Epilepsy Research (2014) 108, 411419

journal homepage: www.elsevier.com/locate/epilepsyres

Acute administration of ginger (Zingiber

ofcinale rhizomes) extract on timed
intravenous pentylenetetrazol infusion
seizure model in mice
Abdolkarim Hosseini, Naser Mirazi
Department of Biology, Faculty of Basic Science, Bu-Ali Sina University, Hamedan, Iran
Received 30 August 2013; received in revised form 3 December 2013; accepted 9 January 2014
Available online 30 January 2014

KEYWORDS
Seizure;
Ginger;
Phenobarbital;
Pentylenetetrazole;
Mice

Summary
Purpose: Zingiber ofcinale (Zingiberaceae) or ginger, which is used in traditional medicine
has antioxidant activity and neuroprotective effects. The effects of this plant on clonic seizure
have not yet been studied. The present study evaluated the anticonvulsant effect of ginger in
a model of clonic seizures induced with pentylenetetrazole (PTZ) in male mice.
Materials and methods: The anticonvulsant effect of Z. ofcinale was investigated using i.v.
PTZ-induced seizure models in mice. Different doses of the hydroethanolic extract of Z. ofcinale (25, 50, and 100 mg/kg) were administered intraperitonal (i.p.), 2 and 24 h before induction
of PTZ. Phenobarbital sodium (30 mg/kg), a reference standard, was also tested for comparison. The effect of ginger on to the appearance of three separate seizure endpoints (myoclonic,
generalized clonus and forelimb tonic extension phase) was recorded.
Results: The results showed that the ginger extract has anticonvulsant effects in all the experimental treatment groups of seizure tested as it signicantly increased the seizure threshold.
Hydroethanolic extract of Z. ofcinale signicantly increased the onset time of myoclonic
seizure at doses of 25100 mg/kg (p < 0.001) and signicantly prevented generalized clonic
(p < 0.001) and increased the threshold for the forelimb tonic extension (p < 0.01) seizure 2 and
24 h before induction of PTZ compared with control group.
Conclusion: Based on the results the hydroethanolic extract of ginger has anticonvulsant effects,
possibly through an interaction with inhibitory and excitatory system, antioxidant mechanisms,
oxidative stress and calcium channel inhibition.
2014 Elsevier B.V. All rights reserved.

Corresponding author. Tel.: +98 91 88125741;

fax: +98 81 18381058.
E-mail address: mirazi205@gmail.com (N. Mirazi).

0920-1211/$ see front matter 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eplepsyres.2014.01.008

