
dokinase, PTZ: Pentylenetetrazol, Rip-1: Receptor-interacting serine/threonine-protein kinase 1, Tnf-α: tumour necrosis factor alpha, ic: Intracortical, ihc: Intrahippocampal, ip:
Intraperitoneal, iv: Intravenous, po: Oral, sc: Subcutaneous.
1504 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
underwent full-text evaluation, whereby the texts were
searched for the principal component used in the study, the
treatment regimen used, the seizure model used and major
relevant study outcomes to compare and contrast them. Nine
results were subsequently removed for ultimately being ir-
relevant to the aim of the review, leaving a total of 34 arti-
cles to be included in this review. The 34 articles are summa-
rised in Table 1 and are discussed in greater detail through-
out this systematic review.
The bioactive components of Curcuma Longa are vari-
able due to the variety, location of cultivation and many
other factors, though curcuminoids, sesquiterpenoids and
monoterpenoids have been identified as the major compo-
nents [17]. However, the major components of Curcuma
Longa can vary between plant parts as well, leading to the
suggestion that the active curcuminoids (curcumin, de-
methoxycurcumin and bisdemethoxycurcumin) can be used
as markers in the rhizome, powder and ex tracts of Curcuma
Longa whereas the major ketonic sesquiterpenes (Ar-
turmerone, α-turmerone and turmerone) can be used as
markers for Curcuma longa oil and oleoresin products [18].
Nevertheless, the studies identified in our search overwhelm-
ingly used the curcuminoid from curcumin. Only two studies
used Curcuma longa extracts, one used Curcuma longa oil
and two used the bisabolene sesquiterpenoids found in
Curcuma longa.
3.1. Curcumin
This section is subdivided according to the seizure model
used due to the large number of studies that fall under this
category. Some studies utilised more than one model and are
thus repeated under their r espective subsections.
3.1.1. Pentylenetetrazol (PTZ) Induced Seizures
A total of 21 studies were found where turmeric principal
constituents were evaluated using the PTZ model. These
studies range from acute to chronic PTZ models, including
kindling models. They also comprised of studies where tur-
meric-derived compounds were used either for single or re-
peated dose administration.
Chronic treatment of curcumin (20 mg/kg, i.p.) for two
weeks reduced the duration of pentylenetetrazol (PTZ) in-
duced generalised tonic-clonic seizures in Wistar rats that
were potentiated by daily exposure to stress [19]. Curcumin
pre-treatment also alleviated seizure activity and severity and
delayed the onset of myoclonic jerks, whereas a single acute
administration of curcumin had no significant effect on the
seizures [19]. In another study, chronic oral treatment of
curcumin at 100mg/kg in mice resulted in increased onset
latency to myoclonic jerks and seizures [25]. The authors
also noted that curcumin could have a synergistic effect with
the standard ASM sodium valproate. A combination of 100
mg/kg of curcumin and a sub-therapeutic dose of sodium
valproate (400 mg/kg) exhibited a similar anti-seizure activ-
ity compared to the therapeutic dose of sodium valproate
alone. In addition, curcumin did not affect the learning and
memory of the mice both before seizures were induced and
after recov ery from seizures. Agarwal et al. reported that an
oral liposomal curcumin formulation significantly delayed
the onset of myoclon ic jerks and generalised seizures [27].
Their results also showed that liposomal curcumin given
intravenously could dose-dependently increase the latency
and decrease clonic seizures' duration during status epilepti-
cus. The authors believed that this formulation of curcumin
would have an enhanced effect over free curcumin as the
phospholipid carriers could more easily cross the blood-brain
barrier (BBB) with an improved half-life. However, the
study does not mention when the liposomal curcumin was
given in relation to the induction of seizures or how many
doses were given.
When curcumin was given intraperitoneally to kindled
male Wistar rats daily for 24 days, 200 mg/kg was found to
be most effective in decreasing the mean frequency of PTZ-
induced epileptiform activity. The dose of 100 mg/kg had a
weaker effect and 50 mg/kg had no significant impact on the
epileptiform activity [33]. Administering nitric oxide syn-
thase inhibitors (N-nitro-L-arginine methyl ester, 7-
Nitroindazole, or aminoguanidine) or a nitric oxide precursor
(L-arginine) alone did not affect epileptiform activity. How-
ever, co-administration of N-nitro-L-arginine methyl ester
and 7-Nitroindazole potentiated the effect of curcumin on
epileptiform activity. In contrast, aminoguanidine had no
impact on the effect of curcumin on epileptiform activity. L-
arginine was found to reverse the effect of curcumin in th e
earlier stages and aggravated interictal activity but aug-
mented curcumin and reduced interictal activity in the later
stages of PTZ-induced epileptiform activity. It should be
noted that this study [33] implies that neuronal nitric oxide
synthase, and not inducible nitric oxide synthase, is at least
partly responsible for the anti-epileptic effect of curcumin,
but another study [31] in this review implies the opposite.
The contradiction in the mechanism will be explored further
in the discussion part of this review. In another study, cur-
cumin was given orally to young male Wistar rats daily for
up to 10 weeks, an hour before kindling with PTZ, and a
dose-dependent protective effect was found against kindling
in terms of reduced seizure scores [37]. Besides seizure
score, a 300 mg/kg dose of curcumin was also found to sig-
nificantly reduce the latency to myoclonic jerks, clonic and
generalised tonic-clonic seizures, and decreased the number
of myoclonic jerks. The study also found that curcumin
dose-dependently reversed PTZ kindling induced hippocam-
pal injury, hippocampal oxidative stress and hippocampal
apoptosis.
When curcumin was given intraperitoneally to adult male
Wistar rats at a dose of 100 mg/kg daily for 40 days, no sig-
nificant effect on seizure score upon a single challenge dose
of PTZ at day 40 after 30 days of concurrent PTZ kindling
on alternate days, was discovered [39]. Moreover, the study
also ran an array of mitochondrial complex activity tests on
the r at hippocampus and cerebral cortex. It determined that
curcumin restored NADH (Nicotinamide adenine dinucleo-
tide): cytochrome c reductase and cytochrome c oxidase ac-
tivity in both regions, despite the presence of PTZ. Similarly,
the PTZ induced mitochondrial swelling and ultrastructural
changes were also prevented by curcumin treatment. In addi-
tion, biochemical studies revealed that curcumin reduced
oxidative stress levels in addition to increasing antioxidant
defenses. Following that, neuronal cell death in both hippo-
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1505
campal and cerebral cortex regions was found to be reduced
by curcumin treatment, in addition to PTZ induced memory
impairment being ameliorated. In a separate follow-up ex-
periment with an identical curcumin treatment and PTZ kin-
dling regime by the same laboratory, curcumin was again
found not to affect seizure score significantly, but a substan-
tial amelioration of PTZ induced memory deficits was found
in this study [40]. Curcumin treatment also produced a re-
duction in hippocampal and cerebral cortex inflammation as
well as a significant reduction in glial and astrocyte activa-
tion was observed. In another study, curcumin was given
orally to male Wistar rats daily for up to 43 days (till the
development of PTZ kindling) and it was found that curcu-
min produced a dose-dependent anti-seizure effect [43]. Cur-
cumin at a dose of 300 mg/kg significantly increased the
latency to myoclonic jerks, clonic seizures, gener alized
tonic-clonic seizures as well as improved the seizure score
and decreased the number of myoclonic jerks, with the lower
doses also producing a lesser but still good anti-seizure ef-
fect. Curcumin was found to significantly reverse PTZ kin-
dling induced cognitive impairment in a dose-dependent
manner as it does not improve memory in healthy rats. Cur-
cumin also dose-dependently reversed PTZ kindling induced
oxidative stress.
