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1.  Evaluation of antiproliferative and anti-inflammatory activities of methanol extract and its fractions from the Mediterranean sponge 
Without doubt, natural products have been, and still are, the cornerstone of the health care armamentarium. Of all natural sources, the marine environment is clearly the last great frontier for pharmaceutical and medical research.
This work progresses in the direction of identifying component(s) from the Mediterranean sponge, Spongia officinalis with pharmacological activities. In the present study we investigated the efficacy of methanol extract and its semi-purified fractions (F2, F3) from Spongia officinalis for their in vivo anti-inflammatory activity using the carrageenan-induced paw edema in rats and their in vitro antiproliferative effects by their potential cytotoxic activity using the MTT colorimetric method and clonogenic inhibition against three human cancer cell lines (A549, lung cell carcinoma, HCT15, colon cell carcinoma and MCF7, breast adenocarcinoma).
The fractions F2 and F3 showed interesting anti-inflammatory and antiproliferative activities in a dose dependent manner.
The present study indicates that the methanolic extrac and its fractions from Spongia officinalis are a significant source of compounds with the antiproliferative and anti-inflammatory activities, and this may be useful for developing potential chemopreventive substances.
PMCID: PMC3441879  PMID: 22587650
Spongia officinalis; Anti-inflammatory activity; Antiproliferative activity
2.  Anticonvulsant potential of ethanol extracts and their solvent partitioned fractions from Flemingia strobilifera root 
Pharmacognosy Research  2013;5(4):265-270.
Flemingia strobilifera (FS) R.Br. (Fabaceae) is an important medicinal plant. In wealth of India it has been reported that roots of FS are used by santals in epilepsy, hysteria, insomnia, and to relieve pain. In Burma also the roots of F. strobilifera are used to treat epilepsy.
To investigate anticonvulsant potential of 95% ethanol extract and four subsequent fractions (petroleum ether, chloroform, ethyl acetate, and aqueous fractions of the roots of FS against pentylenetetrazole (PTZ) and maximal electroshock (MES) induced convulsions.
Material and Methods:
All the fractions and crude ethanol extract were administered (i.e., 200, 400, 600 mg/kg, p.o.) for 7 days and at the end of the treatment convulsions were induced experimentally using pentylenetetrazole and Maximal electroshock Test. Diazepam and phenytoin (4 mg/kg, i.p. and 20 mg/kg, i.p., respectively) were used as reference anticonvulsant drugs against experimentally induced convulsions. The latency of tonic convulsions and the numbers of animals protected from tonic convulsions were noted.
High doses (200 and 300 mg/kg, p.o.) of ethyl acetate fraction and 95% ethanol crude extract (400 and 600 mg/kg, p.o.) significantly reduced the duration of seizure induced by maximal electroshock (MES). The same dose also protected from pentylenetetrzole-induced tonic seizures and significantly delayed the onset of tonic seizures. However, pet, ether, chloroform, and aqueous fraction at any of the doses used (i.e., 100, 200, 300 mg/kg, p.o.) did not show any significant effect on PTZ and MES induced convulsions. The treatment with crude ethanolic extract and ethyl acetate fraction caused signs of central nervous system depressant action in the locomotor activity test, confirmed by the potentiation of sodium pentobarbital sleeping time. Both did not cause disturbance in motor coordination assessed by rotarod test.
The data suggest that crude ethanol extract and ethyl acetate fraction of roots of Flemingia strobilifera have a central nervous system depressant action and behave as a potential anticonvulsant. It may produce its anticonvulsant effect via non-specific mechanism since it reduced the duration of seizures produced by maximal electroshock as well as delayed the latency of seizures produced by pentylenetetrazole.
PMCID: PMC3807991  PMID: 24174820
Antiepileptic; Flemingia strobilifera;  maximal electroshock; pentylenetetrazole; seizures
3.  Effects of the Aqueous Extract of Anethum graveolens Leaves on Seizure Induced by Pentylenetetrazole in Mice 
In this study, the aqueous extract of Anethum graveolens (dill) leaves was studied for its effects on treating convulsions and epilepsy, by using a pentylenetetrazole (PTZ) kindling model. The evaluated plant has a traditional medical reputation for profound anticonvulsant activities, additionally, dill has been claimed to exhibit anti-inflammatory and analgesic properties.
For the PTZ kindling induction, mice were given a dose of PTZ (37 mg/kg, intraperitoneally) every other day, and seizure stages were precisely recorded. During and after kindling, the effects of the non-toxic doses of the aqueous extracts (100, 250, and 400 mg/kg) on seizure latency in stage 2 (S2L), seizure latency in stage 4 (S4L), and seizure duration in stage 5 (S5D) were measured.
The aqueous extract of dill leaves had a noticeable anticonvulsant effect. The 400 mg/kg dose of the extract sample decreased with S5D (P < 0.05), and increased with S2L and S4L significantly (P < 0.05 and P < 0.01, respectively).
The obtained data shows that the aqueous extract possesses anticonvulsant activity against seizure induced by PTZ. The presence of anticonvulsant compounds in this medicinal herb suggests further activity and guided fractionation studies in order to introduce this plant as a valuable source of anticonvulsant agents.