412

Introduction
Epilepsy is a common neurological disorder characterized
by recurrent, unpredictable seizures with a prevalence
rate of about 1% (McNamara, 1986). A great deal of
research is currently being conducted to reveal the mechanisms underlying epilepsy and to nd more effective
drugs for epilepsy treatment. The available antiepileptic medications can be effective in the seizures in only
about 40% of cases, and they merely reduce the frequency of convulsions in other cases (Delgado-Escueta
et al., 1999). Unfortunately, despite the availability of a
diverse array of anti-epileptic drugs (AEDs), approximately
half of patients treated with modern AEDs continue to
experience seizures (Pitkanen, 2002). Furthermore, undesirable side effects of the drugs used clinically often render
treatment difcult; so a demand for new types of anticonvulsants exists. One of the approaches to search for
new antiepileptic drugs is investigation of naturally occurring compounds belonging to new structural classes (Sayyah
et al., 2011).
There is evidence that dietary enrichment with nutritional antioxidants could improve cognitive function (Bisson
et al., 2008; Head, 2009). Zingiber ofcinale Roscoe (Zingiberaceae), or ginger is widely used as a spice. Indians
and Chinese are believed to have produced ginger as a
tonic root for over 5000 years to treat many ailments,
and this plant is now cultivated throughout the humid
tropics, with India being the largest producer (Benzie
and Sissi, 2011). The oleoresin from the rhizomes of
ginger contains many bioactive components, such as [6]gingerol, which is the primary pungent ingredient that
is believed to exert a variety of remarkable pharmacological and physiological activities. Ginger has been used
for thousands of years for the treatment of numerous
ailments, such as colds, arthritis, migraines, and hypertension (Benzie and Sissi, 2011). It is used in traditional
Asian medicine for the treatment of stomachaches (Mascolo
et al., 1989), nausea, diarrhea, and joint and muscle
pain (Ojewole, 2006). Recently, several research groups
have demonstrated that ginger has anti-inammatory effect
(Chang et al., 1995; Lantz et al., 2007), antioxidant activity (Kuo et al., 2005; Nanjundaiah et al., 2011) and a
neuroprotective effect (Waggas, 2009; Shanmugam et al.,
2011). Antioxidants in ginger include gingerols, shogaols and
some phenolic ketone derivatives. The anti-inammatory
and antioxidant properties in ginger help relieve various inammatory disorders such as gout, osteoarthritis,
and rheumatoid arthritis. It provides substantial relief in
pain caused by inammation and help decrease swelling
and morning stiffness (Habib et al., 2008). Another study
suggests that ginger can reduce cell death and restore
motor function in a rat spinal cord injury (Kyung et al.,
2006).
Laboratory models for epilepsy induction make it possible to analyze the mechanisms and predisposing factors
of epilepsy and to evaluate anticonvulsive drugs and treatment modalities. One of these models is an intravenous PTZ
(i.v. PTZ) infusion with a constant ow rate through the
tail vein in mice (Orloff et al., 1949; Nutt et al., 1986)
or the jugular vein catheter in rats (Pollack and Shen,

A. Hosseini, N. Mirazi
1985) elicits seizure response in a reliable, reproducible
and rapid manner. Depending on dosage, PTZ can produce myoclonic jerking movements, clonic convulsions, or
forelimbs/hindlimbs tonic extension (Snead, 1992; Swinyard
et al., 1989). The objective of the present study was
to evaluate the anticonvulsant activity of hydroethanolic
extract of Z. ofcinale in the timed i.v. PTZ seizure test
in mice.

Materials and methods

Plant material
The fresh rhizomes of Z. ofcinale (herbarium code no.
1483) were purchased from the Institute of Medicinal Plants
Tehran, Iran.

Preparation of the extract

Approximately 200 g of the dried rhizome powder from Z.
ofcinale were extracted with 3 L of 80% aqueous ethanol
using the percolation method at room temperature. The
extracts were ltered through lter paper and evaporated
to dryness under reduced pressure at a maximum of 45 C
using a rotary evaporator. Z. ofcinale extract (ZOE) was
dissolved in normal saline to a stock concentration of 50%
(w/v) and then stored at 4 C. The dosage calculations were
based on body weight of animals.

Drugs
Drugs used were PTZ (purchased from the Sigma, Bristol,
UK) and Phenobarbital Na (purchased from the Chemidaru
Industrial Company, Iran). PTZ was prepared in saline as 1%
(w/v) solution. Based on previous study on dose response
of phenobarbital (PB) (Markowitz et al., 2011) the dose of
30 mg/kg (dissolved in physiologic saline solution) was chosen as suitable dose for this investigation.

Experimental animals
Adult male Swiss mice that weighed 2535 g (Razi Institute, Karadj, Iran) were used in the study. The animals were
housed in standard polycarbonate cages in a temperaturecontrolled room (22 2 C) on a 12-h light/dark cycle with
free access to food and water and were acclimated at least
one week before experiments. The experiments were conducted between 9:00 AM and 3:00 PM. All procedures were
conducted in accordance with the European Parliament and
of the Council Directive of 22 September 2010 (2010/63/EU).
The experimental procedures and protocols were approved
by the First Local Ethics Committee at the Medical University
of Tehran. Each mouse was used only once and the animals were euthanized after the experiment. Each treatment
group consisted of at least six animals. The animals were
randomly assigned to the following groups that are shown in
Table 1.