When curcumin was given intraperitoneally to swiss al-
bino mice daily up to 15 days in a study, it was found that
PTZ induced seizure severity was reduced in a dose-
dependent manner in terms of seizure score after administra-
tion of a sub-convulsive PTZ dose to PTZ kindled mice [34].
The study also found that the depressive behaviour and
memory deficit induced by PTZ were both attenuated in a
dose-dependent manner by curcumin. The effect of curcumin
on seizures, depressive behaviour, and memory deficit was
all found to increase with increasing treatment duration up to
the study's 15 days limit. The whole-brain biochemical esti-
mations showed that curcumin increased the levels of brain
serotonin and norepinephrine as well as reduced acetylcho-
linesterase activity and nitrosative stress (nitrite level) after
15 days of treatment. In another study, oral curcumin was
given for 35 days to inbred PTZ kindled male Swiss albino
mice, and a dose-dependent decrease in the seizure incidence
and severity was observed [28]. The 200 mg/kg dose pro-
duced a seizure protection effect comparable to the standard
ASM diazepam (3 mg/kg). The study also found that after 35
days, all the curcumin doses significantly decreased
malondialdehyde (lipid peroxidation marker) and restored
the depressed glutathione levels in PTZ kindled mice's brain
tissue.
When free curcumin was given intraperitoneally to male
NMRI daily for 10 days in a study before kindling with PTZ
every alternate day, there was no anti-seizure effect deter-
mined and no effect on memory was observed [36]. Free
curcumin was also found to have a slight but non-significant
reduction in the level of cell death and glial activation in the
hippocampus. The same study also tested the effect of cur-
cumin-loaded nanoparticles in an identical manner and found
that a 25 mg/kg dose significantly reduced the seizure-
induced behavioural signs and hence the seizure score, im-
proved spatial learning and memory as well as significantly
reduced hippocampal cell death and glial activation. In an-
other study, curcumin-loaded nanoparticles were given in-
traperitoneally to male NMRI mice at a dose of 12.5 mg/k g
for ten days before starting PTZ kindling and 20 days after-
wards; it was found that the treatment significantly alleviated
PTZ induced hippocampal neuronal cell death [42]. This
observation was also supported by the downregulated hippo-
campal level of tumour necrosis factor-alpha (Tnf-α). In con-
trast, klotho (life-extension factor) levels and erythropoietin
(neuroprotective) were upregulated, reversing the effects of
PTZ. The study also tested free curcumin under the same
conditions and found a similar effect on the parameters
measured but to a significantly lesser degree.
When curcumin was given orally to male albino mice
(Laka strain) before infusing PTZ intravenously, only the 80
mg/kg curcumin dose significantly decreased the PTZ
threshold required for tonic onset extension but no effect on
either myoclonic jerks or generalised clonus was observed
[30]. The lower doses were ineffective on all three parame-
ters and the same was also true for the higher 120 mg/kg
dose, however the authors did not explore the reason for this.
In addition, the study also determined that the PTZ threshold
for the onset of tonic extension increased at every 15-minute
timepoint up to a maximum at 45 minutes post 80 mg/kg
curcumin administration and decreased thereafter. All subse-
quent testing was done with piperine (an inhibitor of hepatic
and intestinal glucuronidation to increase curcumin bioav ail-
ability) which was given orally 15 minutes before curcumin
administration; curcumin itself was given orally 45 minutes
before intravenous PTZ. This subsequent testing revealed
that both a nonselective adenosine A1/A2 receptor antagonist
and a selective adenosine A1 receptor antagonist blocked
curcumin's effect on the PTZ seizure threshold. They also
found the reverse to be true, with a nonselective adenosine
A1/A2 receptor agonist and a selective adenosine A1 receptor
agonist both potentiating the effect of even a sub-effective
dose of curcumin (40 mg/kg). In contrast, both a selective
adenosine A2A antagonist and a selective adenosine A2A
agonist did not affect the action of curcumin. The study also
confirmed using a peripheral adenosine receptor antagonist
that the effects of curcumin were mediated via central adeno-
sine receptors.
When curcumin was given intraperitoneally to male
NMRI albino mice in a study, it was found that curcumin
administration 75 minutes before the infusion of PTZ did not
significantly alter the seizure threshold [31]. In contrast,
when nanoparticles of curcumin C3 complex (a standardised
product with a specific ratio of curcumin, demethoxycurcu-
min and bisdemethoxycurcumin [53]) were given intraperi-
toneally to male NMRI albino mice, the study found a dose-
dependent increase in seizure threshold, with 80 mg/kg being
the most effective. It was also found that the 80 mg/kg dose
of nanoparticles significantly increased the seizure threshold
starting from 45 minutes following administration, with a
maximal effect at 60 minutes. In the case of the nanoparti-
cles, they found that L-arginine given 15 minutes before the
nanoparticles dose-dependently reversed the effect of
nanoparticle pre-treatment on the seizure threshold. In con-
trast, both the non-selective nitric oxide synthase inhibitor
and the selective inducible nitric oxide synthase inhibitor
potentiated a sub-effective nanoparticle dose of 10 mg/kg in
1506 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
a dose-dependent manner. The study also noted that a selec-
tive neuronal nitric oxide synthase inhibitor did not signifi-
cantly affect the seizure threshold. As previously mentioned,
the results of this study [31] contradict that of anoth er study
in this review [33].
When curcumin was given intraperitoneally to male mice
25 minutes beforehand, a study found that seizure and tonic-
clonic latency was significantly increased, and the duration
of both tonic and tonic-clonic seizures was reduced consid-
erably, though the loss of balance and mortality were not
significantly affected by curcumin [32]. The study also
found that curcumin was inhibited and even reversed in
some instances when brain serotonin levels were depleted
over four days. In addition, the serotonin 5-HT1A, 5-HT2C
and 5-HT4 receptor antagonists individually diminished the
effect of curcumin, but the 5-HT7 antagonist potentiated it.
However, antagonising all the four serotonin receptors at
once prevented the effect of curcumin, and only the expres-
sion level of 5-HT7 was reduced in the hippocampus. In an-
other study, a curcuminoids mixture from Curcuma longa
containing curcumin, demethoxycurcumin and bisde-
methoxycurcumin was used to pre-treat seven days post-
fertilisation (dpf) zebrafish larvae of the Tg (fli 1a: EGFP)y1
strain by adding it directly into the water, for an hour in
darkness before the addition of PTZ [46]. Every dose of the
curcuminoids mixture showed significant anticonvulsant
activity in a dose-dependent manner.
When wild type zebrafish larvae were exposed to curcu-
min and micronized curcumin at a dose of 1 µM in the water
for 30 minutes, a study found that both did not induce behav-
ioural alterations in terms of travelled distance and the num-
ber of times that the larvae crossed from the centre of the
well to the periphery [50]. A different set of larvae was simi-
larly exposed to curcumin but exposed to PTZ 30 minutes
after the curcumin treatment. Micronized curcumin signifi-
cantly reduced the occurrence of seizures in terms of seizure
stages as well as increased the latency to the different stages.