PMCID: PMC3957353  PMID: 24643194
Anethum graveolens; anticonvulsant; kindling; mice; pentylenetetrazole
4.  Experimental study of neuropharmacological profile of Euphorbia pulcherrima in mice and rats 
Euphorbia pulcherrima (EP) belongs to the family: Euphorbiaceae and Genus: Euphorbia. Many species of Euphorbia have been reported as having beneficial properties like anticonvulsive effect, central analgesic properties, antipyretic action, central depressant action and strong sedative effect. However, little study has been done and published on EP.
To observe and evaluate various neuropharmacological effects like antinociceptive effect, anticonvulsant effect, motor in-coordination, pentobarbital induced sleeping time and behavioral responses of EP in mice and rats.
Setting and Design:
Quantitative experimental study in mice and rats by various experimental models.
Materials and Methods:
Different experimental models were used to assess the antinociceptive effect (hotplate, tail flick and acetic acid induced writhing test), anticonvulsant effect (Maximal Electroshock Seizure test [MES] and Pentylenetetrazole induced seizures [PTZ]), motor in-coordination effect (Rota rod test), pentobarbital induced sleeping time and behavioral responses of EP in mice and rats after oral administration of EP crude dried extracts in three different doses (250, 500 and 1000 mg/kg).
Statistical Analysis Used:
The significance of difference with respect to control was evaluated using the Mann-Whitney U test. A probability (P-value) level less than 0.05 was considered as significant.
In MES test model, duration of tonic hind limb extension in mice treated with EP was significantly less as compared to vehicle treated group. EP was most effective in a dose of 1000 mg/kg. There was also significant increase in the latency and decrease in the incidence of convulsions with the use of EP in three different doses in PTZ induced seizure model.
This study showed EP (crude dried) extracts to possess anticonvulsant properties but no effect on motor co-ordination and anxiety.
PMCID: PMC3505323  PMID: 23188984
Anticonvulsant effect; antinociceptive effect; anxiolytic; pentobarbital induced sleeping time; sedative
5.  Anticonvulsant Activity of Hydroalcoholic Extract and Aqueous Fraction of Ebenus stellata in Mice 
Fabaceae is the third largest family of flowering plants. Lack of essential oils in the plants of this family can be considered as an advantage and can favor them in search for safe and antiepileptic medicines. The effects of Fabacea family plants including Ebenus stellata (E. stellata), Sophora alopecuroides and Caesalpinia gilliiesii were evaluated in pentylenetetrazole (PTZ) and maximal electroshock (MES) seizure tests.
Materials and Methods
The hydroalcoholic extracts were obtained by percolation of 100 g aerial parts of each plant in 900 ml ethanol 80%. Acute toxicity of the extracts was assessed. Non-toxic doses of the extracts were injected to the mice intraperitoneally (i.p.) and occurrence of clonic seizures induced by PTZ (60 mg/kg, i.p.) or tonic seizures induced by MES (50 mA, 50 Hz, 1 sec), were monitored up to 30 min after each administration. The anticonvulsant extract was then fractionated by dichloromethane and water. Phytochemical screening of the effective extract was also carried out by thin layer chromatography to verify active constituents.
Among the extracts used, only E. stellata had no toxicity and inhibited clonic seizures in a significant and dose-dependent (3-7 g/kg) manner with ED50 of 4 g/kg. Fractionation of the extract resulted in dose-dependent (1-5 g/kg) anticonvulsant activity, which was observed in aqueous fraction with ED50 of 1.74 g/kg. Phytochemical screening revealed the presence of terpens/sterols, alkaloids, flavonoids, tannin and saponins in the extract.
The presence of anticonvulsant compounds in E. stellata suggests further activity-guided fractionation and analytical studies to find the potential of this plant as a source of anticonvulsant agents.
PMCID: PMC3586894  PMID: 23493240
Anticonvulsants; Ebenus stellata; Fabaceae
6.  Increased Seizure Latency and Decreased Severity of Pentylenetetrazol-Induced Seizures in Mice after Essential Oil Administration 
The effect of pretreatment with essential oils (EOs) from eight aromatic plants on the seizure latency and severity of pentylenetetrazol- (PTZ-) induced seizures in mice was evaluated. Weight-dependent doses of Rosmarinus officinalis, Ocimum basilicum, Mentha spicata, Mentha pulegium, Lavandula angustifolia, Mentha piperita, Origanum dictamnus, and Origanum vulgare, isolated from the respective aromatic plants from NE Greece, were administered 60 minutes prior to intraperitoneal (i.p.) injection of a lethal dose of PTZ to eight respective groups of Balb-c mice. Control group received only one i.p. PTZ injection. Motor and behavioral activity of the animals after EOs administration, development of tonic-clonic seizures, seizure latency and severity, and percentage of survival after PTZ administration were determined for each group. All groups of mice treated with the EOs showed reduced activity and stability after the administration of the oil, except for those treated with O. vulgare (100% mortality after the administration of the oil). After PTZ administration, mice from the different groups showed increased latency and reduced severity of seizures (ranging from simple twitches to complete seizures). Mice who had received M. piperita demonstrated no seizures and 100% survival. The different drastic component and its concentration could account for the diversity of anticonvulsant effects.