Ginger extract on timed intravenous pentylenetetrazol infusion seizure model

Table 1 Experimental assigned groups, 2 and 24 h before
PTZ injection.
Groups

Treatment

Group I

Vehicle control
(normal saline)
Phenobarbital (PB)
Zingiber ofcinale
extract (ZOE)
Zingiber ofcinale
extract (ZOE)
Zingiber ofcinale
extract (ZOE)

Group II
Group III
Group IV
Group V

Dose
1 ml/kg i.p.
30 mg/kg i.p.
25 mg/kg i.p.
50 mg/kg i.p.
100 mg/kg i.p

The timed i.v. PTZ infusion test in mice

The test was conducted in mice based on the previously
reported method (Mandhane et al., 2007) with some modication. A buttery cannula (needle size 30G, DENTSPLY
MPL Technologies, England) attached to an insulin syringe
prelled with PTZ solution was used. For the purpose of
infusion, the animal was restrained and needle was inserted
into the tail vein. The needle was connected by polyethylene tubing with a plastic syringe that was placed in the
syringe pump (GMS Syringe Pump, Singapore). The accuracy
of needle placement in the vein was conrmed by appearance of blood in the cannula. The needle was secured to
the tail by a special tape. The animal was kept in a transparent Perspex box with holes for ventilation. In this way
animal could move freely in the box without strain on the
attached cannula with no severe struggling. The syringe
contained 1% solution of PTZ in saline, which was administered into the vein of unrestrained animal at a constant rate
of 1 ml/min. The time intervals from the start of infusion
of PTZ solution to the appearance of three separate endpoints, i.e., rst myoclonic twitch, generalized clonus with
loss of righting reex and forelimb tonus, were recorded.
The thresholds were calculated separately for each endpoint
according to the following formula: threshold dose of PTZ
(mg/kg) = (infusion duration (s) infusion rate (ml/s) PTZ
concentration (mg/ml) 1000)/body weight kg.

Statistical analysis
Seizure thresholds were expressed as the amount of PTZ (in
mg/kg) SEM (standard error of the mean) needed to produce the rst apparent sign of each endpoint, and analyzed
with the one-way analysis of variance (ANOVA) followed by
Tukeys post hoc test. P < 0.05 was considered statistically
signicant.

Results
An intravenous infusion of PTZ with a constant ow rate in
mice elicited stereotyped seizure response in the following
sequence: myoclonic twitch, generalized clonus with loss of
righting reex and forelimb tonus. The seizure manifestation progressed from one stage to the other, as the infusion
progressed. It was possible to limit the seizure activity by

413

controlling the infusion. The concentration of PTZ solution

and its rate of infusion were constant. Therefore, body
weight of animal and time duration of infusion were the
only variables required to be used in the calculation of
threshold dose for an individual animal.

Effect of different doses of ginger on the threshold

for the myoclonic seizures
The effect of ginger on seizure thresholds for the rst
myoclonic twitch in the i.v. PTZ seizure threshold test in
mice is shown in Fig. 1 (F4,29 = 29.847, p < 0.001; Fig. 1A and
F4,29 = 26.992, p < 0.001; Fig. 1B). Ginger at doses ranging
from 25 to 100 mg/kg and phenobarbital inuenced in rising of thresholds for myoclonic (Fig. 1A and B) seizures in
the timed i.v. PTZ infusion test in mice (p < 0.001) in both
2-h and 24-h treatment group. The mean PTZ injection dose
for appearance of the myoclonic seizures in each treatment
group is presented in Table 2.

Effect of different doses of ginger on the threshold

for the generalized clonic seizures
As shown in Fig. 2, ginger affect thresholds for the generalized clonic seizures (F4,29 = 7.727, p < 0.001; Fig. 2A and
F4,29 = 9.416, p < 0.001; Fig. 2B) provoked by i.v. PTZ infusion in mice. Statistically signicant raise in the threshold
for clonic seizures was also observed in groups of animals
treated with phenobarbital (30 mg/kg (p < 0.01) in 2-h treatment and (p < 0.001) in 24-h treatment) and ginger at the
dose of 100 mg/kg (p < 0.001) in 2-h treatment (Fig. 2A), but
ginger at doses of 25 and 50 mg/kg had no impact on increasing of the threshold. In 24-h treatment ginger at dose of
50 (p < 0.01) and 100 mg/kg (p < 0.001) caused a statistically
signicant increase in the seizure threshold compared with
control group, but ginger at dose of 25 mg/kg had no effect
on increasing of the seizure threshold (Fig. 2B). The mean
PTZ injection dose for appearance of the generalized clonic
seizures in each treatment group is presented in Table 3.