In contrast, curcumin did not affect the occurrence of sei-
zures but did increase the latency to the different stages. The
authors of the study also repeated their experiment in adult
zebrafish using the intraperitoneal route at a dose of 0.5 µM
and found that both curcu min and micronized curcumin re-
duced the travelled distance of the adult zebrafish but did not
have any effect on the number of times that the zebrafish
crossed the top, centre and bottom of the tank. In the PTZ
seizure model, micronized curcumin significantly reduced
the occurrence of the most severe stage III seizures and de-
layed the onset of each stage.
In contrast, curcumin did not affect seizure occurrence
but significantly delayed the onset of each seizure stage. In
another study, curcumin was given orally to male Wistar rats
at a dose of 300 mg/kg, 60 minutes before PTZ seizure in-
duction, and a significant increase in the myoclonic jerk la-
tency that was comparable to a sub-therapeutic dose of the
standard ASM valproate was found [49]. When the sub-
therapeutic dose of valproate was co-administered with 300
mg/kg of curcumin, the study found that the myoclonic jerk
latency increase was more r emarkable than when they were
given individually. However, there was no significant differ-
ence found in the serum level of valproate. Whole-brain es-
timation of oxidative stress parameters revealed a similar
story whereby a moderate reduction was demonstrated when
curcumin or valproate was given alone, and a more signifi-
cant reduction was observed when given together. The study
also measured the rats' learning and memory ability after
seizure induction compared to before induction but found no
significant improvement in the PTZ induced learning and
memory deficiencies when the sub-therapeutic dose of val-
proate or curcumin was given alone. In contrast, a significant
improvement was found when the two were co-administered.
3.1.2. Kainic Acid-Induced Seizures
Kainic acid, a neurotoxic analogue of glutamate, is com-
monly used to induced seizures in rodent models. Curcumin
treatment at 100 mg/kg daily for seven days could modulate
kainic acid-induced epileptogenesis by upregulating the anti-
inflammatory cytokines Interleukin 10 Receptor Subunit
Beta (Il10rb), Chemokine (C-X-C motif) ligand 16 (Cxcl16),
and Cxcl17 as well as protect against hippocampal cell death
by up-regulating nicastrin [22]. Curcumin treatment for 2
weeks was also able to reduce abnormal electroencephalo-
graphy (EEG) spike frequency and spontaneous recurrent
seizures as measured via seizure scoring [38]. Moreover, the
learning and memory deficit induced by kainic acid was al-
most completely reversed by curcumin treatment. In addi-
tion, analysis of hippocampal tissue showed that curcumin
significantly reduced the elevated Interleukin 1 beta (Il-1β)
and Tnf-α levels caused by kainic acid as measured via
ELISA three days after kainic acid administration. Gfap and
Nissl staining seven days after kainic acid administration
showed that curcumin reduced astrocyte activation (and
hence pro-inflammatory cytokine production) as well as neu-
ronal loss in the dentate hilus (DH) and CA3 regions of the
hippocampus as a result of kainic acid. The study also found
less mossy fibre sprouting because of kainic acid.
In another study, curcumin was given at a dose of 200
mg/kg either seven days before the administration of kainic
acid (protected group) or three d ays after the administratio n
(treated group) [51]. However, it was not clear from the sta-
tistical analysis if there was a significant difference in out-
comes between the two treatment conditions, and they were
often mentioned together in the paper during a discussion of
the outcomes. Hence, this review h as considered both condi-
tions to not be significantly different from each other in
terms of outcome. Both time points have also been deemed
to be not substantially different from each other due to a lack
of clarity in the statistical analysis and a lack of differentia-
tion between the authors' two time-points. The study found
that curcumin treatment reduced the level of oxidative stress
and inflammation as measured by the serum level of sialic
acid, TNF-α and Il-1β as well as the brain tissue levels of
superoxide dismutase, catalase and glutathione peroxidase,
L- malondialdehyde, glutathione, nitric oxide, 8-Oxo-2'-
deoxyguanosine, activator protein 1 and myeloperoxidase.
The caspase 3 activity level and DNA fragmentation were
also reduced by curcumin treatment, which implies a reduc-
tion in kainic acid-induced neuronal death. Histopathological
examination of the brain tissue showed that curcumin treat-
ment reduced several pathological alterations such as haem-
orrhage, oedema, neural degeneration and encephalomalacia,
to differing degr ees.
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1507
3.1.3. Pilocarpine Induced Seizures
Pilocarpine induces status epilepticus condition in ro-
dents characterized by tonic-clonic generalised seizures.
Typically, pilocarpine injections induce epilepsy-like condi-
tion mimicking clinical epilepsy in patients. Pre-treatment o f
oral curcumin at doses of 50 - 200 mg/kg for 3 days de-
creased the occurrence and latency of both lithium – pilo-
carpine-induced seizures and status epilepticus in a dose-
dependent manner [20]. The study also showed that curcu-
min could ameliorate status epilepticus induced cognitiv e
dysfunction as measured via the Morris water maze and also
oxidative stress in both the hippocampus and striatum of the
brain. Curcumin 80 mg/kg daily for 21 days restored hippo-
campal Na+/K+-ATPase activity to normal, and this was as-
sociated with a decrease in cellular excitability and, hence,
seizure appearance propagation [26]. The study also found
that curcumin reversed the oxidative stress caused by pilo-
carpine in terms of the oxidative stress markers nitric oxide,
glutathione and malondialdehyde. In addition, although the
study found that acetylcholinesterase levels were slightly
increased by curcu min; the decrease in catalase levels by
pilocarpine was actually potentiated by curcumin, although
the authors have suggested that catalase does not play a ma-
jor role in the rat brain in response to oxidative stress. Cur-
cumin treatment also protected from seizure-like behaviour,
such as facial automatisms, forelimb clonus, rearing and fal-
ling [45]. The study determin ed an alteration in the equilib-
rium ratio between inhibitory amino acids (γ-aminobutyric
acid [GABA], glycine, taurine and glutamine) and excitatory
amino acids (glutamate and aspartate) levels by enhancing
the former and inhibiting the later in the rat hippocampus
and cortex. In addition, light microscopy examinations of the
hippocampus and cortex showed that pilocarpine-induced
neuronal histological changes and death were reduced by
curcumin treatment.
Another study showed that curcumin treatment markedly
increased the number of surviving hippocampal neurons as
determined via Nissl staining and the terminal deoxynucleo-
tidyl transferase dUTP nick end labelling (TUNEL) assay,
starting from the 24-hour time point in almost all four re-
gions of the post-SE hippocampus (CA1, CA3, dentate
gyrus, and hilus). Curcumin treatment resulted in an induc-
tion of autophagy proteins (beclin-1 and LC3BII/LC3BI) as
determined via Western blotting and also inhibited the
upregulation of necroptosis proteins (mixed lineage kinase
domain-like pseudokinase [MLKL] and receptor-interacting
serine/threonine-protein kinase 1 [RIP-1]) as determined via
immunohistochemistry. Similarly, the number of auto-
phagosomes as determined via transmission electron micros-
copy was also found to be decreased by curcumin treatment.
Curcumin nanoparticle treatment reduced excitability in
the cortex and hippocampus by preven ting a pilocarpine-
induced reduction in acetylcholinesterase activity, although
it was unable to do so for Na+/K+-ATPase. The study also
found that curcumin exhibited anti-inflammatory activity and
reversed the pilocarpine-induced increase in cortical
malondialdehyde levels but not in the hippocampus, whereas
the level of glutathione was only slightly increased in both
regions. In contrast, Tnf-α levels in the hippocampus meas-
ured using ELISA were markedly reduced, whereas cortical
levels were still elevated by pilocarpine. The decrease in the
hippocampus's nitric oxide level due to pilocarpine was also
prevented by curcumin treatment, but the decrease was not
significant in the cortex. The study also determined that cur-
cumin treatment produced an anti-apoptotic effect in the cor-
tex and hippocampus, as estimated using ELISA determined
caspase-3 levels.
