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Anticonvulsant effects of thymoquinone, the major constituent of Nigella sativa seeds, in mice.



Summary

The anticonvulsant effects of thymoquinone, the major constituent of Nigella sativa Nigella sativa,
n See nigella.
 seeds, were investigated using pentylenetetrazole (PTZ PTZ Pan-Tilt-Zoom (camera)
PTZ Pentylenetetrazol
PTZ Photo Zenith Tube
PTZ Poisson Truncated At Zero Model
PTZ Point Zero
)- and maximal electroshock electroshock /elec·tro·shock/ (-shok) shock produced by applying electric current to the brain.

e·lec·tro·shock
n.
See electroconvulsive therapy.

v.
 (MES (Manufacturing Execution Software) Software that provides real time access to plant activities that include equipment, labor, orders and inventory. An MES integrates the data with enterprise resource planning (ERP) systems so that management has complete control of )-induced seizure models. We also studied the effect of thymoquinone on pentobarbital-induced hypnosis, locomotor activity, and motor coordination. In PTZ-induced seizure, the intraperitoneally injection of thymoquinone with doses of 40 and 80 mg/kg, prolonged the onset of seizures and reduced the duration of myoclonic myoclonic

pertaining to myoclonus.


myoclonic epilepsy
see glycoproteinosis.

myoclonic jerk
a generalized seizure consisting of a jerk of most muscles in the body.
 seizures. The protective effect of thymoquinone against mortality was 71.4% and 100% in the mentioned doses, respectively. In MES model, thymoquinone failed to reduce the duration of seizure, whereas exhibited a complete protection against mortality. In PTZ model, flumazenil (10 mg/kg, ip), an antagonist of benzodiazepine benzodiazepine (bĕn'zōdīăz`əpēn'), any of a class of drugs prescribed for their tranquilizing, antianxiety, sedative, and muscle-relaxing effects. Benzodiazepines are also prescribed for epilepsy and alcohol withdrawal.  (BZD BZD

In currencies, this is the abbreviation for the Belize Dollar.

Notes:
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion.
) site in the GAB[A.sub.A]-BZD receptor complex, inhibited the prolongation of seizure latency, but did not show any effect on the duration of myoclonic seizures. Also, pretreatment pretreatment,
n the protocols required before beginning therapy, usually of a diagnostic nature; before treatment.

pretreatment estimate,
n See predetermination.
 with naloxone naloxone /nal·ox·one/ (nal-ok´son) an opioid antagonist, used as the hydrochloride salt in opioid toxicity, opioid-induced respiratory depression, and hypotension associated with septic shock.  (0.1 and 0.3 mg/kg, ip) inhibited the prolongation of myoclonic seizure latency and antagonized the reduction of myoclonic seizure duration induced by thymoquinone (40 and 80 mg/kg) in the PTZ model. Moreover, thymoquinone (40 and 80 mg/kg) did not have any hypnosis effect in the pentobarbital-induced hypnosis, but impaired the motor coordination and reduced the locomotor activity. These results indicate that thymoquinone may have anticonvulsant activity in the petit mal epilepsy Noun 1. petit mal epilepsy - epilepsy characterized by paroxysmal attacks of brief clouding of consciousness (and possibly other abnormalities); "she has been suffering from petit mal since childhood"
epilepsia minor, petit mal
 probably through an opioid receptor-mediated increase in GABAergic tone.

Key words: thymoquinone, Nigella sativa, anticonvulsant, pentylenetetrazole, electroshock, GAB[A.sub.A]-BZD receptor, opioid receptors

**********

Introduction

Nigella sativa L. is a member of the Ranunculaceae family growing in countries bordering the Mediterranean Sea, Pakistan, India and Iran. For thousands of years N. sativa seeds (which are called black seeds or black cumin black cumin,
n Latin name:
Nigella sativa; parts used: seeds; uses: in Ayurveda, pacifies vata and kapha doshas (pungent, bitter, light, dry, sharp), antimicrobial, hepatoprotective, carminitive, stimulant, diuretic, anthelmintic, indigestion,
) have been used for edible and medicinal purposes in many countries (Jansen, 1981). Recently, many medicinal properties have been attributed to the black cumin seeds extracts and/or its oil, including antihistaminic antihistaminic /an·ti·his·ta·min·ic/ (-his-tah-min´ik)
1. counteracting the effect of histamine.

2. antihistamine.


an·ti·his·ta·min·ic
adj.
 (Chakravarty, 1993; El-Dakhakhny, 1965; Mahfouz et al. 1965), antihypertensive antihypertensive /an·ti·hy·per·ten·sive/ (-ten´siv) counteracting high blood pressure, or an agent that does this.

an·ti·hy·per·ten·sive
adj.
Reducing high blood pressure.

n.
 (El-Tahir et al. 1993), analgesic analgesic (ăn'əljē`zĭk), any of a diverse group of drugs used to relieve pain. Analgesic drugs include the nonsteroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, narcotic drugs such as morphine, and synthetic drugs  and anti-inflammatory (Al-Ghamdi, 2001; Houghton et al. 1995; Abdel-Fattah et al. 2000), hypoglycemic hypoglycemic /hy·po·gly·ce·mic/ (-gli-sem´ik)
1. pertaining to, characterized by, or causing hypoglycemia.