Effect of different doses of ginger on the threshold

for the forelimb tonic extension
In Fig. 3, ginger signicantly increased threshold in comparison with control (saline-treated) group for the forelimb tonic
extension (F4,29 = 5.562, p < 0.01; Fig. 3A and F4,29 = 5.209,
p < 0.01; Fig. 3B) in the timed i.v. PTZ infusion test in mice.
One-way ANOVA revealed that ginger statistically signicant
raised the threshold for tonic seizures and post hoc analysis
showed signicant anticonvulsant effect for the dose of 50
(p < 0.05) and 100 mg/kg (p < 0.01) in 2-h treatment (Fig. 3A),
however, ginger at dose of 25 mg/kg had no impact on
increasing of the seizure threshold. In 24-h treatment ginger
at dose of 25, 50 (p < 0.05) and 100 mg/kg (p < 0.001) caused
a statistically signicant increase in the seizure threshold
compared with control group (Fig. 3B). The mean PTZ injection dose for appearance of the forelimb tonic extension in
each treatment group is presented in Table 4.

414

A. Hosseini, N. Mirazi

Figure 1 Panels A and B: The effect of different doses of ginger (25100 mg/kg) on the threshold for the myoclonic seizures
2-h before PTZ injection (panel A) and 24-h before PTZ injection (panel B) in the i.v. PTZ seizure threshold test in mice. Data are
presented as mean SEM of at least 6 mice in each group. One-way ANOVA followed by the Tukeys post hoc multiple comparison
test was used to analyze the data (PB: phenobarbital; ZOE: Zingiber ofcinale Extract). ***p < 0.001 vs. vehicle control (saline).

Table 2 The mean PTZ injection dose (mg/kg) for appearance of the myoclonic seizures, 2 and 24-h before PTZ injection in
the i.v. PTZ seizure threshold test in mice.
Treatment
Group
Group
Group
Group
Group

I
II
III
IV
V

PTZ dose (mg/kg)

(2-h treatment)
Vehicle control (Saline)
Phenobarbital (30 mg/kg)
Z. ofcinale extract (25 mg/kg)
Z. ofcinale extract (50 mg/kg)
Z. ofcinale extract (100 mg/kg)

22.14
48.64
39.48
42
55.5

1.12
2.52a
2.29a
2.99a
1.82a

PTZ dose (mg/kg)

(24-h treatment)
21.14
41.64
37.16
42.31
44.16

1.13
2.52a
1.69a
1.8a
1.71a

Results are presented as mean SEM of at least 6 mice in each group. One-way ANOVA followed by the Tukeys post hoc multiple
comparison test was used to analyze the data. All treatments were administered i.p. at times and doses scheduled from the PTZ test.
a P < 0.001 compared with vehicle control (normal saline) group.

Discussion
The present study investigated the anticonvulsant activity
of Z. ofcinale in the timed PTZ infusion test in mice.
This test is considered as a very sensitive model of acute

seizures which enables screening of various agents with

different mechanisms of action, both pro- and anticonvulsant. Additionally, it makes possible to assess inuence
of the investigated compounds on separate components of
seizure behavior. Although PTZ-induced seizures are one of

Table 3 The mean PTZ injection dose (mg/kg) for appearance of the generalized clonic seizures, 2 and 24-h before PTZ
injection in the i.v. PTZ seizure threshold test in mice.
Treatment (mg/kg)
Group
Group
Group
Group
Group

I
II
III
IV
V

PTZ dose (mg/kg)