PMCID: PMC3684096  PMID: 23819045
7.  Antinociceptive and anticonvulsant activities of hydroalcoholic extract of Jasminum grandiflorum (jasmine) leaves in experimental animals 
Pharmacognosy Research  2013;5(4):286-290.
Jasminum grandiflorum belongs to the family Oleaceae and is known to have anti-inflammatory, antimicrobial, antioxidant, and antiulcer activities. The present study was undertaken to study its analgesic and anticonvulsant effects in rats and mice. The antinociceptive activity of the hydroalcoholic extract of J. grandiflorum leaves (HEJGL) was studied using tail flick and acetic acid – induced writhing method. Similarly, its anticonvulsant activity was observed by maximal electroshock (MES) method and pentylenetetrazol (PTZ) method. Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by Dunnett's test. At doses of 50, 100, and 200 mg/kg, HEJGL showed significant analgesic and anticonvulsant effects in experimental animals. In view of its analgesic and anticonvulsant activity, the JGL extract can be used in painful conditions as well as in seizure disorders.
PMCID: PMC3807994  PMID: 24174823
Acetic acid; Jasminum grandiflorum; maximal electro shock; pentylenetetrazole; tail flick
8.  Anticonvulsant Effect of Cicer arietinum Seed in Animal Models of Epilepsy: Introduction of an Active Molecule with Novel Chemical Structure 
Iranian Biomedical Journal  2015;19(1):45-50.
Background: Cicer arietinum (Chickpea) is one of the most important harvests in the world with high nutritional value. Lack of essential oils in the seeds of Chickpea is an advantage in search for drug-like molecules with less toxicity. We evaluated anticonvulsant effect of C. arietinum in common animal models of epilepsy. Methods: Dichloromethane extract was obtained from C. arietinum seeds by percolation. Acute toxicity of the extract was assessed in mice. Protective effect of the extract was examined against tonic seizures induced by maximal electroshock (MES; 50 mA, 50 Hz, 1 s) in mice, clonic seizures induced by pentylenetetrazole (PTZ; 60 mg/kg, i.p.) in mice, and electrical kindling model of complex partial seizures in rats. The extract was fractionated by n-hexane to f1 and f2 fractions. The extract and fractions underwent phytochemical analysis by thin layer chromatography. The active anticonvulsant fraction, f1, was subjected to matrix assisted laser desorption/ionization (MALDI) mass analysis. Results: The crude extract had neither toxicity up to 7 g/kg nor protective activity in MES and kindling models. However, it significantly inhibited clonic seizures induced by PTZ. f1 fraction mimicked protective effect of the extract. Phytochemical screening revealed the presence of considerable amount of alkaloids in the extract and fractions. Moreover, a novel structural class was detected in f1 fraction. Conclusion: Finding an anticonvulsant molecule pertaining to a new structural class in the seeds of C. arietinum promises an effective and inexpensive source of antiepileptic medication. Further studies are needed to identify its mechanism of action and more clues into its structure-activity relationship.
PMCID: PMC4322232  PMID: 25605489
Anticonvulsants; Cicer; Kindling; Pentylenetetrazole (PTZ)
9.  Evaluation of the Anticonvulsant Activity of the Leaves of Glycyrrhiza glabra var. glandulifera Grown in Iran, as a Possible Renewable Source for Anticonvulsant Compounds 
A review of the publications in traditional medicine indicates that the root of Glycyrrhiza glabra L., Fabaceae, is recommended for treatment of epilepsy. As a renewable source, the leaves of G. glabra var. glandulifera growing in Iran were examined for possible anticonvulsant activity.
The anticonvulsant activity of the leaves’ ethanol extract and dichloromethane, f1, n-Hexane, f1A, and methanol, f1B, fractions were evaluated intraperitoneally in mice using maximal electroshock (MES) and pentylenetetrazol (PTZ) seizure tests. Acute toxicity of the extract and the fractions were also assessed. Phytochemical screening of the extract and the fractions for their active constituents was also carried out by thin layer chromatography and various chemical reagents.
The extract and the fractions showed anticonvulsant effect in PTZ test. The ED50 value of 2.11 g/Kg and 1.30 g/Kg was obtained for the crude extract and f1 fraction, respectively. The LD50 value of 3.0 g/Kg was found for the extract. Triterpenes/sterols, alkaloids, flavonoids, anthraquinones and tannins were present in the extract and fractions. Triterpenes and anthraquinones were the highest in the extract, while triterpenes and tannins were prevailing in f1 fraction. The anticonvulsant activity of the extract and f1 fraction could be mainly attributed to the compounds of triterpenes/sterols class present in the leaves of the plant. The therapeutic index of the leaves’ extract was narrow and in this regard it has low anticonvulsant potential. Evaluation of the possible anticonvulsant activity of the leaves of the other varieties of G. glabra grown in Iran (e.g., var. violacea) is suggested.