2. an agent that lowers blood glucose levels.
 (Al-Hader et al. 1993), antibacterial and antifungal (Topozada et al. 1965; Hanafy and Hatem, 1991), antihelmenthic (Salomi et al. 1992), and antitumour effects (Panikkar, 1992; Salomi et al. 1992; Worthen et al. 1998).

The composition and properties of N. sativa seeds have been fairly investigated, and the results of the researches have been reviewed (Riaz et al. 1996; Siddiqui and Sharma, 1996; Worthen et al. 1998). N. sativa seeds contain 36%-38% fixed oils, proteins, alkaloids alkaloids,
n alkaline phytochemicals that contain nitrogen in a heterocyclic ring structure. They can have powerful pharmacological effects and are more often used in traditional medicine than in herbal treatments.
, saponin saponin: see soap plant.  and 0.4%-2.5% essential oil. The fixed oil is composed mainly of unsaturated fatty acids. The essential oil was analysed using GC-MS. Many components were characterized, but the major ones were thymoquinone (27.8%-57.0%), [rho]-cymene (7.1%-15.5%), carvacrol car·va·crol  
n.
An aromatic phenolic compound, C10H14O, found in plants such as oregano and savory and used in flavorings and fungicides.
 (5.8%-11.6%), t-anethole (0.25%-2.3%), 4-terpineol (2.0%-6.6%) and longifoline (1.0%-8.0%). Thymoquinone readily dimerizes to form dithymoquinone. Four alkaloids have been reported as constituents of N. sativa seeds. Two, nigellicine and nigellidine have an indazole nucleus, whereas nigellimine and its N-oxide are isoquinolines (Ali and Blunden, 2003). Most properties of whole seeds or their extracts are mainly attributed to quinone quinone

Any member of a class of cyclic organic compounds comprising a six-membered unsaturated ring (see saturation) to which two oxygen atoms are bonded as carbonyl groups (−C=O; see functional group).
 constituents, of which thymoquinone is a more abundant compound (Mahfouz et al. 1960; DAntuono et al. 2002). More recently, a great deal of attention has been given to this pharmacologically active quinone. It has been shown that thymoquinone possesses several properties including analgesic and anti-inflammatory actions (Abdel-Fattah et al. 2000; Houghton et al. 1995), protection against chemicals induced carcinogenesis car·ci·no·gen·e·sis
n.
The production of cancer.



carcinogenesis

production of cancer.


biological carcinogenesis
viruses and some parasites are capable of initiating neoplasia.
 (Hassan and El-Dakhakhny, 1992; Worthen et al. 1998), the inhibition of eicosanoids generation and membrane lipid peroxidation (Houghton et al. 1995).

To our knowledge, no data are available concerned with the pharmacological effects of N. sativa seed extracts or its oil and thymoquinone in the central nervous system (CNS See Continuous net settlement.

CNS

See continuous net settlement (CNS).
), apart from Khanna et al. (1993) who reported analgesic and CNS depressant activities of N. sativa oil, and Abdel-Fattah et al. (2000) who determined the antinociceptive effect of thymoquinone with a central mechanism through opioid receptors.

In the present study, to clarify the neuropharmacological profiles of thymoquinone, as the major constituent of N. sativa seeds, we investigated the anticonvulsant activity of thymoquinone using pentylenetetrazole (PTZ) and maximum electroshock induced seizures as petit mal and grand mal epilepsy Noun 1. grand mal epilepsy - epilepsy in which the attacks involve loss of consciousness and tonic spasms of the musculature followed by generalized jerking
epilepsia major, generalized epilepsy, grand mal
 models in mice, respectively. We further studied the effect of thymoquinone in pentobarbital-induced hypnosis and its effects on motor coordination with the rotarod test. We also elucidated the possible mechanism(s) underlying the actions of thymoquinone on the CNS and assessed the probable involvement of benzodiazepine receptors and opioid system.

Materials and Methods

Animals

Male albino albino (ălbī`nō) [Port.,=white], animal or plant lacking normal pigmentation. The absence of pigment is observed in the body covering (skin, hair, and feathers) and in the iris of the eye.  mice (BALB/c strain) weighing 25-30 g were obtained from Razi Institute (Mashhad, Iran) and housed in groups of five in standard laboratory conditions. They were kept at constant room temperature (21 [+ or -] 2 [degrees]C) under a 12/12 h light/dark cycle at least 10 days prior to testing. Commercial food pellets and tap water were freely available. They were transferred to the laboratory at least 1 h before the start of experiments. The experiments were performed during the light portion between 08:00-12:00 a.m. to avoid circadian circadian /cir·ca·di·an/ (ser-ka´de-an) denoting a 24-hour period; see under rhythm.

cir·ca·di·an
adj.
Relating to biological variations or rhythms with a cycle of about 24 hours.
 influences. All animal experiments were carried out in accordance with Mashhad University of Medical Sciences Mashhad University of Medical Sciences (MUMS) is a medical school in Iran.

Located in Razavi Khorasan province in the city of Mashhad, it was established in 1949 along with Ferdowsi University of Mashad, and separated in 1986 from its parent institution by national
, Ethical Committee acts.