3.1.4. Iron Induced Seizures
When curcumin supplemented food pellets were given
for six months to one-month-old male Wistar rats at a con-
centration of 1500 parts per million (ppm) (or approximately
100 mg/kg based on the author estimated rat daily food in-
take), a study found a significant reduction (but not cessa-
tion) in the development and occurrence of iron chloride
seizures (induced at the end of the fifth month of treatment)
as determined via cortical electroencephalographic and mul-
tiple-unit activity measurements [41]. The study also deter-
mined that the basal electrical activity of the brain was not
affected by curcumin treatment. Besides that, the mRNA
(RT-PCR) and protein levels (immunohistochemistry) of
Nav1.1 (Sodium Voltage-Gated Channel Alpha Subunit 1,
Scn1a) were determined to be reduced in the cortex but not
the hippocampus. In contrast, the mRNA expression levels
of Nav1.6 (Scn8a) were found to be unchanged, yet protein
levels w ere reduced in both the cortex and hippocampus;
these results were described as inconclusive by the authors.
3.1.5. Penicillin Induced Seizures
When curcumin was given intraperitoneally to adult male
Wistar rats at doses of 50, 100 or 200 mg/kg ten minutes
after the intracortical administration of penicillin to induce
seizures, a study found that 100 or 200 mg/kg of curcumin
significantly reduced both the frequency and the amplitude
of spike waves [29]. The study also found that a sub-
therapeutic dose of curcumin (50 mg/kg) could still potenti-
ate the effect of the ASM diazepam at therapeutic doses.
3.1.6. Electricity Induced Seizures
When curcumin was given orally to three to four months
old Swiss albino mice at doses of 50 or 100 mg/kg for 14
consecutive days in a study, both doses did not significantly
affect Maximal Electroshock Seizure (MES) induced tonic
hind limb extension [25]. However, the study found that the
100 mg/kg dose significantly reduced the clonic phase dura-
tion. The study also found that neither curcumin dose af-
fected the mice's learning and memory, as measured using
the elevated plus-maze, before seizures were induced nor
after the recovery from seizures.
In the presence of a liposomal curcumin formulation
given orally to inbred male Swiss albino mice at doses of 25
or 50 mg/kg, a study found that the current threshold re-
quired to induce seizures in the Increasing Current Electro-
shock Seizures (ICES) test was significantly increased in a
dose-dependent manner [27]. The study's authors believed
that this formulation of curcumin had an enhanced eff ect
over free curcumin as the phospholipid carriers could more
easily cross the blood-brain barrier (BBB) and exhibited a
prolonged half-life. However, the study does not mention
1508 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
when the liposomal curcumin was given in relation to the
induction of seizures or how many doses were given.
When curcumin was given intraperitoneally to adult male
Swiss mice at a dose of 300 mg/kg at four different pre-
treatment times of 15,30, 60 or 120 minutes, a study found
that curcumin had no anti-convulsive effect regardless of
pre-treatment time in the MES model as defined by the oc-
currence of tonic hind limb extension [35].
When curcumin was given orally to male Wistar rats at a
dose of 300 mg/kg at 60 minutes before seizure induction
using the MES model, a study found a 33% protection
against tonic hind limb extension that was comparable to
sub-therapeutic doses of the standard ASMs phenytoin and
phenobarbitone given 30 minutes before PTZ seizure induc-
tion, but inferior to the 50% afforded by the ASM carba-
mazepin [49]. When the sub-therapeutic dose of carba-
mazepine was co-administered with 300 mg/kg of curcumin,
the study found that the protection was greater than when
they were given individually, though there was no significant
difference found in the serum level of the ASMs. The whole
brain estimation of oxidative stress parameters revealed that
the levels of malondialdehyde and glutath ione demonstrated
a moderate reduction in oxidative stress when curcumin was
given alone, but not when the sub-therapeutic dose of ASMs
was given alone. However, a significant decrease in oxida-
tive stress was seen when the two were given together. The
study also measured the rats' learning and memory ability
after seizure induction compared to before induction using
the elevated plus maze and passive avoidance tests but found
no significant improvement in the MES induced learning and
memory deficiencies when the sub-therapeutic dose of
ASMs or curcumin was given alone. In contrast, a significant
improvement was found when the two were co-administered.
3.1.7. Non-In Vivo Models
Using Glide to run molecular docking studies against the
human 4-aminobutyrate-aminotransferase, a study found that
curcumin binds to human 4-aminobutyrate-aminotransferase,
which is an enzyme that catalyses the breakdown of the in-
hibitory neurotransmitter GABA. The study found that the
contact points of this b inding were Leu299, Leu301, Ala135,
Gln267, Arg164 and Tyr161 [21].
Using patch-clamp electrophysiology on Human Embry-
onic Kidney cells 293 (HEK293) that express the calcium
impermeable homomeric GluA1 and calcium-permeable
heteromeric GluA1/A2 L-α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) excitatory receptors, a
study found that curcumin at a dose of 20 µM did not sig-
nificantly change several gating biophysical properties that
were peak current, deactivation and desensitisation [48]. As
a comparison, the study also found that certain five-
membered ring heterocyclic moiety derivatives of curcumin
had inhibitory effects on the gating biophysical properties,
but these derivatives are not naturally found in Curcuma
longa and thus will not be considered further in this review.
3.2. Curcuma longa Crude Extract
An aqueous extract of Curcuma longa produced via sox-
hlet extraction in distilled water was given orally once daily
to adult albino mice for 21 days in a study at the doses of 50,
100 or 200 mg/kg [23]. The study found that 100 and 200
mg/kg of the extract could delay the onset of pentylenetetra-
zol-induced seizures, though 50 mg/kg of the extract had no
significant effect. In contrast, the same 100 mg/kg dose did
not affect tonic hind limb extension in the MES test, but 200
mg/kg of the extract was sufficient to significantly reduce
the duration. The authors noted that none of the doses used
in their study could completely prevent the occurrence of
seizures in either model.
A methanolic extract of Curcuma longa at concentrations
of 3.1, 6.2 or 12.5 µg/ml was used to pre-treat seven dpf ze-
brafish larvae of the Tg (fli 1a: EGFP)y1 strain by adding it
directly into the water, for an hour in darkness in a study
[46]. Only a 12.5 µg/ml concentration showed significant
anticonvulsant activity to significantly counteract the in-
crease in locomotor activity induced by PTZ.
3.3. Curcuma longa Oil
Curcuma longa oil was used to pre-treat seven dpf larval
zebrafish of the Tg (fli 1a: EGFP)y1 strain at concentrations
of 2.5, 5.0 or 10.0 µg/ml by adding it directly into the water,
for an hour in darkness in a study [46]. Only a 10 µg/ml con-
centration showed significant anticonvulsant activity in
terms of significan tly counteracting the increase in locomo-
tor activity induced by pentylenetetrazol. However, Curcum a
longa oil by itself was found to increase locomotor activity.