PMCID: PMC3869590  PMID: 24363684
Anticonvulsant; Glycyrrhiza glabra var. glandulifera; Leaves; Maximal electroshock; Pentylenetetrazole
10.  Antiepileptic activity of lobeline isolated from the leaf of Lobelia nicotianaefolia and its effect on brain GABA level in mice 
To investigate the anticonvulsant activity of the lobeline isolated from the Lobelia nicotianaefolia in chemoconvulsant-induced seizures and its biochemical mechanism by investigating relationship between seizure activities and altered gamma amino butyric acid (GABA) in brain of mice in Pentylenetetrazol (PTZ) seizure models.
The anticonvulsant activity of the isolated lobeline (5, 10, 20 and 30 mg/kg, i.p.) was investigated in PTZ and strychnine induced seizures in mice and the effect of isolated lobeline on brain GABA level in seizures induced by PTZ. Diazepam was used as reference anticonvulsant drugs for comparison.
Isolated lobeline (10, 20 and 30 mg/kg, i.p.) significantly delayed and antagonized (P < 0.050–0.001) the onset of PTZ-induced seizures. It also antagonized strychnine induced seizures. The mortality was also prevented in the test group of animals. In biochemical evaluation, isolated lobeline (5, 10 and 20 mg/kg, i.p.) significantly increased the brain GABA level. And at dose of 30 mg/kg GABA level showed slight decrease in PTZ model.
In our findings, isolated lobeline (20mg/kg) exhibited potent anticonvulsant activity against PTZ induced seizures. Also a biochemical evaluation suggested significant increase in barain GABA level at 20 mg/kg i.p. of isolated lobeline. Hence, we may propose that lobeline reduces epileptic seizures by enhancing the GABA release supporting the GABAergic mechanism.
PMCID: PMC3609340  PMID: 23569966
Lobelia nicotianaefolia; Lobeline; Brain GABA level; Antiepileptic activity; Pentylenetetrazol (PTZ); Strychnine
11.  The Anticonvulsant Effects of SR 57227 on Pentylenetetrazole-Induced Seizure in Mice 
PLoS ONE  2014;9(4):e93158.
Recently, studies have shown that serotonin plays an important role in the control of seizure. However, the specific role of 5-HT receptor subtypes is not yet well described, in particular that of the 5-HT3 receptor. The present study was aimed to investigate the role of 5-HT3 receptor on the pentylenetetrazole (PTZ)-induced seizure in mice. Firstly, seizure latency was significantly prolonged by a 5-HT3 receptor agonist SR 57227 in a dose-dependent manner. Seizure score and mortality were also decreased by SR 57227 in PTZ-treated mice. Furthermore, these anticonvulsant effects of SR 57227 were inhibited by a 5-HT3 receptor antagonist ondansetron. However, ondansetron alone had no effect on seizure latency, seizure score or mortality at different doses. Immunohistochemical studies have also shown that c-Fos expression was significantly increased in hippocampus (dentate gyrus, CA1, CA3 and CA4) of PTZ-treated mice. Furthermore, c-Fos expression was significantly inhibited by ondansetron in mice treated with PTZ and SR 57227. An ELISA study showed that SR 57227 attenuated the PTZ-induced inhibitory effects of GABA levels in hippocampus and cortex, and the attenuated effects of SR 57227 were antagonized by ondansetron in hippocampus but not cortex. Our findings suggest that activation of 5-HT3 receptor by SR 57227, which plays an important role on the control of seizure induced by PTZ, may be related to GABA activity in hippocampus. Therefore, 5-HT3 receptor subtype is a potential target for the treatment of epilepsy.
PMCID: PMC3972186  PMID: 24690630
12.  Screening of the anticonvulsant activity of some plants from Fabaceae family in experimental seizure models in mice 
Background and purpose of the study
Fabaceae is the third largest family of flowering plants. Lack of essential oils in the plants of this family can be an advantage in search for safe and effective medicines. In this study the anticonvulsant effect of the leaves of Albizzia julibrissin, Acacia juliflora, Acacia nubica and aerial parts of Astragalus obtusifolius was evaluated in pentylenetetrazole (PTZ) and maximal electroshock (MES) seizure tests.
The hydroalcoholic extracts of the plants were obtained by percolation. Different doses of the extracts were injected to the mice intraperitoneally (i.p.) and occurrence of clonic seizures induced by PTZ (60 mg/kg, i.p.) or tonic seizures induced by MES (50 mA, 50Hz, 1sec) were monitored up to 30 min after administration. Acute toxicity of the extracts was also assessed. The safe and effective extract was then fractionated by dichloromethane and anticonvulsant activity of the fractions was determined. Finally, the constituents of the extract and the fractions were screened by thin layer chromatography.
Among the extracts, only A. obtusifolius extract showed low toxicity and protective effect against clonic seizures with ED50 value of 3.97 g/kg. Fractionation of the extract led to increase in anticonvulsant activity and ED50 value of 2.86 g/kg was obtained for the aqueous fraction. Phytochemical screening revealed the presence of alkaloids, flavonoids, anthrones and saponins in the aqueous fraction.
Major conclusion
The presence of anticonvulsant compounds in A. obtusifolius suggests further activity-guided fractionation and analytical studies to find out the potential of this plant as a source of anticonvulsant agent.