Drugs and dosage

Thymoquinone was purchased from Aldrich Chemical Co., pentylenetetrazole and pentobarbital pentobarbital /pen·to·bar·bi·tal/ (pen?to-bahr´bi-tal) a short- to intermediate-acting barbiturate; the sodium salt is used as a hypnotic and sedative, usually presurgery, and as an anticonvulsant.  were purchased from Sigma Chemical Co. The other agents used in this investigation were flumazenil (Roche), diazepam diazepam /di·az·e·pam/ (di-az´e-pam) a benzodiazepine used as an antianxiety agent, sedative, antipanic agent, antitremor agent, skeletal muscle relaxant, anticonvulsant, and in the management of alcohol withdrawal symptoms.  (IPDIC, Rasht, Iran) and naloxone (Tolid Daru Co., Tehran, Iran). Agents were dissolved in normal saline. Thymoquinone was suspended in 0.8% (v/v) Tween tween  
n.
A child between middle childhood and adolesence, usually between 8 and 12 years old.



[Blend of teen1 and between.]
 80. All compounds were prepared freshly each time and administered intraperitoneally (ip) in a volume of 0.1ml/10 g body weight. Control animals received the same volume of vehicle.

Anticonvulsant activity

* Pentylenetetrazole (PTZ)-induced seizure: The mice were divided into 13 groups of seven animals each. In the first and second groups, the mice were given PTZ at a dose of 90 mg/kg, 30 min after administration of vehicle (normal saline + Tween 80) and normal saline as negative controls respectively in order to compare them with treatment groups and also to determine the influence of Tween 80 in our experiments. Animals in the next five groups were treated with diazepam as a positive control in the increment doses of 0.1, 0.5, 1.0, 1.5, and 3.0 mg/kg, 30 min before PTZ challenge (90 mg/kg). Groups 8 to 10 received thymoquinone at the doses of 10.20, and 40 mg/kg, 30 min before the injection of PTZ (90 mg/kg). In the remaining 3 groups, animals were received thymoquinone at the doses of 20, 40, and 80 mg/kg, 60 min before the injection of PTZ (90 mg/kg). The animals were individually placed in plastic boxes and observed immediately after PTZ injection for a period of 30 min. The latency and duration of myoclonic jerks, as well as the percentage of protection against incidence of seizure and mortality were recorded (Hosseinzadeh and Khosravan, 2002; Hosseinzadeh and Madanifard, 2000).

* Effects of flumazenil on anticonvulsant activity of thymoquinone: We also studied the effects of selective GAB[A.sub.A]-BZD receptor antagonist, flumazenil (File et al. 1982; File and Pellow, 1986), on the anticonvulsant activity of thymoquinone in order to investigate the probable involvement of GAB[A.sub.A]-BZD receptors. We selected two groups of seven mice each. In the first group, mice were given flumazenil (10 mg/kg) 5 min before the administration of thymoquinone (40 mg/kg) (75 min before the injection of PTZ). In the second group, the animals received flumazenil 5 min before the administration of diazepam (1 mg/kg) (35 min before the injection of PTZ). The anticonvulsant activity of thymoquinone and diazepam in mice pretreated with flumazenil was assessed and compared with controls and thymoquinone treated animals.

* Effects of naloxone on anticonvulsant activity of thymoquinone: We further investigated the probable modulatory properties of opioid receptors on the anticonvulsant activity of thymoquinone in PTZ-induced seizure. Herein, we applied naloxone as an opioid receptor antagonist (Mannino and Wolf, 1974; Cowan et al. 1979; Lauretti et al. 1994) at the doses of 0.1 and 0.3 mg/kg, 15 min before the administration of thymoquinone (40 and 80 mg/kg) and 75 min before the injection of PTZ. The anticonvulsant activity of thymoquinone in groups pretreated with naloxone was assessed and compared with animals pretreated only with thymoquinone and control groups, which received naloxone and vehicle.

* Maximal electroshock seizure (MES) test: The animals were divided into 10 groups of seven mice each. The controls and different doses of thymoquinone 30 min and 60 min before the induction of MES were given to the separate groups of mice. Then, the stimulus train was applied via ear-clip electrodes (sinusoidal sinusoidal /si·nus·oi·dal/ (si?nu-soi´dal)
1. located in a sinusoid or affecting the circulation in the region of a sinusoid.

2. shaped like or pertaining to a sine wave.
 pulses 150 mA and 50 Hz for 0.2 s) by means of a constant current stimulator (Digital Electroshock Model 150, EghbalTeb Co., Mashhad, Iran). A drop of 0.9% saline solution was poured on each ear of animals prior to placing the electrode. The latency and duration of tonic seizure (tonic hindlimb hindlimb

the pelvic limb; back leg.
 extension) were determined. The percentage of protection against the incidence of seizure and mortality were also recorded (Hosseinzadeh and Khosravan. 2002; Hosseinzadeh and Madanifard, 2000).

Pentobarbital-induced hypnosis test

In this experiment, the mice were treated with thymoquinone (40 and 80 mg/kg) or diazepam (1 mg/kg). The control mice received the vehicle (normal saline + Tween 80). Thirty minutes after the administration of diazepam and control, and sixty minutes after treatment with thymoquinone, pentobarbital sodium (30 mg/kg, Nogueira and Vassilieff, 2000) was given to animals. Each animal was placed gently on its back and kept at 21 [+ or -] 2 [degrees]C. If the animal remained on its back 60 seconds, the loss of the righting reflex was considered to occur. The latency (the interval between the injection of pentobarbital sodium and loss of the righting) and duration of hypnosis (the interval between the loss and the recovery of the writhing) were measured (Christina et al. 1982; Villar et al. 1992).