The same study also determined the effect of Curcuma longa
oil on EEG recordings under identical conditions as previ-
ously described. Curcuma longa oil was found to partly pro-
tect ag ainst pentylenetetrazol seizures in terms of signifi-
cantly reducing the number and the duration of ictal-like
discharges as well as shortening the cumulative duration of
all forms of epileptiform discharges [46]. The study also
confirmed that Curcuma longa oil is not pro-convulsive as it
did not significantly affect the number and duration of inter-
ictal-like spikes compared to vehicle control. The same study
also used Curcuma longa oil to pre-treat 10-week-old male
C57Bl/6 mice intravenously for 10 minutes at doses of 50
and 100 mg/kg before pentylenetetrazol was infused intrave-
nously into the mice. The study found that 50 mg/kg of Cur-
cuma longa oil increased the PTZ dose required to trigger all
behavioural endpoints (ear twitch, myoclonic twitch, tail
twitch, forelimb clonus, falling, tonic hindlimb extension and
death), whereas 100 mg/kg significantly delayed seizure
generation for all seizure parameters including death.
3.4. Curcuma longa Bisabolene Sesquiterpenoids
The bisabolene sesquiterpenoids α,β-turmerone, ar-
turmerone and α-atlantone were isolated from Curcuma
longa oil using reversed-phase HPLC in a study [46]. The
study pre-treated seven dpf larval zebrafish of the Tg (fli 1a:
EGFP)y1 strain with the bisabolene sesquiterpenoids by add-
ing it directly into the water, for an hour in darkness at th e
doses of 5, 11, 23 or 46 µM. The study found that α,β-
turmerone significantly counteracted the increase in locomo-
tor activity induced by PTZ at 46 µM, ar-turmerone at 23
µM and α-atlantone at 23 µM, though all three also slightly
increased locomotor activity when given alone. The same
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1509
study also used the bisabolene sesquiterpenoids to pre-treat
10-week-old male C57Bl/6 mice intravenously for 10 min-
utes before PTZ was infused intravenously into the mice.
The study found that 50 mg/kg of ar-turmerone or 100 mg/kg
of α,β-turmerone significantly incr eased the PTZ dose re-
quired to trigger all behavioural endpoints (ear twitch, myo-
clonic twitch, tail twitch, forelimb clonus, falling, tonic
hindlimb extension and death), though they did not test α-
atlantone due to the small amount available.
In another study, the bisabolene sesquiterpenoid ar-
turmerone was also intraperitoneally given to 10-week-old
male NMRI mice at doses of 0.01, 0.1, 1, 20 or 50 mg/kg 30
minutes before electrical stimulation using the 6-Hz psy-
chomotor seizure assay [47]. Mice given ar-turmerone at a
dose of at least 0.1 mg/kg displayed normal exploratory and
locomotion behaviour and were all protected from electri-
cally induced sudden behavioural arrest, whisker trembling,
head nodding, facial and mouth jerking, forelimb clonus and
dorsiflexion of the tail (Straub tail). When given intraperito-
neally 24 hours before electrical stimulation, 50 mg/kg of ar-
turmerone still protected 70% of the mice. The same dose of
ar-tumerone was also found to persist in the mouse brains as
early as 15 minutes after administration and for at least 24
hours using reversed-phase HPLC. The same study also
treated 10-week-old C57Bl/6 mice with ar-tumerone via the
intraperitoneal route and found that a 10-minute pre-
treatment of 1 mg/kg of at-tumerone was sufficient to raise
the PTZ dose necessary to cause tonic hind limb extension
and death, whereas a 20 mg/kg dose had the same effect only
on death. When given intraperitoneally 10 minutes before-
hand, a 50 mg/kg dose of ar-tumerone was found not to af-
fect the balance of 10-week-old C57Bl/6 mice in the beam
walking test in contrast with the established ASM diazepam
which impairs balance. The authors of the study also found
that when 46 µM of ar-tumerone was added into water con-
taining seven dpf AB strain zebrafish larvae for an hour be-
fore subsequent exposure to PTZ, ar-tumerone counteracted
PTZ induced c-fos upregulation but did not affect the expres-
sion of the GABAA receptor and Il-10, as determined using
RT PCR. Interestingly, they found that ar-tumerone alone
upregulated brain-derived neurotrophic factor (bdnf) and this
upregulation was even more prominent when also exposed to
PTZ.
4. DISCUSSION
This systematic review has discovered a significant num-
ber of studies that experimentally demonstrate the potential
of Curcuma longa and its bioactive components for the man-
agement of epileptic seizures. However, all the studies in this
review were non-clinical studies that did not involve human
testing, which is a major stumbling block towards the goal of
managing epileptic seizures in human patients. In addition,
relying on published works carries the inherent risk of publi-
cation bias as studies demonstrating a lack of positive results
are less likely to be published. Therefore, the three studies
with negative results in this review [31, 35, 36] will be
weighed and examined equally for any contradictions to the
other positive findings. Nevertheless, there could be some
insights gained by analyzing all the results of the substantial
number of studies in this review. Two of these major insights
would be treatment parameters as well as possible mecha-
nisms of action and will be discussed below.
4.1. Treatment Parameters for Curcuma longa and Its
Neuroactive Components for the Management of Epilep-
tic Seizures
To compare treatment parameters between the different
studies, four main points were considered, namely which
component of Curcuma longa has been used, treatment pa-
rameters for that component (dose, route and duration), sei-
zure model (induction method, dose, route and duration) and
finally the animal model used. Next, non-animal in vivo
models were excluded due to lower clinical relevance (the
seizure phenotype cannot be expressed) and the difficulties
in converting the treatment parameters to in vivo models due
to pharmacokinetic differences. This exclusion leaves three
in vivo animal models, rats, mice and zebrafish, with rats and
mice being the overwhelmingly dominant animal models.
Unfortunately, given that there are currently no guidelines
for converting zebrafish doses to mammalian equivalents
[54], this analysis is left with the mice and rat models for
which human equivalent dose calculations exist [55, 56]. The
next exclusion criterion would be the use of different formu-
lations (such as micronized, n anoparticles, liposomal) or
synthetic analogs of Curcuma longa components as these
parameters are more likely to be study-specific and are not
components of Curcuma longa in a sense that they are not
naturally occurring. After applying all the exclusion criteria,
the selected studies along with the main parameters are tabu-
lated in Table 2. The human treatment parameters are based
on the lowest dose and shortest treatment duration for a
given administration route if multiple studies are being con-
sidered for a particular model. These treatment parameters
make the simplistic assumption that the base seizure severity
of all the studies for a given model is similar and that the
treatment ou tcomes are similar. Thus, these treatment pa-
rameter recommendations should be treated as a starting
point for further exploration and refinement of the dose,
treatment duration, and possibly the route of administration.
The first seizure model is the PTZ induced seizure model
in which PTZ antagonizes the GABAA receptor to produce
primary generalized seizures [57]. The studies in this review
used PTZ in three different ways, single-dose, continuous
intravenous infusion, or kindling (repeated, intermittent ad-
ministration of sub-convulsive doses that ultimately produce
a tendency to develop seizures [58]. The second seizure
model is the kainic acid-induced seizure model, as kainic
acid is a cyclic analog of L-glutamate and an agonist of
ionotropic kainic acid receptors, which causes excitatory
responses in cortical neurons, making it a model of temporal
lobe epilepsy [59]. The third seizure model is the pilo-
carpine-induced seizure model of epilepsy as pilocarpine is a
muscarinic receptor agonist and may be administered with
lithium to increase rats' susceptibility to this model of tempo-
ral lobe epilepsy [60]. The fourth seizure model utilized by
the selected studies is the iron-induced seizure model, which
is believed to occur due to cortical neurons' reaction to iron-
induced oxidative stress and is said to be a model of post-
traumatic epilepsy [61]. The fifth seizure model is the peni-
cillin-induced seizure model which appears to interact with
1510 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
Table 2. Details of the treatment parameters and the seizure model for selected relevant rodent studies in this systematic review. A
green background represents working treatments and a red background represents non-working treatments. For working
treatments, the lowest working dose/du ration and the highest dose/du ration used fo r non-working treatments is given.