PMCID: PMC3304383  PMID: 22615673
Pentylenetetrazole; Maximal electroshock; A. obtusifolius
13.  Tanshinone IIA Exhibits Anticonvulsant Activity in Zebrafish and Mouse Seizure Models 
ACS Chemical Neuroscience  2013;4(11):1479-1487.
Danshen or Chinese red sage (Salvia miltiorrhiza, Bunge) is used by traditional Chinese medicine (TCM) practitioners to treat neurological, cardiovascular, and cerebrovascular disorders and is included in some TCM formulations to control epileptic seizures. In this study, acetonic crude extracts of danshen inhibited pentylenetetrazol (PTZ)-induced seizure activity in zebrafish larvae. Subsequent zebrafish bioassay-guided fractionation of the extract resulted in the isolation of four major tanshinones, which suppressed PTZ-induced activity to varying degrees. One of the active tanshinones, tanshinone IIA, also reduced c-fos expression in the brains of PTZ-exposed zebrafish larvae. In rodent seizure models, tanshinone IIA showed anticonvulsive activity in the mouse 6-Hz psychomotor seizure test in a biphasic manner and modified seizure thresholds in a complex manner for the mouse i.v. PTZ seizure assay. Interestingly, tanshinone IIA is used as a prescription drug in China to address cerebral ischemia in patients. Here, we provide the first in vivo evidence demonstrating that tanshinone IIA has anticonvulsant properties as well.
PMCID: PMC3837379  PMID: 23937066
Tanshinone IIA; Salvia miltiorrhiza; zebrafish PTZ model; mouse seizure models; pentylenetetrazol
14.  Anticonvulsant Effect of Guaifenesin against Pentylenetetrazol-Induced Seizure in Mice 
Background: There have been some reports about the possible N-methyl-D-aspartate (NMDA) antagonist activity of Guaifenesin. As drugs with a similar structure to Guaifenesin (i.e. Felbamate) and those with NMDA antagonist activity have been clinically used as anticonvulsants, the aim of this study was to determine whether Guaifenesin has an anticonvulsant effect in an animal model of seizure.
Methods: Anticonvulsant effect of Guaifenesin was assessed via Pentylenetetrazol (PTZ)-induced convulsion. Male albino mice received Guaifenesin (100, 200, 300, or 400 mg/kg; n=8-10) or 0.25% Tween (vehicle) intraperitoneally 30 minutes before the injection of PTZ (95 mg/kg). Diazepam (3 mg/kg; n=8) was used as a reference drug. The latency time before the onset of myoclonic, clonic, and tonic-clonic convulsions, percentage of animals exhibiting convulsion, and percentage of mortality were recorded. In addition, the effect of Guaifenesin on neuromuscular coordination was assessed using the Rotarod.
Results: Guaifenesin at all the studied doses significantly increased the latency to myoclonic and clonic convulsions in a dose-dependent manner. In addition, Guaifenesin at the dose of 300 mg/kg increased the latency to tonic-clonic seizure. The ED50s of Guaifenesin for protection against PTZ-induced clonic and tonic-clonic seizures and death were 744.88 (360-1540), 256 (178-363), and 328 (262-411) mg/kg, respectively. Guaifenesin at all the investigated doses significantly reduced neuromuscular coordination, compared to the vehicle-treated group.
Conclusion: These results suggest that Guaifenesin possesses muscle relaxant and anticonvulsant properties and may have a potential clinical use in absence seizure.
PMCID: PMC3700057  PMID: 23825891
Guaifenesin; Anticonvulsant; Pentylenetetrazol
15.  Experimental re-evaluation of flunarizine as add-on antiepileptic therapy 
Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy.
Materials and Methods:
Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD50 and CD99 values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100–300 mg/kg), lamotrigine (3–12 mg/kg) and flunarizine (5–20 mg/kg), and then each group of mice was injected with CD99 dose of PTZ (65mg/kg i.p.). Another group of mice received single ED50 dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal–Wallis ANOVA on Ranks test.
As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection.
As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy.
PMCID: PMC3103921  PMID: 21687355
Flunarizine; lamotrigine; PTZ; seizure; sodium valproate
16.  Anticonvulsant Activity of B2, an Adenosine Analog, on Chemical Convulsant-Induced Seizures 
PLoS ONE  2013;8(6):e67060.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed. N6-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is a N6-substitued adenosine analog. Here we describe an investigation of the effects and mechanisms of B2 on chemical convulsant-induced seizures. Seizures were induced in mice by administration of 4-aminopyridine (4-AP), pentylenetetrazol (PTZ), picrotoxin, kainite acid (KA), or strychnine. B2 has a dose-related anticonvulsant effect in these chemical-induced seizure models. The protective effects of B2 include increased latency of seizure onset, decreased seizure occurrence, shorter seizure duration and reduced mortality rate. Radioligand binding and cAMP accumulation assays indicated that B2 might be a functional ligand for both adenosine A1 and A2A receptors. Furthermore, DPCPX, a selective A1 receptor antagonist, but not SCH58261, a selective A2A receptor antagonist, blocked the anticonvulsant effect of B2 on PTZ-induced seizure. c-Fos is a cellular marker for neuronal activity. Immunohistochemical and western blot analyses indicated that B2 significantly reversed PTZ-induced c-Fos expression in the hippocampus. Together, these results indicate that B2 has significant anticonvulsant effects. The anticonvulsant effects of B2 may be attributed to adenosine A1 receptor activation and reduced neuronal excitability in the hippocampus. These observations also support that the use of adenosine receptor agonist may be a promising approach for the treatment of epilepsy.