Motor coordination (Rotarod Test)

The effect on motor coordination was assessed using the rotarod apparatus (RotaRod 3375-5, TSE See Tokyo Stock Exchange.

TSE

1. See Tokyo Stock Exchange (TSE).

2. See Toronto Stock Exchange (TSE).
 System) as described earlier (Dunham and Myia, 1957). In brief, mice were trained to remain for 5 min on the rod rotating at the initial and final speed of 10 and 20 rpm, respectively (the acceleration time was 20 sec). On the next day, thymoquinone (40 and 80 mg/kg), diazepam (1 mg/kg), and control (normal saline + Tween 80) were administered and the length of time each animal remained on the rotating rod (time-on-rod) was recorded 30 (first trial) and 60 min (second trial) after the administration.

Locomotor activity (Open-field test)

The effect of thymoquinone on locomotion locomotion

Any of various animal movements that result in progression from one place to another. Locomotion is classified as either appendicular (accomplished by special appendages) or axial (achieved by changing the body shape).
 was studied in an open-field test. The apparatus, made of white wood, had a floor of 100 X 100 cm divided by red lines into 25 squares of 20 X 20 cm. The walls, 30 cm high, were also painted in white. The test room was illuminated at the same intensity as the colony room. Thirty minutes after the administration of thymoquinone (20, 40, and 80 mg/kg), diazepam (1.5 and 3 mg/kg), and the control (normal saline + Tween 80), the animal was placed in the center of the open-field and its behavior was observed for 10 min. The evaluated parameters were the total number of squares crossed, the number of outer squares (those adjacent to the walls) crossed, and the number of inner squares crossed; the three measures were referred to as total, peripheral, and central locomotion, respectively (Pardon et al. 2000). At the end of each test, the whole area was cleaned with a wet sponge and a dry paper towel.

Statistical analysis

The data were expressed as mean values [+ or -] S.E.M. and tested with analysis of variance (ANOVA anova

see analysis of variance.

ANOVA Analysis of variance, see there
) followed by the multiple comparison test of Tukey-Kramer.

Results

PTZ-induced seizure

In the PTZ-induced seizure, the administration of thymoquinone with a dose of 40 mg/kg, 30 min, and with doses of 40 and 80 mg/kg, 60 min before the injection of PTZ, prolonged the latency of myoclonic seizures. Also, thymoquinone with the doses of 40 and 80 mg/kg 60 min before the injection of PTZ reduced the duration of myoclonic seizures (Table 1). As it is shown in Table 1, thymoquinone exhibited its anticonvulsant activity through a dose-dependent manner. Although, the protection against seizure of thymoquinone with the doses of 40 and 80 mg/kg was only 14%, it interestingly protected the animals against mortality 71.4 and 100%, respectively. There was no significant difference between seizure parameters of mice in control group (normal saline + Tween 80) and those treated only with normal saline. Furthermore, diazepam prolonged the duration and shortened the-latency of myoclonic seizures dose-dependently (Table 1).

Maximal electroshock seizure (MES) test

In Table 2, it is shown that thymoquinone did not have any effect on tonic seizure in MES. However, thymoquinone with all doses tested, exhibited complete protection (100%) against mortality.

Effects of flumazenil on the anticonvulsant activity of thymoquinone

In PTZ-induced seizure model, the administration of flumazenil (10 mg/kg) 5 min before thymoquinone (40 mg/kg) antagonized the effect of thymoquinone in the prolongation of seizure latency (p < 0.001). There was no significant difference between the latency of seizure in mice received thymoquinone (40 mg/kg) pretreated with flumazenil and the control group. On the other hand, flumazenil (10 mg/kg) could not antagonize the effect of thymoquinone in the reduction of the seizure duration. There was no significant difference between the duration of seizure in mice received thymoquinone (40 mg/kg) pretreated with flumazenil and the group treated with thymoquinone (40 mg/kg). Flumazenil significantly antagonized the anticonvulsant activity of diazepam (p < 0.001) (Table 3).

Effects of naloxone on the anticonvulsant activity of thymoquinone

As it is shown in Table 4, pretreatment with naloxone (0.1 mg/kg) 15 min before the injection of thymoquinone with doses of 40 and 80 mg/kg inhibited the prolongation of myoclonic seizure latency in the PTZ-induced seizure method (p < 0.01 and p < 0.05, respectively). By increasing the dose of naloxone, the inhibition was magnified, so that the application of naloxone with higher dose (0.3 mg/kg) induced further inhibition in the prolongation of myoclonic seizure latency in this test. The time course of seizure threshold in the mice pretreated with naloxone (15 min before the administration of thymoquinone) did not have any significant difference with control group (Table 4).

Also, the pretreatment of mice with naloxone (15 min before the administration of the thymoquinone) inhibited the reduction of myoclonic seizure duration. In the PTZ-induced seizure, naloxone with doses of 0.1 and 0.3 mg/kg increased the duration of seizures in mice treated with thymoquinone at doses of 40 mg/kg (p < 0.001) and 80 mg/kg (p < 0.05 and p < 0.01, respectively). The duration of myoclonic seizure in mice pretreated with naloxone (15 min before the administration of thymoquinone) had no significant difference with the control group (Table 4).