Component
Dose
(mg/kg)
Route
Treatment
Duration
Seizure Induction
Method
Convulsant Dose
Seizure
Route
Duration of Seizure
Induction
Animal
Curcumin [19]
20
ip
14 days
PTZ
60 mg/kg
ip
Single dose
Wistar Rats
Curcumin [20]
50
po
3 days
Lithium +
Pilocarpine
3 mEq/ml/kg +
20 mg/ml/kg
ip + sc
Single dose
SD Rats
Curcumin [22]
100
ip
7 days
Kainic Acid
10 mg/kg
ip
Single dose
Wistar Rats
CL Extract
[23]
200
po
21 days
MES
-
-
-
Albino Mice
CL Extract
[23]
100
po
21 days
PTZ
80 mg/kg
ip
Single dose
Albino Mice
Curcumin [24]
20
ip
14 days
PTZ
60 mg/kg
ip
Single dose
Wistar Rats
Curcumin [25]
100
po
14 days
PTZ
95 mg/kg
ip
Single Dose
Swiss Al-
bino Mice
Curcumin [25]
100
po
14 days
MES
-
-
-
Swiss Al-
bino Mice
Curcumin [26]
80
po
21 days
Pilocarp ine
380 mg/kg
ip
Single dose
Wistar Al-
bino Rats
Curcumin [28]
50
po
7 days
PTZ
25 mg/kg
ip
35 days alternately
Swiss Al-
bino Mice
Curcumin [29]
100
ip
10 minutes
(single dose)
Penicillin
200 IU, 1 µl
ic
Single dose
Wistar Rats
Curcumin [30]
80
po
45 minutes
(single dose)
PTZ
0.5% (w/v)
Infusion
Continuous (up to three
minutes or onset of
extension phase)
Albino Mice
Curcumin [31]
80
ip
75 minutes
(single dose)
PTZ
0.5% (w/v)
Infusion
Continuous (up to onset
of forelimb clonus)
NMRI Mice
Curcumin [32]
150
ip
25 minutes
(single dose)
PTZ
80 mg/kg
ip
Single dose
Mice
Curcumin [33]
100
ip
24 days
PTZ
35 mg/kg
ip
24 days alternately
Wistar Rats
Curcumin [34]
50
ip
15 days
PTZ
35 mg/kg
ip
15 days alternately
Swiss Al-
bino Mice
Curcumin [35]
300
ip
120 minutes
(single dose)
MES
-
-
-
Swiss Mice
Curcumin [36]
25
ip
10 days
PTZ
36.5 mg/kg
ip
10 days alternately
NMRI Mice
Curcumin [37]
100
po
10 weeks
PTZ
35 mg/kg
ip
10 weeks alternately
Wistar Rats
Curcumin [38]
100
ip
14 days
Kainic Acid
0.8 µg
ihc
Single dose
Wistar Rats
Curcumin [39]
100
po
40 days
PTZ
40 mg/kg
ip
30 days alternately
Wistar Rats
Curcumin [40]
100
po
40 days
PTZ
40 mg/kg
ip
30 days alternately
Wistar Rats
Curcumin [41]
100
Food
6 months
FeCl3
100 mM
ic
Single dose
Wistar Rats
Curcumin [42]
12.5
ip
30 days
PTZ
36.5 mg/kg
ip
20 days alternately
NMRI Mice
Curcumin [43]
100
po
43 days
PTZ
30 mg/kg
ip
43 days alternately
Wistar Rats
(Table 2) contd….
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1511
Component
Dose
(mg/kg)
Route
Treatment
Duration
Seizure Induction
Method
Convulsant Dose
Seizure
Route
Duration of Seizure
Induction
Animal
Curcumin [45]
80
po
21 days
Pilocarp ine
380 mg/kg
ip
Single dose
Wistar
Albino Rats
CL Oil [46]
50
iv
-
PTZ
7.5 mg/ml,
150 µl/min
iv
Continuous (infused
until death occurs be-
tween three to five
minutes after starting)
C57BI/6
Mice
α,β-turmerone
[46]
100
iv
-
PTZ
7.5 mg/ml,
150 µl/min
iv
Continuous (infused
until death occurs be-
tween three to five
minutes after starting)
C57BI/6
Mice
Ar-Tumerone
[46]
50
iv
-
PTZ
7.5 mg/ml,
150 µl/min
iv
Continuous (infused
until death occurs be-
tween three to five
minutes after starting)
C57BI/6
Mice
Ar-Tumerone
[47]
50
ip
10 minutes
(single dose)
6 Hz Corneal
Stimulation
-
-
-
NMRI Mice
Ar-Tumerone
[47]
50
ip
30 minutes
(single dose)
PTZ
7.5 mg/ml,
150 µl/min
iv
Continuous
C57BI/6
Mice
Curcumin [49]
300
po
60 minutes
(single dose)
PTZ
60 mg/kg
ip
Single dose
Wistar Rats
Curcumin [49]
300
po
60 minutes
(single dose)
MES
-
-
-
Wistar Rats
Curcumin [51]
200
po
3 days
Kainic Acid
10 mg/kg
ip
Single dose
Swiss
Albino Mice
Curcumin [52]
200
po
2 weeks
Lithium + Pilo-
carpine
125 mg/kg +
20 mg/kg
ip
Single dose
SD Rats
Abbreviations: CL: Curcu ma longa , MES: Maxima l ElectroShock, PTZ: Pen tylenetetrazol, SD: Sprague-Dawley, ic: Intracortical, ihc: Intrahippocampal, ip: Intraperitoneal,
po: Oral, sc: Subcutaneous.
GABA to reduce its inhibitory activity via penicillin’s β-
lactam ring [62], and is a model of focal mo tor seizures [63].
The sixth seizure model is the MES-induced seizure model,
whereby electrical stimulation is used to predict effective
drugs against tonic-clonic (grand mal) type generalized sei-
zures [64]. The seventh model is the 6 Hz corneal stimula-
tion model, which produces seizures that resemble the be-
haviors seen in human limbic epilepsy [65].
4.1.1. Treatment Parameters for Curcumin
This section is subdivided according to seizure type due
to the large number of studies that fall under this category.
4.1.1.1. Treatment Parameters for Generalised Seizures
(PTZ Induced)
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], a 12.20
mg/kg dose of curcumin given as an intraperitoneal injection
25 minutes beforehand [32] or a 3.226 mg/kg dose of cur-
cumin given as an intraperitoneal injection daily for 14 days
to a 60 kg human could treat single generalized seizure
events [19, 24] (single dose PTZ acute seizure model). Sin-
gle seizure events could also be treated by a 48.39 mg/kg
dose of curcumin given orally 60 minutes beforehand [49] or
an 8.130 mg/kg dose of curcumin given orally daily for 14
days [25]. Using the same recommendations, a 4.065 mg/kg
dose of curcumin given as an intraperitoneal injection daily
for 15 days [34] or a 1.016 mg/kg dose of curcumin given as
an intraperitoneal injection daily for 30 days to a 60 kg hu-
man could be used to treat recurrent generalized seizure
events [42] (PTZ kindling model). Recurrent generalized
seizure events could also be treated by a 6.504 mg/kg dose
given orally 45 minutes beforehand [30] (PTZ infusion
model) or a 4.065 mg/kg dose given orally daily for 7 days
[28] (PTZ kindling model) to a 60 kg human.