PMCID: PMC3692431  PMID: 23825618
17.  Monoterpenoid Terpinen-4-ol Exhibits Anticonvulsant Activity in Behavioural and Electrophysiological Studies 
Terpinen-4-ol (4TRP) is a monoterpenoid alcoholic component of essential oils obtained from several aromatic plants. We investigated the psychopharmacological and electrophysiological activities of 4TRP in male Swiss mice and Wistar rats. 4TRP was administered intraperitoneally (i.p.) at doses of 25 to 200 mg/kg and intracerebroventricularly (i.c.v.) at concentrations of 10, 20, and 40 ng/2 μL. For in vitro experiments, 4TRP concentrations were 0.1 mM and 1.0 mM. 4TRP (i.p.) inhibited pentylenetetrazol- (PTZ-) induced seizures, indicating anticonvulsant effects. Electroencephalographic recordings showed that 4TRP (i.c.v.) protected against PTZ-induced seizures, corroborating the behavioural results. To determine whether 4TRP exerts anticonvulsant effects via regulation of GABAergic neurotransmission, we measured convulsions induced by 3-mercapto-propionic acid (3-MP). The obtained results showed involvement of the GABAergic system in the anticonvulsant action exerted by 4TRP, but flumazenil, a selective antagonist of the benzodiazepine site of the GABAA receptor, did not reverse the anticonvulsant effect, demonstrating that 4TRP does not bind to the benzodiazepine-binding site. Furthermore, 4TRP decreased the sodium current through voltage-dependent sodium channels, and thus its anticonvulsant effect may be related to changes in neuronal excitability because of modulation of these channels.
PMCID: PMC4142302  PMID: 25180069
18.  Anti-Convulsant Activity of Boerhaavia diffusa: Plausible Role of Calcium Channel Antagonism 
“Ethnopharmacological” use of roots of Boerhaavia diffusa (B. diffusa) in the treatment of epilepsy in Nigerian folk medicine and reports showing the presence of a calcium channel antagonistic compound “liriodendrin” in its roots, led us to undertake the present study. The study was designed to investigate the methanolic root extract of B. diffusa and its different fractions including liriodendrin-rich fraction for exploring the possible role of liriodendrin in its anti-convulsant activity. Air-dried roots of B. diffusa were extracted with methanol by cold maceration. The methanol soluble fraction of extract thus obtained was successively extracted to obtain liriodendrin-rich fraction and two side fractions, that is, chloroform fraction and phenolic compound fraction. Anti-convulsant activity of methanolic extract (1000, 1500 and 2000 mg kg−1, intraperitoneally (i.p.)) and its different fractions, that is, liriodendrin-rich fraction (10, 20 and 40 mg kg−1, i.p., chloroform fraction (20 mg kg−1, i.p.) and phenolic compound fraction (1 mg kg−1, i.p.) were studied in pentylenetetrazol (PTZ)-induced seizures (75 mg kg−1, i.p.). The crude methanolic extract of B. diffusa and only its liriodendrin-rich fraction showed a dose-dependent protection against PTZ-induced convulsions. The liriodendrin-rich fraction also showed significant protection against seizures induced by BAY k-8644. These findings reiterated the anti-convulsant activity of methanolic extract of B. diffusa roots. Furthermore, it can be concluded that the observed anti-convulsant activity was due to its calcium channel antagonistic action as this activity was retained only in the liodendrin-rich fraction, which has additionally been confirmed by significant anti-convulsant activity of liriodendrin-rich fraction in BAY k-8644-induced seizures.
PMCID: PMC3135233  PMID: 19948752
19.  Effect of Gentiana olivieri on experimental epilepsy models 
Pharmacognosy Magazine  2011;7(28):344-349.
Flowering herbs of Gentiana olivieri Griseb. (Gentianaceae) are widely used as bitter tonic, stomachic, stimulant of appetite, antipyretic, anticonvulsant, antidiabetic and for mental problems in the different regions of Turkey.
To establish the anticonvulsant activity potential of G. olivieri.
Materials and Methods:
In this work, the ethanol extract of G. olivieri was tested in three doses (200, 750 and 1000 mg/kg) for anticonvulsant activity against seizures produced in mice by pentylenetetrazole (PTZ), picrotoxin (PIC) and maximal electroshock (MES). Neurotoxicity of the ethanol extract was also determined by the Rota rod test to evaluate the safety. Ethosuximide (150 mg/kg), diazepam (0.5 mg/kg) and carbamazepine (30 mg/kg) were used as reference drugs.