Pentobarbital-induced hypnosis test

Pretreatment with thymoquinone (40 and 80 mg/kg) 60 min before the injection of pentobarbital (30 mg/kg) did not alter the onset and duration of sleeping time of mice, so that there was no significant difference between the hypnosis of groups treated with thymoquinone (40 and 80 mg/kg) and control. In this test, diazepam (1 mg/kg) increased significantly (p < 0.001) the duration of sleeping from 26.4 [+ or -] 1.2 to 44.9 [+ or -] 1.9 min and reduced significantly (p < 0.001) the onset of sleeping from 7.9 [+ or -] 0.7 to 3.7 [+ or -] 0.3 min, respectively (Table 5).

Motor coordination (Rotarod test)

In this test, 60 min after the administration (first trial) of thymoquinone (40 mg/kg), the remaining time of animals on the rotating rod reduced from 300.0 [+ or -] 0.0 to 211.2 [+ or -] 27.1 sec (p < 0.01). This effect was faded 90 min after administration (second trial) of thymoquinone (40 mg/kg) (Table 6). Also, thymoquinone at the dose of 80 mg/kg (60 and 90 min after administration) induced a motor incoordination incoordination /in·co·or·di·na·tion/ (in?ko-or?di-na´shun) ataxia.

in·co·or·di·na·tion
n.
See ataxia.
 and reduced the remaining time of mice on rotating rod from 300.0 [+ or -] 0.0 to 36.3 [+ or -] 8.3 sec for first trial and from 300.0 [+ or -] 0.0 to 26.7 [+ or -] 4.5 sec for second trial (p < 0.001) (Table 6).

Locomotor activity (Open-field test)

Thymoquinone with doses of 20, 40 and 80 mg/kg reduced central and peripheral locomotion, as well as total locomotion (Table 7).

Discussion

The results of our study indicate that thymoquinone exhibits anticonvulsant activity in the PTZ-induced seizure model. Generally, compounds with the anticonvulsant activity in the petit mal epilepsy, are effective in PTZ-induced seizure model (Vida, 1995). So, thymoquinone may be useful in petit mal epilepsy. On the other hand, as thymoquinone did not exhibit any anticonvulsant property in MES model, it can not exert a protective activity against the grand mal epilepsy, because compounds which possess anticonvulsant activity in MES, may be considered as an effective drug against the grand mal epilepsy (Vida, 1995).

As it is shown in Table 1, the intraperitoneally administration of thymoquinone at the dose of 40 mg/kg, 30 min before the injection of PTZ, delayed the onset of seizures from 44.4 to 128.5 sec and decreased the duration of seizures from 12.2 to 9.9 sec. Whereas, the administration of thymoquinone with the same dose (40 mg/kg) 60 min before the injection of PTZ, delayed the onset of seizures from 44.4 to 265.7 sec and decreased the duration of myoclonic seizures from 12.2 to 5.8 sec. Accordingly, it seems that the optimum time of the onset of anticonvulsant activity of thymoquinone is 60 min after its administration. This may be related to the slow absorption of thymoquinone from the peritoneum peritoneum (pĕrətənē`əm), multilayered membrane which lines the abdominal cavity, and supports and covers the organs within it. The part of the membrane that lines the abdominal cavity is called the parietal peritoneum.  to the circulation and gradual permeation across the blood-brain barrier.

The experimental animal models of epilepsy induced by the systemic administration of chemicals have been used to study the mechanism of drug action. Some studies have indicated that PTZ diminishes the GABAergic tone (Macdonald and Barker, 1977) by the inhibition of BZD site of the GABA GABA ?.

GABA
abbr.
gamma-aminobutyric acid


GABA (gamma-aminobutyric acid)
A neurotransmitter that slows down the activity of nerve cells in the brain.
 receptors (Rehavi et al. 1982). In order to determine the role of BZD receptors participation in the thymoquinone-induced anticonvulsant effects, flumazenil, a specific antagonist of the benzodiazepine site in the GAB[A.sub.A]-BZD receptor complex (File et al. 1982; File and Pellow, 1986; Brogden and Goa, 1988), was used. The results obtained from PTZ-induced seizure model in mice pretreated with flumazenil suggest that thymoquinone could facilitate the inhibitory activity of the GABAergic system probably through a competitive agonist action in the BZD site of the GABA receptors. Although flumazenil could not decrease the prolongation of seizure latency induced by thymoquinone (40 mg/kg), it significantly (p < 0.001) antagonized the effect of thymoquinone on the reduction of the duration of myoclonic seizure in PTZ model (Table 3). These findings have shown that flumazenil pretreatment reversed the anticonvulsant activity of thymoquinone and consequently, thymoquinone may affect the GAB[A.sub.A]-BZD receptor complex.

It has been previously shown that thymoquinone produce antinociceptive effects through indirect activation of the opioid receptors (Abdel-Fattah et al. 2000). They showed that, naloxone significantly blocked the thymoquinone-induced antinociception in the early phase of the formalin formalin /for·ma·lin/ (for´mah-lin) formaldehyde solution.

for·ma·lin
n.
An aqueous solution of formaldehyde that is 37 percent by weight.
 test. Moreover, nor-binaltorphimine, the [kappa]-opioid receptor antagonist, significantly reversed thymoquinone-induced antinociception in the early phase of the formalin test (Abdel-Fattah et al. 2000). These results suggest that thymoquinone produce antinociceptive effects through activation of the [kappa]-opioid receptor subtypes.