(2-h treatment)
Vehicle control (Saline)
Phenobarbital (30 mg/kg)
Z. ofcinale extract (25 mg/kg)
Z. ofcinale extract (50 mg/kg)
Z. ofcinale extract (100 mg/kg)

39.68
62.72
49.31
53.75
69.25

1.99
3.27a
1.79
6.09
5.16b

PTZ dose (mg/kg)

(24-h treatment)
37.72
55.72
47.32
51.55
54.32

2.32
3.26b
2.02
1.89a
2.02b

Results are presented as mean SEM of at least 6 mice in each group. One-way ANOVA followed by the Tukeys post hoc multiple
comparison test was used to analyze the data. All treatments were administered i.p. at times and doses scheduled from the PTZ test.
a P < 0.01 compared with vehicle control (normal saline) group.
b P < 0.001 compared with vehicle control (normal saline) group.

Ginger extract on timed intravenous pentylenetetrazol infusion seizure model

415

Figure 2 Panels A and B: The effect of different doses of ginger (25100 mg/kg) on the threshold for the generalized clonic
seizures 2-h before PTZ injection (panel A) and 24-h before PTZ injection (panel B) in the i.v. PTZ seizure threshold test in mice.
Data are presented as mean SEM of at least 6 mice in each group. One-way ANOVA followed by the Tukeys post hoc multiple
comparison test was used to analyze the data (PB: phenobarbital; ZOE: Zingiber ofcinale extract). **p < 0.01 and ***p < 0.001 vs.
vehicle control (saline).

the most common experimental models of seizures, mechanism(s) by which PTZ causes convulsions is not entirely
known. It is widely accepted that its proconvulsant activity is at least partially mediated by interactions with the
chloride ion channel in the complex of -aminobutyric acid
(GABA) type A receptors (Mandhane et al., 2007). Moreover,
experimental evidence demonstrated that PTZ increased
the level of cGMP in many brain regions including cerebral
cortex, hippocampus, striatum and cerebellum (Ferrendelli
et al., 1980).

High antioxidant activity of ginger and its compounds

has been demonstrated in numerous reports (Ghasemzadeh
et al., 2010; Rehman et al., 2011). [6]-gingerol a bioactive
component of ginger was reported to dose-dependently
inhibit nitric oxide (NO) production and reduce inducible
nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)stimulated mouse macrophages (Ippoushi et al., 2003).
Reactive nitrogen species, such as NO, inuence signal
transduction and cause DNA damage, which contributes to
disease processes such as seizure. Nitric oxide is produced

Figure 3 Panels A and B: The effect of different doses of ginger (25100 mg/kg) on the threshold for the forelimb tonic extension
2-h before PTZ injection (panel A) and 24-h before PTZ injection (panel B) in the i.v. PTZ seizure threshold test in mice. Data are
presented as mean SEM of at least 6 mice in each group. One-way ANOVA followed by the Tukeys post hoc multiple comparison
test was used to analyze the data (PB: phenobarbital; ZOE: Zingiber ofcinale Extract). *p < 0.05 and **p < 0.01 vs. vehicle control
(saline).

416

A. Hosseini, N. Mirazi

Table 4 The mean PTZ injection dose (mg/kg) for appearance of the forelimb tonic extension seizures, 2 and 24-h before PTZ
injection in the i.v. PTZ seizure threshold test in mice.
Treatment (mg/kg)
Group
Group
Group
Group
Group

I
II
III
IV
V

PTZ dose (mg/kg)

(2-h treatment)
Vehicle control (Saline)
Phenobarbital (30 mg/kg)
Z. ofcinale extract (25 mg/kg)
Z. ofcinale extract (50 mg/kg)
Z. ofcinale extract (100 mg/kg)

60.65
90.88
83.08
90.4
98.58

6.25
3.17a
7.03
6.64a
6.49b

PTZ dose (mg/kg)

(24-h treatment)
60.15
83.88
80.71
80.97
88.1

7.02
3.17a
6.01a
2.87a
2.94b

Results are presented as mean SEM of at least 6 mice in each group. One-way ANOVA followed by the Tukeys post hoc multiple
comparison test was used to analyze the data. All treatments were administered i.p. at times and doses scheduled from the PTZ test.
a P < 0.05 compared with vehicle control (normal saline) group.
b P < 0.01 compared with vehicle control (normal saline) group.

by iNOS, which is stimulated in response to various stresses.