Intraperitonally, injection of the extract significantly prolonged the onset of seizures at doses of 200 and 750 mg/kg, but did not alter the incidence of PTZ-induced seizures. Onset of PIC-induced seizures was delayed by the injection of the extract (1000 mg/kg). Moreover, only 750 mg/kg of the extract protected 25% of the mice against PIC-induced seizures. On the other hand, G. olivieri extract (200, 750 and 1000 mg/kg) showed a significant protective effect against MES-induced seizures. In the Rota rod test, the ethanol extract (200 mg/kg, ip) induced disturbance in motor coordination.
The results indicate that G. olivieri has possessed anticonvulsant activity against MES-induced seizures in mice.
PMCID: PMC3261070  PMID: 22262939
Anticonvulsant; Gentiana olivieri; maximum electroshock; pentylenetetrazole; picrotoxin; Rota rod
20.  Phytochemical screening and anticonvulsant studies of ethyl acetate fraction of Globimetula braunii on laboratory animals 
To investigate the phytochemical properties and the anticonvulsant potential of the ethyl acetate soluble fraction of ethanol leaf extract of Globimetula braunii, a plant used in ethnomedicine for the treatment of epilepsy.
The phytochemical screening was carried out using standard protocol while the anticonvulsant activity was studied using maximal electroshock test in chicks, pentylenetetrazole and 4-aminopyridine-induced seizures in mice.
The preliminary phytochemical screening carried out on the crude ethanol extract revealed the presence of saponins, carbohydrates, flavonoids, tannins, anthraquinones and steroids. Similarly, tannins, flavonoids and steroids/terpenes were found to be present in the ethyl acetate fraction. In the pharmacological screening, 150 mg/kg of the fraction protected 83.33% of animals against pentylenetetrazole-induced seizure in mice whereas sodium valproate a standard anti-epileptic drug offered 100% protection. In the 4-aminopyridine-induced seizure model, the fraction produced a significant (P<0.05) increase in the mean onset of seizure in unprotected animals. The fraction did not exhibit a significant activity against maximal electroshock convulsion. The median lethal dose of the fraction was found to be 1 261.91 mg/kg.
These results suggest that the ethyl acetate fraction of Globimetula braunii leaves extract possesses psychoactive compound that may be useful in the management of petit mal epilepsy and lend credence to the ethnomedical use of the plant in the management of epilepsy.
PMCID: PMC3929791  PMID: 25182552
Epilepsy; Globimetula braunii; Seizure; Medicinal; Pentylenetetrazole
21.  Plausible antioxidant biomechanics and anticonvulsant pharmacological activity of brain-targeted β-carotene nanoparticles 
β-Carotene has been established as a known free radical scavenger with chain-breaking antioxidant properties. It has been documented for the treatment of epileptic convulsions at a 200 mg/kg body weight dose. The reported pathogenesis for epileptic convulsions is oxidative stress. Hence, experimental epileptic convulsions via oxidative stress was induced in albino mice epileptic models (maximal electroshock seizure and pentylenetetrazole [PTZ]). A dose concentration equivalent to 2 mg/kg was efficaciously administered in the form of brain-targeted polysorbate-80-coated poly(d,l-lactide-co-glycolide) nanoparticles. The nanoparticles were prepared by solvent evaporation technique and further characterized for their physical parameters, in-vitro release kinetics, and in-vivo brain release via various standard methods. Normal β-carotene nanoparticles (BCNP) and polysorbate-80-coated β-carotene nanoparticles (P-80-BCNP) of 169.8 ± 4.8 nm and 176.3 ± 3.2 nm in size, respectively, were formulated and characterized. Their zeta potential and polydispersity index were subsequently evaluated after 5 months of storage to confirm stability. In vivo activity results showed that a 2 mg unformulated β-carotene dose was ineffective as an anticonvulsant. However, salutary response was reported from BCNP at the same dose, as the hind limb duration decreased significantly in maximal electroshock seizure to 9.30 ± 0.86 seconds, which further decreased with polysorbate-80 coating to 2.10 ± 1.16 seconds as compared to normal control (15.8 ± 1.49 seconds) and placebo control (16.50 ± 1.43 seconds). In the PTZ model, the duration of general tonic–clonic seizures reduced significantly to 2.90 ± 0.98 seconds by the use of BCNP and was further reduced on P-80-BCNP to 1.20 ± 0.20 seconds as compared to PTZ control and PTZ-placebo control (8.09 ± 0.26 seconds). General tonic–clonic seizures latency was increased significantly to 191.0 ± 9.80 seconds in BCNP and was further increased in P-80-BCNP to 231.0 ± 16.30 seconds, as compared to PTZ (120.10 ± 4.50 seconds) and placebo control (120.30 ± 7.4 seconds). The results of this study demonstrate a plausible novel anticonvulsant activity of β-carotene at a low dose of 2 mg/kg, with brain-targeted nanodelivery, thus increasing its bioavailability and stability.
PMCID: PMC3419510  PMID: 22915852
anticonvulsant; blood–brain barrier (BBB); targeted brain delivery; polysorbate-80-coated β-carotene nanoparticles (P-80-BCNP); maximal electroshock seizure (MES); pentylenetetrazole (PTZ)
22.  Anticonvulsant and neurotoxicity profile of the rhizome of Smilax china Linn. in mice 
Indian Journal of Pharmacology  2011;43(1):27-30.