4.1.1.2. Treatment Parameters for Temporal Lobe Epilepsy
(Kainic Acid-Induced)
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], a 16.13
mg/kg dose of curcumin given as an intraperitoneal injection
daily to a 60 kg human for seven days [22] or a 16.26 mg/kg
dose of curcumin given orally daily for three days [51] could
treat temporal lobe epilepsy.
1512 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
4.1.1.3. Treatment Parameters for Temporal Lobe Epilepsy
(Pilocarpine Induced)
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], an 8.065
mg/kg dose of curcumin given orally daily to a 60 kg human
for three days [20] could treat temporal lobe epilepsy.
4.1.1.4. Treatment Parameters for Post-Traumatic Epilepsy
(Iron Induced)
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], a 16.13
mg/kg dose of curcumin intake daily by a 60 kg human for
six months could treat post-traumatic epilepsy [41].
4.1.1.5. Treatment Parameters for Focal Motor Seizures
(Penicillin Induced)
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], a 16.13
mg/kg dose of curcumin given as an intraperitoneal injection
to a 60 kg human 10 minutes beforehand [29] could treat
focal motor seizures.
4.1.1.6. Treatment Parameters for Tonic-Clonic (Grand
Mal) Type G eneralised Seizures ( MES Induced)
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], a 48.39
mg/kg dose of curcumin given orally to a 60 kg human 60
minutes beforehand [49] or an 8.130 mg/kg dose of curcu-
min given orally daily to a 60 kg human for 14 days [25]
could treat tonic-clonic (grand mal) type generalized sei-
zures.
4.1.2. Treatment Parameters for Aqueous Curcuma longa
Extract
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], an 8.130
mg/kg dose of aqueous Curcuma longa extract delivered as a
daily intraperitoneal injection into a 60 kg human for 21 days
[23] could treat tonic-clonic (grand mal) type generalized
seizures and a 16.26 mg/kg dose [23] primary generalized
seizures.
4.1.3. Treatment Parameters for Curcuma longa Oil
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], a 4.065
mg/kg intravenous infusion of Curcuma longa oil [46] into a
60 kg human could treat primary generalized seizures.
4.1.4. Treatment Parameters for α,β-turmerone
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], an 8.130
mg/kg continuous intravenous infusion of α,β-turmerone
[46] into a 60 kg human could treat primary generalized sei-
zures.
4.1.5. Treatment Parameters for Ar-turmerone
Using the United States Food and Drug Administration
human equivalent dose recommendations [56], a 4.065
mg/kg continuous intravenous infusion of Ar-turmerone or
an intraperitoneal injection with the same dose 30 minutes
beforehand [46] into a 60 kg human could treat primary gen-
eralized seizures. A 4.065 mg/kg dose of Ar-turmerone de-
livered as an intraperitoneal injection 10 minutes beforehand
[47] into a 60 kg human could treat human limbic epilepsy.
4.1.6. Overall Discussion of Treatment Parameters
Only three studies reported negative results in this re-
view, which were only related to the usage of curcumin in
the P TZ and MES models. Using these few cases in which
treatment with curcumin was unsuccessful, a general obser-
vation could be made. When given as a single dose a short
period (tens of minutes to several hours) before seizure in-
duction, a high curcumin concentration is required to be ef-
fective. However, increasing the number of doses over a
prolonged period (days to weeks) reduces the concentration
of curcumin needed in each dose to be effective. This could
be due to the well-known bioavailability problems of curcu-
min. However, it is safe in human clinical trials even at a
high dose of 12 g per day [66], which could allow for the
bioavailability problems to be offset by giving a higher dose.
Curcumin has bioavailability problems as it is relatively
poorly absorbed by the small intestine and undergoes exten-
sive conjugative and reductive metabolism in the liver when
given orally [67]. This correlates with the earlier observation
that a high dose or repeated doses are required as this low
bioavailability must be overcome. The curcumin treatment
parameters recommended by this review also suggest the
intraperitoneal route, which is rarely used in humans [68],
but can result in a higher and faster peak plasma concentra-
tion as quickly as after 15 minutes in mice but it may decline
rapidly thereafter in comparison to the oral route, in which
the plasma concentration peaks after one hour but declines
more gradually over several hours [69]. In addition, the half-
life of curcumin when taken orally differs from species to
species such as around 32 minutes for rats [70] and around
six to seven hours in humans [71. However, the rapid degra-
dation of curcumin may not be negative as it has been sug-
gested that the efficacy of curcumin despite its degradation
could be due to its degradation products being the active
compounds rather than curcumin itself [72]. Alternative ap-
proaches to bioavailability have also been explored by some
of the studies in this review, which are the creation of syn-
thetic curcumin analogues [48] or different formulations [27,
36, 42, 44, 50]. When the studies in this review compared
the different formulations of curcumin to the base free cur-
cumin, they found that the curcumin formulation was more
effective at a given dose [36, 42, 50]. The compound piper-
ine, which is found in black pepper, can also greatly increase
curcumin bioavailability due to its inhibition of hepatic and
intestinal glucuronidation [73].
4.2. Possible Anti-Epileptic Mechanism of Action for
Curcuma longa and Its Neuroactive Components for the
Management of Epileptic Seizures
Similar to the determination of the suggested treatment
parameters, this review will attempt to infer a mechanism of
action for the various bioactive components by analyzing the
proposed mechanism of action hypothesized by each study in
this review and synthesizing them together to a better under-
standing of the overall mechanism. This synthesis will take
into account all the studies in this review that have positive
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1513
results as well as both directly (such as the measurement of
oxidative stress markers for antioxidant activity) and indi-
rectly (such as a decrease in oxidative stress being associated
with a particular outcome) to determine mechanisms of ac-
tion. Most of these studies analyzed either the whole br ain or
specific regions of the brain (commonly the hippocampus
and the cortex) from one species (typically rats or mice), and
so it is unclear if these mechanisms would apply outside the
brain or in other species. The possible mechanisms are
graphically summarized in Fig. 2, and are discussed in
greater detail further below.
4.2.1. Possible Anti-Epileptic Mechanism of Action for
Curcumin
Antioxidant Effect
a Increases brain endogenous antioxidant defenses
i Increase in glutathione levels.
ii Activation of oxidative stress defensive
genes.
b Reduces brain oxidative stress
i Reduces lipid peroxidation.
ii Scavenges reactive oxygen species or re-
duces its production.
iii Reduces protein carbonylation.
c Restores brain mitochondrial functions
i Restores activities of the mitochondrial
complexes in the hippocampus and cere-
bral cortex due to a reduction in oxidative
stress.
ii Prevents mitochondrial swelling due to
membrane permeability changes.
iii Possibly due to phenolic and β-diketone
curcumin functional groups which scav-
enge free radicals and ameliorate oxidative
stress.
Anti-Inflammatory Effect
a Upregulates anti-inflammatory cytokines
b Downregulates pro-inflammatory cytokines
c Inhibits the inflammatory signaling cascade
i Inhibits the mammalian target of rapamy-
cin (mTOR) pathways and inflammatory
mechanisms.
ii Inhibits the activation of astrocytes and
microglia.