In addition to the above ndings, NO also increases the
level of cyclic guanosine monophosphate (cGMP) through
the activation of soluble guanylyl cyclase (sGC), which
inuences a wide range of physiological functions including regulation of seizure threshold (Ni Dhi et al., 1999).
Numerous experimental studies and clinical observations
indicate that ginger inuences some central nervous system
effects (Ccero et al., 2008), but accurate mechanisms of
its action are not precisely known. It is highly possible that
the observed effects result from the elevated intracellular
cGMP level. It was noted that cGMP and its downstream targets, including PDEs, cGMP-dependent channels and PKG,
regulate neurotransmission, long-term potentiation, gene
expression, neurotoxicity and neurodegenerative processes
(Wang and Robinson, 1997). Components of the NO/cGMP
pathway modulate release of both excitatory and inhibitory
amino acids in the central nervous system (Prast and
Philippu, 2001; Yu and Eldred, 2005). Because imbalance
between the excitatory and inhibitory neurotransmission is
the main reason of epileptic discharges, cGMP may affect
convulsant activity in brain (Garthwaite and Boulton, 1995).
Therefore, it seems that antioxidant property of ginger and
its nitric oxide synthase inhibitory effect can be, at least in
part, responsible for such inhibiting response in this study.
Most AEDs act by three main mechanisms of pharmacological action. They intensify inhibitory potential of GABAergic
system, reduce excitatory neurotransmission and/or affect
voltage-dependent ion channels, mainly calcium, sodium
and potassium (Laso
n et al., 2011). Pharmacological action
of the AEDs, like phenobarbital, is above all connected
to the inuence on GABAergic system. Phenobarbital is an
agonist of GABA and its development was strictly associated with GABAergic hypothesis of epilepsy. In addition to
effects on GABAA receptors, barbiturates block AMPA receptors, and they inhibit glutamate release through an effect
on high-voltage activated calcium channels. These channels are categorized into several subtypes-L, N, P/Q and
R-type, according to their electrophysiological properties
(Armijo et al., 2005). In addition to effects on GABAA receptors, barbiturates block AMPA/kainate receptors, and they
inhibit glutamate release through an effect on P/Q-type
high-voltage activated calcium channels and in this way
reduces calcium inux into the neurons, which subsequently

diminishes generation of action potentials in neuronal cells

n et al., 2011; Czapi
(Laso
nski et al., 2005). Block of Ca2+
channels, which has been demonstrated in a series of in vivo
and in vitro studies, is an important pharmacological action
of ginger (Ghayur et al., 2008a,b; Heinemann et al., 1977).
Not surprisingly, plants such as ginger with Ca2+ channel
blockade property could exert such observed effects. Thus,
the data indicate that the mechanism underlying the prevention of PTZ-induced seizure by ginger extract involves
mediation, at least in part, by attenuating the effect of
seizure threshold on calcium channel inhibition and calcium
homeostasis disturbance.
Data presented in our study showed that ginger increased
the threshold for both myoclonic and generalized clonic
seizures induced by the i.v. injection of PTZ in mice. Increasing in NO fallowing PTZ-induced seizures leads to the raise in
the intracellular cGMP level and subsequently might activate
PKG, a major intracellular receptor for cGMP. Although PKG
was noted in the brain only at low levels, it plays a signicant
role in regulation of calcium concentration in neurons, generation of action potentials and neurotransmitters release.
These results might be mediated by the impact of PKG on
some ion channels, including calcium channels. Phosphorylation of calcium channels by this enzyme leads to their
blockade, decrease in the intracellular calcium level and
reduction of the neuronal excitability (Wang and Robinson,
1997). The NO/cGMP/PKG pathway was also reported to
inhibit activity of N- and P/Q type voltage dependent
calcium channels which might decrease neurotransmitter
release in neurons (Yu and Eldred, 2005). Moreover, PKG
was also reported to modulate calcium-activated potassium channels. These channels are the major constituents
regulating membrane potentials by modulation of potassium efux and their phosphorylation consequently leads
to hyperpolarization of neurons and inhibition of voltagegated calcium channels (Wang and Robinson, 1997). It has
been reported ginger bioactive components such as [6]shogaol, 1-dehydro-[10]-gingerdione, and [10]-gingerdione
also decreased LPS-induced NO production, and [6]-shogaol
and 1-dehydro-[10]-gingerdione were reported to effectively reduce iNOS expression (Koh et al., 2009). These
evidence seem to suggest that ginger and some of its
components are effective antioxidants in vitro and may
be interfering with the NO/cGMP/PKG pathway due to