Recently, Yajima et al. (2000) reported that selective [kappa]-opioid receptor agonist U-50,488H produced a dose-dependent suppression of the bicuculline-induced seizures. The inhibitory effect of U-50,488H was completely blocked by pretreatment with nor-binaltorphimine. This study demonstrates that the stimulation of [kappa]-opioid receptors has an anticonvulsive effect. It is well documented that [kappa]-opioid receptor agonists affect mostly [Ca.sup.2+] channels, resulting in the blockade of [Ca.sup.2+] entry (Werz and Macdonald, 1984, 1985). Although the mechanism of the anticonvulsive effect with [kappa]-opioid receptor agonists is presently unclear, one possibility that should be mentioned is that postsynaptically localized [kappa]-opioid receptors may contribute to the inhibition of excitability excitability

readiness to respond to a stimulus; irritability.
 induced by postsynaptic postsynaptic /post·sy·nap·tic/ (-si-nap´tik) distal to or occurring beyond a synapse.

post·syn·ap·tic
adj.
Situated behind or occurring after a synapse.
 blockade of GAB[A.sub.A] receptors through the reduction of [Ca.sup.2+] entry.

On the basis of these documents, it can be strongly taken this assumption into consideration that [kappa]-opioid receptors may participate in thymoquinone-induced anticonvulsant effect. In order to determine this hypothesis, naloxone, a non-specific opioid receptor antagonist, was used. As it is shown in Table 4, naloxone dose-dependently reversed the anticonvulsant activity of thymoquinone so that the mice pretreated with naloxone, exhibited the same myoclonic seizure profile as the control group. This finding is supported with the fact that the administration of [kappa]-opioid receptor agonists elicits a sedative sedative, any of a variety of drugs that relieve anxiety. Most sedatives act as mild depressants of the nervous system, lessening general nervous activity or reducing the irritability or activity of a specific organ.  action on locomotor activity in the mouse (Ivamoto, 1981; Vonvoigtlander et al. 1983; Funada et al. 1993; Mizoguchi et al. 1996) that is in line with our results obtained from open-field test (Table 7). As it is shown in table 7, thymoquinone (20, 40, and 80 mg/kg) produced the sign of depression including the reduction of locomotion activity. These results coupled with the fact that thymoquinone caused motor incoordination (rotarod test, Table 6) indicates the probably impairment of motoneurons as a side effect of anticonvulsant activity of thymoquinone. On the other hand, thymoquinone did not have any potentiation potentiation /po·ten·ti·a·tion/ (po-ten?she-a´shun)
1. enhancement of one agent by another so that the combined effect is greater than the sum of the effects of each one alone.

2. posttetanic p.
 effect on pentobarbital-induced hypnosis at doses in which exhibited anticonvulsant activity (40 and 80 mg/kg).

Badary et al. (1998) reported that after acute oral administration, the acute toxicity of thymoquinone is very low [LD50: 2.4 g/kg with 95% C.L. (1.52-3.77)] in mice. Maximum non-fatal dose was 500 mg/kg which is approximately 12 times the anticonvulsive activity dose (40 mg/kg). It is generally well tolerated when given subchronically in drinking water at doses 30, 60, and 90 mg/kg/day. Hypoglycemia hypoglycemia: see diabetes.
hypoglycemia

Below-normal levels of blood glucose, quickly reversed by administration of oral or intravenous glucose. Even brief episodes can produce severe brain dysfunction.
 was the only effect associated with subchronic administration of thymoquinone.

In conclusion, the present study showed that thymoquinone suppresses the seizures induced by PTZ, probably through an opioid receptors-mediated increase in GABAergic tone (a point that needs to be elucidated further), which is supported by our other results discussed formerly. Also, it is important to point out that thymoquinone failed to potentiate po·ten·ti·ate
v.
1. To make potent or powerful.

2. To enhance or increase the effect of a drug.

3. To promote or strengthen a biochemical or physiological action or effect.
 the hypnosis induced by pentobarbital.
Table 1. Effects of thymoquinone on PTZ-induced seizure in mice.

Treatment (dose mg/kg)  Latency (sec)            Duration (sec)

Normal saline
  (0.1 ml/10 g)          54.5 [+ or -] 2.6       10.1 [+ or -] 0.7
Control (0.1 ml/10 g)    44.4 [+ or -] 2.1       12.2 [+ or -] 0.6
Diazepam (0.1)           45.6 [+ or -] 2.6        9.7 [+ or -] 0.4*
Diazepam (0.5)          121.7 [+ or -] 4.9***     7.9 [+ or -] 0.5***
Diazepam (1)            415.6 [+ or -] 10.5***    5.1 [+ or -] 0.4***
Diazepam (1.5)          587.1 [+ or -] 1.4***     0***
Diazepam (3)            600.0 [+ or -] 0.0***     0***
Thymoquinone (10)        70.6 [+ or -] 6.4       14.1 [+ or -] 1.5
Thymoquinone (20)        70.6 [+ or -] 4.9       11.5 [+ or -] 0.9
Thymoquinone (40)       128.5 [+ or -] 17.9***    9.9 [+ or -] 0.7
Thymoquinone (1) (20)    60.6 [+ or -] 2.8            [+ or -] 0.6
Thymoquinone (1) (40)   265.7 [+ or -] 53.2*          [+ or -] 0.5***
Thymoquinone (1) (80)   341.1 [+ or -] 69.1**     6.5 [+ or -] 0.6***