Neuroprotective Effect
a Increases neurogenesis
i Reverses stress-induced decrease in pro-
genitor cell proliferation in the subgranular
zone.
ii Proliferation and recruitment of neural
stem cells increased by overexpression of
erythropoietin or klotho due to downregu-
lation of Tnf-α via NFκB and the reduction
in the level of the erythropoietin receptor.
iii Erythropoietin has neuroprotective proper-
ties.
a Reduces apoptosis and necroptosis
b Induces autophagy
Fig. (2). Summary of the possible mechanisms of action for the bio activ e components of Curcuma longa as hypothesized by the studies ana-
lyzed in this sy stematic review. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
1514 Current Neuropharmacology, 2021, Vol. 19, No. 9 Choo and Shaikh
c Decreases cell death due to a reduction in oxidative
stress
d Upregulates nicastrin, CX3CL1 and CXCL16
e Regulates microglial activation and microglial genes
Improvement of Cognition
a Modulates BDNF, synapsin I and cyclic adenosine
monophosphate response element-binding protein
(CREB) levels
b Reduces neuronal loss, gliosis, abnormal mossy fiber
sprouting
Modulation of Neurotransmitter Signalling
a Promotes neuronal inhibition
i Increases GABA synthesis (possibly by an
increase in its precursor g lutamine) at the
expense of the major excitatory amino acids.
ii Direct or indirect activation of adenosine
A1 but not A2A receptors.
iii Increases serotonin levels and/or serotonin
Receptor 1A (HTR1A), HTR2C and HTR4
activation. Reduces HTR7 protein expression.
iv Inhibits monoamine oxidase A.
v Reduces acetylcholinesterase activity.
vi Inhibits the catecholaminergic mechanism.
a Reduces neuroexcitation
i Reduces the activity of glutamate receptors
(N-methyl-D-aspartate [NMDA], kainate)
but does not appear to affect AMPA.
ii Reduces hyperexcitability by reducing ex-
citatory glutamate activity and protects
against glutamate-induced cytotoxicity by
influencing intracellular calcium homeo-
stasis via the modulation of taurine.
b Reduction of nitric oxide production
i Mediated through the L-arginine – Nitric
Oxide pathway.
ii Inhibition of nitrosative stress.
iii Conflicting reports on whether neuronal
nitric oxide synthase or inducible nitric ox-
ide synthase is responsible.
Downregulation of Sodium Ion Channels
a It may be associated with the downregulation of
Nav1.1 in the cortex
Downregulation of Corticosterone
a Reduces corticosterone levels under stressful condi-
tions to reduce stress potentiated seizure activity
b Attenuates neuronal death in the hippocampal CA1
and CA3 areas by normalizing corticosterone blood
serum levels
4.2.1.1. Overall Discussion of the Anti-Epileptic Mecha-
nism of Curcumin
As represented in Fig. 2, both antioxidant effects [74] and
anti-inflammatory effects [75] are associated with neuropro-
tection due to a reduction in neuronal loss, which is itself
associated with an improvement in cognition [76, 77]. Simi-
larly, the promotion of neuroinhibition and the reduction of
neuroexcitation via the modulation of neurotransmitter sig-
nalling or sodium ion channels have the potential to help in
the management of epileptic seizures as they are the basis by
which many current ASMs exert their action [78]. The abil-
ity of curcumin to possibly reduce stress potentiated seizure
activity is essential as conventional therapies focus on strate-
gies to minimize stress rather than treating it pharmacologi-
cally, though the relationship between stress and seizures is
not entirely clear [79]. While the associations are depicted in
this way, signif icant relationships have been observed be-
tween the differen t mechanisms of action as neuronal cell
death can also potentiate seizures, and also, seizures can also
cause neuronal cell death [80]; hence, ameliorating one will
also benefit the other. Inflammation [81] and oxidative stress
[82] are also related to the occurrence of seizures, and BDNF
plays a role in cognition and seizures, oxidative stress, and
inflammation as well [83]. One of the studies in this review
has also shown that normalizing corticosterone blood serum
levels also attenuates hippocampal neuronal death [24] and
further emphasizes how intertwined the various mechanisms
are.
Also intertwined are epilepsy and its various comorbid-
ities, which are exceedingly common in epilepsy patien ts
and are categorised into medical (such as obesity and diabe-
tes), psychiatric (such as depression and anxiety) and cogni-
tive (such as learning disabilities and dementia) [84]. This
association is perhaps what led some studies in this review to
examine the effect of curcumin on depression [34] as well as
the learning and memory aspect of cognitive dysfunction
[20, 24, 25, 34, 36, 38, 39, 43] using rodent models. Those
studies have identified ameliorative properties of curcumin
on these comorbidities and thus raised the intriguing possi-
bility of curcumin not only for seizure management but also
the management of psychiatric and neurological comorbid-
ities, such as depression and memory loss in particular.
The contradiction on whether inhibition of neuronal nitric
oxide synthase [33] or inducible nitric oxide synthase [31] is
responsible for reducing nitric oxide levels could be ex-
plained by two significant differences in their treatment pa-
rameters. The first significant difference is the treatment
compound whereby one study used pure curcumin, and an-
other used a mixture of curcumin, demethoxycurcumin and
bisdemethoxycurcumin. The treatment times also signifi-
cantly different, with the combination being given 75 min-
utes beforehand and the pure curcumin being given daily for
24 days. As the effect of each component of the mixture and
Mechanism of Curcuma longa and Its Neuroactive Components Current Neuropharmacology, 2021, Vol. 19, No. 9 1515
the effect of treatment duration have not been compared
equivalently, it is difficult to identify the cause of this con-
tradiction as the different components of the mixture differ
in th e strength of their effects [85] and cou ld also differ in
their mechan isms of action.
4.2.2. Possible Anti-Epilep tic Mechanism of Action for
Aqueous Curcuma longa Extract
The possible anti-epileptic mechanism of action for an
aqueous extract of Curcuma longa could not be determined
by the lone study in this review that used it.
4.2.3. Possible Anti-Epilep tic Mechanism of Action for
Curcuma longa Oil
The possible anti-epileptic mechanism of action for Cur-
cuma longa oil is a neuroprotective action due to the sup-
pression of oxidative DNA damage and lipid peroxidation.
4.2.4. Possible Anti-Epilep tic Mechanism of Action for
Bisabolene Sesquiterpenoids
The possible anti-epileptic mechanism of action for the
bisabolene sesquiterpenoids is speculated to be due to their
antioxidant effects. However, the exact mechanism of action
is not known for α,β-turmerone and α-atlantone. For ar-
tumerone, its anticonvulsant effects could be due to GABA-
mediated inhibition and the upregulation of BDNF, which
could have a neuroprotective effect. It is also possible that
metabolites of ar-tumerone could be responsible for its ap-
parent activity as ar-tumerone concentrations in the brain
after treatment would be low.
CONCLUSION
The present systematic review indicates that an aqueous
extract of Curcuma longa itself and Curcuma longa oil, as
well as the curcumin and bisabolene sesquiterpenoids found
in Curcuma longa, have been experimentally proven to have
the poten tial for epileptic seizure managemen t as well as the
depression and memory loss comorbidities. Suggested hu-
man treatment parameters and the possible mechanism of
action for their epileptic seizure management effects have
also been discussed to pave the way for future research and
ASM development.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING!
This work was funded by the Tropical Medicine and Bi-
ology Platform of Monash University, Malaysia (TMB-
2020-SG3185140921-BCKM/MFS).!
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Fig. (2) uses images designed by Freepik
(http://www.freepik.com).
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