Ginger extract on timed intravenous pentylenetetrazol infusion seizure model

anticonvulsant effects and thereby elevation of the seizure
threshold.
Glutamate in high doses produced neuroendocrine
abnormalities (Moreno et al., 2005), neurodegeneration,
neurotoxicity (Chapano-Hue et al., 2002) and oxidative
damage in different organs (Farombi and Onyema, 2006;
Pavlovic et al., 2007). The expression of glutamate receptors
known as mGluRI was strongly suggestive of the initiation of an epileptogenic process, one in which normal
neuronal cortex is converted into a persistently hyperexcitable state with a lowered threshold for the production
of seizure discharges. It was proposed that this form of
epileptogenesis was likely to be clinically relevant because
the instigating agent was acting at glutamate receptors,
and glutamate was long recognized as the key excitatory transmitter in the CNS underlying the expression of
seizure discharges (Merlin and Wong, 1997; Anwyl, 2009).
It has been shown that ginger has neuroprotective and
inhibitory effect on glutamate receptors, which may be
responsible for the anticonvulsant activity and the prevention of seizure discharges (Waggas, 2009; Shanmugam et al.,
2011).
Various investigators (Huang et al., 1990; Abdel-Aziz
et al., 2006; Riyazi et al., 2007) have previously demonstrated that extract of ginger and its fractions have
anti-5HT3 -receptor effects. 5-HT3 -receptor stimulation contributes to fast excitatory synaptic transmission in the
central nervous system (Sugita et al., 1992; Ferezou
et al., 2002) and also modulates the release of several
neurotransmitters including acetylcholine, cholecystokinin
(CCK), dopamine, glutamate, norepinephrine and particularly -aminobutyric acid (GABA), the exocytosis of
which is enhanced by direct Ca2+ inux through the
ionophore of presynaptic 5-HT3 -receptors (Chameau and
Van-Hooft, 2006; Fink and Gothert, 2007). Zingerone and
other derivatives from ginger inhibits the release of
most neurotransmitter especially serotonin (Marles et al.,
1992; Hasenohrl et al., 1996). 5-HT3 -receptor antagonists
have multiple pharmacological actions. It has been shown
that 5-HT3 -receptor antagonists also possess anticonvulsant activity (Vishwakarma et al., 2002). Therefore ginger
extract with modulatory effect on 5HT3 -receptor may alter
PTZ-induced seizures and elevate the seizure threshold.

Conclusion
In conclusion, in the present study we demonstrated that
ginger extract has anticonvulsant effect in the timed PTZ
infusion test in mice. Summing up, we can hypothesize
that the anticonvulsant effect of ginger may have been
mediated by antioxidant mechanisms, oxidative stress inhibition and simultaneous inuence on different kinds of
calcium channels and both excitatory and inhibitory systems
of neurotransmission. The precise molecular mechanism of
interactions between the AEDs and ginger should be investigated in further experiments. Our results might support new
treatment methods using ginger in patients with epileptic
seizure. Due to favorable pharmacodynamic characteristics
and lack of acute side effects, the tested interactions might
be benecial and worthy of consideration for testing in clinical trials.

417

Acknowledgments
The authors declare that they have no competing interests.
We would like to thank Mr. Ali Gomar for assistant in this
research project.

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