Treatment (dose mg/kg)  Protection           Protection
                        against seizure (%)  against mortality (%)

Normal saline
  (0.1 ml/10 g)           0                       0
Control (0.1 ml/10 g)     0                       0
Diazepam (0.1)            0                       0
Diazepam (0.5)            0                     100
Diazepam (1)             42.8                   100
Diazepam (1.5)           85.7                   100
Diazepam (3)            100                     100
Thymoquinone (10)         0                       0
Thymoquinone (20)         0                       0
Thymoquinone (40)         0                      42.8
Thymoquinone (1) (20)     0                      25
Thymoquinone (1) (40)    14.3                    71.4
Thymoquinone (1) (80)    14.3                   100

Drugs and controls were administered 30 min before the injection of PTZ;
Control: Normal saline + Tween 80 (0.8%, v/v); (1) Thymoquinone was
administered 60 min before the injection of PTZ; Values are the mean
[+ or -] SEM for 7 mice; ***p < 0.001, **p < 0.01, *p < 0.05, as
compared to control, Tukey-Kramer.

Table 2. Effects of thymoquinone on MES-induced seizure in mice.

Treatment (dose mg/kg)  Duration (sec)        Protection   Protection
                                                against      against
                                                seizure     mortality
                                                  (%)          (%)

Normal saline
  (0.1 ml/10 g)         14.1 [+ or -] 0.2          0            0
Control (0.1 ml/10 g)   13.1 [+ or -] 0.8          0           42.8
Diazepam (0.25)         11.9 [+ or -] 0.5          0          100
Diazepam (0.5)           8.6 [+ or -] 0.2***       0          100
Diazepam (3)             7.1 [+ or -] 0.9***      14.3        100
Thymoquinone (10)       14.7 [+ or -] 0.7          0          100
Thymoquinone (20)       13.8 [+ or -] 1.1         14.3        100
Thymoquinone (40)       14.1 [+ or -] 0.9          0          100
Thymoquinone (1) (40)   13.1 [+ or -] 0.6          0          100
Thymoquinone (1) (80)   14.2 [+ or -] 0.4          0          100

Drugs and controls were administered 30 min before the MES model;
Control: Normal saline + Tween 80 (0.8%, v/v); (1) Thymoquinone was
administered 60 min before the MES model; Values are the mean [+ or -]
SEM for 7 mice; ***p < 0.001, as compared to control. Tukey-Kramer.

Table 3. Effect of flumazenil on the anticonvulsant activity of
thymoquinone and diazepam in PTZ-induced seizure model in mice.

Treatment (dose mg/kg)  Latency (sec)           Duration (sec)

Normal saline
  (0.1 ml/10 g)          54.5 [+ or -] 2.6      10.1 [+ or -] 0.7
Control (0.1 ml/10 g)    44.4 [+ or -] 2.7      12.2 [+ or -] 0.6
Diazepam (1)            406.3 [+ or -] 55.1***   7.8 [+ or -] 0.3***
Diazepam (1)
  + Flumazenil (10)     106.5 [+ or -] 4.9      12.2 [+ or -] 0.9***
Thymoquinone (40)       265.7 [+ or -] 53.2***   6.4 [+ or -] 0.5***
Thymoquinone (40)
  + Flumazenil (10)     106.3 [+ or -] 7.4       8.2 [+ or -] 0.8***

Treatment (dose mg/kg)  Protection against mortality (%)

Normal saline
  (0.1 ml/10 g)                0
Control (0.1 ml/10 g)          0
Diazepam (1)                 100
Diazepam (1)
  + Flumazenil (10)           71.4
Thymoquinone (40)             71.4
Thymoquinone (40)
  + Flumazenil (10)           57.1

Control: Normal saline + Tween 80 (0.8%, v/v); Normal saline, control,
and diazepam were administered 30 min and thymoquinone was administered
60 min before the injection of PTZ; Flumazenil was administered 5 min
before thymoquinone or diazepam; Values are the mean [+ or -] SEM for 7
mice; ***p < 0.001, as compared to control, Tukey-Kramer.

Table 4. Effect of naloxone on the anticonvulsant activity of
thymoquinone in PTZ-induced seizure model in mice.

Treatment (dose mg/kg)  Latency (sec)           Duration (sec)

Normal saline
  (0.1 ml/10 g)          45.8 [+ or -] 2.1      14.5 [+ or -] 1.1
Control (0.1 ml/10 g)    48.4 [+ or -] 1.9      14.8 [+ or -] 0.9
Thymoquinone (40)        92.5 [+ or -] 5.7***    7.6 [+ or -] 1.1***
Naloxone (0.1)
  + Thymoquinone (40)    69.4 [+ or -] 3.8**    12.9 [+ or -] 0.3
Naloxone (0.3)
  + Thymoquinone (40)    56.7 [+ or -] 3.7      13.3 [+ or -] 0.6
Thymoquinone (80)       196.1 [+ or -] 28.2***   6.1 [+ or -] 1.3***
Naloxone (0.1)
  + Thymoquinone (80)   122.6 [+ or -] 20.9*    12.1 [+ or -] 1.2
Naloxone (0.3)
  + Thymoquinone (80)    87.2 [+ or -] 3.9      14.9 [+ or -] 2.1
Naloxone (0.1)           42.8 [+ or -] 1.1      12.8 [+ or -] 0.7
Naloxone (0.3)           38.3 [+ or -] 2.9      14.3 [+ or -] 0.9

Naloxone was administered 15 min before Thymoquinone or controls. PTZ
was injected 60 min after the administration of thymoquinone and
controls; Control: Normal saline + Tween 80 (0.8%, v/v); Values are the
mean [+ or -] SEM for 7 mice; ***p < 0.001, **p < 0.01, *p < 0.05, as
compared to control, Tukey-Kramer.