To study the anticonvulsant activity and neurotoxicity of ethanolic extract and ethyl acetate fraction of the rhizome of Smilax china (EESC and EAF, respectively) in mice.
Materials and Methods:
The anticonvulsant activities of EESC and EAF were studied against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced seizures in mice and neurotoxicity was determined using rotarod test.
The duration of hindleg extension in MES test was reduced significantly (P < 0.001) by EESC at a dose level of 400 mg/kg and EAF at both higher dose levels (200 and 400 mg/kg). In PTZ model, the seizure latency was prolonged by all the test groups.
The EESC and EAF may help to control petit mal and grand mal seizures.
PMCID: PMC3062115  PMID: 21455417
Epilepsy; China root; Smilax china; neurotoxicity
Ancient Science of Life  2002;22(1):17-27.
The alcoholic extract of Achyranthes bidentata (AAB) has been studied for analgesic, anticonvulsant and CNS depressant activities in animal models. Analgesic activity was studied using acetic acid-induced writing test for assessing peripheral analgesic effect and tail immersion test for central analgesic effect. Anticonvulsant activity was performed by maximal electroshock induced convulsions; while the locomotor activity was evaluated using actophotometer. AAB (250-500 mg/kg) significantly reduced the number of wriths induced by acetic acid and elevated pain threshold in hot water test. The extract (500mg/kg) exhibited anticonvulsant activity significantly (P<0.001) against tonic seizures induced by MES. The results of locomotor activity showed the significant (P<0.01) CNS depressant effect at the three doses (250,375 and mg/kg) employed. The results suggest that AAB exhibited analgesic, anticonvulsant and CNS depressant activity in a dose dependent pattern.
PMCID: PMC3330995  PMID: 22557071
Achyranthes bidentata: Writhing; Tail-flick; Tonic extensor; Locomotor
24.  Anti-biofilm activity of an exopolysaccharide from a sponge-associated strain of Bacillus licheniformis 
Secondary metabolites ranging from furanone to exo-polysaccharides have been suggested to have anti-biofilm activity in various recent studies. Among these, Escherichia coli group II capsular polysaccharides were shown to inhibit biofilm formation of a wide range of organisms and more recently marine Vibrio sp. were found to secrete complex exopolysaccharides having the potential for broad-spectrum biofilm inhibition and disruption.
In this study we report that a newly identified ca. 1800 kDa polysaccharide having simple monomeric units of α-D-galactopyranosyl-(1→2)-glycerol-phosphate exerts an anti-biofilm activity against a number of both pathogenic and non-pathogenic strains without bactericidal effects. This polysaccharide was extracted from a Bacillus licheniformis strain associated with the marine organism Spongia officinalis. The mechanism of action of this compound is most likely independent from quorum sensing, as its structure is unrelated to any of the so far known quorum sensing molecules. In our experiments we also found that treatment of abiotic surfaces with our polysaccharide reduced the initial adhesion and biofilm development of strains such as Escherichia coli PHL628 and Pseudomonas fluorescens.
The polysaccharide isolated from sponge-associated B. licheniformis has several features that provide a tool for better exploration of novel anti-biofilm compounds. Inhibiting biofilm formation of a wide range of bacteria without affecting their growth appears to represent a special feature of the polysaccharide described in this report. Further research on such surface-active compounds might help developing new classes of anti-biofilm molecules with broad spectrum activity and more in general will allow exploring of new functions for bacterial polysaccharides in the environment.
PMCID: PMC3196911  PMID: 21951859
25.  Modulation of c-Fos and BDNF Protein Expression in Pentylenetetrazole-Kindled Mice following the Treatment with Novel Antiepileptic Compound HHL-6 
BioMed Research International  2014;2014:876712.
Brain-derived neurotrophic factor (BDNF) and c-Fos are shown to promote epileptogenesis and are taken as a marker of neuronal activity. The present study investigated the expression of BDNF and c-Fos in mice brain with pentylenetetrazol- (PTZ-) induced generalized seizure and evaluated the effect of novel tryptamine derivative HHL-6 on the expression of these two markers. The subconvulsive dose of PTZ (50 mg/kg) was administered on alternate days in the experimental groups until the seizure scores 4-5 developed in the PTZ-control group. At the end of each experiment, animals were sacrificed, brain samples were collected and cryosectioned, and immunohistochemical analysis of BDNF and c-Fos protein was performed. Data obtained from two sections per mouse (n = 12 animals/group) is presented as means ± S.E.M. The test compound HHL-6 demonstrated a potent anticonvulsant activity in the PTZ-induced seizure in mice. Significant reduction in the BDNF (P < 0.003) and c-Fos (P < 0.01) protein expression was observed in the HHL-6 treated group. Based on these results we suggest that one of the possible mechanisms of HHL-6 to inhibit epileptogenesis might be due to its controlling effect on the cellular and molecular expression of the factors that contribute to the development of epileptogenic plasticity in the CNS.
PMCID: PMC3925558  PMID: 24605339

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