Table 5. Effect of thymoquinone on pentobarbital-induced hypnosis in
mice.

Treatment (dose mg/kg)  Onset of sleeping (min)  Duration of
                                                 sleeping (min)

Normal saline
  (0.1 ml/10 g)         8.2 [+ or -] 0.5         27.5 [+ or -] 1.8
Control (0.1 ml/10 g)   7.9 [+ or -] 0.7         26.4 [+ or -] 1.2
Diazepam (1)            3.7 [+ or -] 0.3***      44.9 [+ or -] 1.9***
Thymoquinone (40)       9.3 [+ or -] 1.1         25.5 [+ or -] 1.6
Thymoquinone (80)       8.1 [+ or -] 0.5         30.6 [+ or -] 2.1

Pentobarbital (30 mg/kg) was injected 60 min and 30 min after the
administration of thymoquinone and diazepam, respectively; Control:
Normal saline + Tween 80 (0.8%, v/v); Values are the mean SEM for 10
mice; ***p < 0.001, as compared to control, Tukey-Kramer.

Table 6. Effect of thymoquinone on motor coordination of mice in rotarod
test.

Treatment (dose mg/kg)  Time-on-rod (sed)
                        First trial             Second trial

Normal saline
  (0.1 ml/10 g)         300.0 [+ or -] 0.0      300.0 [+ or -] 0.0
Control (0.1 ml/10 g)   300.0 [+ or -] 0.0      300.0 [+ or -] 0.0
Diazepam (1)              3.7 [+ or -] 0.4***     5.2 [+ or -] 0.8***
Thymoquinone (40)       211.2 [+ or -] 27.1**   240.3 [+ or -] 31.7
Thymoquinone (80)        36.3 [+ or -] 8.3***    26.7 [+ or -] 4.5***

Thymoquinone and diazepam were administered 60 and 30 min prior to the
test, respectively; Values are the length of time each animal remained
on the rotating rod (time-on-rod) recorded 30 (first trial) and 60 min
(second trial) after the administration of agents; Control: Normal
saline + Tween 80 (0.8%, v/v); Values are the mean [+ or -] SEM for 10
mice; ***p < 0.001, **p < 0.01 as compared to control, Tukey-Kramer.

Table 7. Effect of thymoquinone on locomotor activity of mice in
open-field test.

Treatment (dose mg/kg)  Central locomotion  Peripheral locomotion

Normal saline
  (0.1 ml/10 g)         70.6 [+ or -] 9.8   225.6 [+ or -] 10.8
Control (0.1 ml/10 g)   67.4 [+ or -] 6.8   206 [+ or -] 13.6
Diazepam (1.5)          55.2 [+ or -] 8.8   244.5 [+ or -] 33.9
Diazepam (3)            39.1 [+ or -] 7.7*  131.3 [+ or -] 13.6*
Thymoquinone (20)       29.3 [+ or -] 5.2*  104.2 [+ or -] 17.2**
Thymoquinone (40)       11 [+ or -] 3.8***   46.5 [+ or -] 14.5**
Thymoquinone (80)        2***                 3 [+ or -] 2.5***

Treatment (dose mg/kg)  Total locomotion

Normal saline
  (0.1 ml/10 g)         296.2 [+ or -] 15.1
Control (0.1 ml/10 g)   273.4 [+ or -] 10.2
Diazepam (1.5)          299.7 [+ or -] 21.3
Diazepam (3)            191.3 [+ or -] 24.5**
Thymoquinone (20)       133.5 [+ or -] 11.2***
Thymoquinone (40)        57.5 [+ or -] 9.1***
Thymoquinone (80)         5 [+ or -] 1.2***

Thymoquinone and diazepam were administered 30 min prior to the test;
The parameters evaluated were the total number of squares crossed, the
number of outer squares (those adjacent to the walls) crossed, and the
number of inner squares crossed; the three measures were referred to as
total, peripheral, and central locomotion, respectively; Values are the
mean SEM for 10 mice; ***p < 0.001, **p < 0.01, *p < 0.05, as compared
to control, Tukey-Kramer.


Acknowledgments

The authors are thankful to the Vice Chancellor of Research, Mashhad University of Medical Sciences for financial support.

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H. Hosseinzadeh (1) and S. Parvardeh (2)

(1) Pharmaceutical Research Center, Department of Pharmacodynamy and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

(2) Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Address

Hossein Hosseinzadeh, Pharmaceutical Research Center, Department of Pharmacodynamy and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences, P.O. Box: 1365-91775, Mashhad, I. R. Iran Fax: ++98-5118623251; e-mail: hosseinzadehh@yahoo.com
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