Anticonvulsant Tests Research Articles

Anxiolytic and Anticonvulsant Potential of Biosynthetic Limonene Derivatives in Adult Zebrafish.

This study investigated the anxiolytic and anticonvulsant effects and safety profile of limonene enantiomers and their oxidized derivatives.The toxicity test was performed by monitoring the animals for 96 hours, with no deaths or significant toxicity observed up to the highest dose, which allowed the determination of the LD50. Doses of 4, 20 and 40 mg/kg were tested, with no toxicity observed up to 96h (LD50 > 40 mg/kg). Anxiolytic activity was measured in a preference test for light and dark areas, and the effect of the compounds was evaluated in the presence of serotonergic antagonists. The (S)-(-)-LIM and (R)-(+)-LIM enantiomers showed anxiolytic effects, with (S)-(-)-LIM being effective at all doses. In the anticonvulsant test, the oxidized derivatives, such as perilyl acid (PAC), significantly delayed PTZ-induced seizures, an effect blocked by flumazenil (FMZ). The oxidized derivatives, especially perilyl acid (PAC), showed anxiolytic effects at all doses and significantly delayed the three PTZ-induced seizure events. This effect was blocked by FMZ, suggesting a relationship between PAC and the GABAergic pathway. PAC, being the most oxidized derivative, was the most effective for both anxiety and delaying seizure progression, suggesting that oxidation of limonene compounds may increase their therapeutic efficacy.

Green supported of silver nanoparticles on the surface of reduced graphene oxide: Investigation of its anti-epileptic activity on experimental models of epilepsy in mice

This research demonstrated a novel, simple and environmentally safe process for the fabrication of graphene/silver composite using Malva sylvestris flower extract as a capping and reducing agent. Initially, the Malva sylvestris flower was used to make modified reduced graphene oxide that was coated by extract. The phytochemical groups of extract that have poylphenolic function can act as the green reducing agent for capping and reducing Ag ions on the surface of rGO (Reduced Graphene Oxide) to make the desired rGO/M.S./Ag NPs nanocomposite. The FT-IR, TEM, FE-SEM-EDX and XRD results confirmed the successful fabrication of the desired nanocomposite. The efficacy of the rGO/M.S./Ag NPs was first tested using the 6-Hz-induced seizure model. Subsequently, its effectiveness was assessed against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Additionally, the impact of the potent rGO/M.S./Ag NPs nanocomposite on Gamma amino butyric acid (GABA) levels in the brain was investigated to elucidate its potential mechanism of action. Furthermore, the effective rGO/M.S./Ag NPs nanocomposite underwent an actophotometer test to evaluate its potential to induce deficits in locomotor activity. During the 6-Hz seizure test, the rGO/M.S./Ag NPs nanocomposite demonstrated a significant and dose-dependent reduction in 6-Hz-induced seizures at doses of 30 and 90 µg/kg. Subsequently, the rGO/M.S./Ag NPs nanocomposite was assessed in MES and PTZ models. Interestingly, rGO/M.S./Ag NPs provided substantial and dose-dependent protection against MES (P < 0.01) and PTZ-induced (P < 0.01) seizures in mice. The rGO/M.S./Ag NPs nanocomposite exhibited a notable increase in brain GABA levels (P < 0.01) compared to the control, while showing no significant change in locomotor activity across all tested doses. Notably, a higher dose of rGO/M.S./Ag NPs nanocomposite (90 µg/kg, p.o.) and Diazepam (5 mg/mg, p.o.) completely prevented convulsions in all anticonvulsant tests. These results indicate that the rGO/M.S./Ag NPs nanocomposite possesses significant anticonvulsant properties, with one potential mechanism being the enhancement of GABA levels in the brain.

In vitro and In vivo Anticonvulsant Effect of Hydroalcoholic Extracts of Clutia abyssinica in Mice Model

Background: Epilepsy is a chronic disorder of the brain that affects people of all ages worldwide. In the search of safe and effective antiepileptics traditional treatment practices are one area of research to obtain novel molecules. Research is also needed to validate and standardize the traditional claim. Clutia abyssinica leaves were one of the medicinal plants claimed for use against epilepsy and evil eye and other diseases in different parts of Ethiopia. But there was no scientific research evidence for the claimed use of the plant. Therefore this work was designed to evaluate the anticonvulsant effect of hydroalcoholic extract of Clutia abyssinica leaves.&#x0D; Methods: The dry residue of the plant extract was used for the test. In vitro 0Mg2+ mice model at dose 0.7 mg/kg of extract, diazepam (3μM) and untreated brain slice groups were used to compare the presence of seizure like event (SLE). In vivo pentylenetetrazol (PTZ) model with 85 mg/kg subcutaneously was used to compare the seizure onset time with two extract doses and diazepam 5 mg/kg. The data was presented with mean± standard error. In maximum electric shock (MES) model 54 mA was passed for 0.2 second transauricularly in mice. The mean time of hind limb extension was recorded for doses 400 mg/kg and 800mg/kg of the extract and 10 mg/kg phenytoin. The means were compared for statistical significance using one way ANOVA post hoc LSD whereas proportions were compared using Fishers exact test with P-value &lt; .05. &#x0D; Results: In vitro anticonvulsant tests C. abyssinica extract effect was not statistically significant compared to negative control (P&gt;0.05).A positive control using the known anticonvulsant diazepam (3μM), showed significant anticonvulsant activity (P&lt;0.05). The in vivo PTZ test showed no statistically significant effect in plant extract at all dose levels (P&gt;0.05). In the in vivo MES test the extract of Clutia abyssinica both low and higher dose didn't show statistically significant effect (P&gt;0.05) compared with the negative control. But the extract improved survival (p&lt;0.05). The qualitative secondary metabolite test evidenced the presence of alkaloids, cardiac glycosides, flavanoids, phenols, saponins, sterols and terpeoids in Clutia abyssinica extract.&#x0D; Conclusion: The hydroalcoholic crude extract result of the C. abyssinica as anticonvulsant is weak based on the models used in this study. For most of the local preparation are mixes of different plants it may have synergistic action with other plants. Or it may have action with other models of chronic epilepsy.

Chalcones reverse the anxiety and convulsive behavior of adult zebrafish

In the treatment of anxiety and seizures, drugs of the benzodiazepine (BZD) class are used, which act on the Central Nervous System (CNS) through the neurotransmitter gamma-aminobutyric acid (GABA). Flavonoids modulate GABAA receptors. The aim of this study was to evaluate the anxiolytic and anticonvulsant effects of synthetic chalcones and their mechanisms of action via the GABAergic system, using adult zebrafish (ZFa). The animals were treated with chalcones (4.0 or 20 or 40 mg/kg; 20 µL; i.p) and submitted to the open field and 96 h toxicity test. Chalcones that cause locomotor alteration were evaluated in the light and dark anxiolytic test. The same doses of chalcones were evaluated in the anticonvulsant test. The lowest effective dose was chosen to assess the possible involvement in the GABAA receptor by blocking the flumazenil (fmz) antagonist. No chalcone was toxic and altered ZFa’s locomotion. All chalcones had anxiolytic and anticonvulsant effects, mainly chalcones 1, where all doses showed effects in both tests. These effects were blocked by Fmz (antagonist GABAA), where it shows evidence of the performance of these activities of the GABA system. Therefore, this study demonstrated in relation to structure–activity, that the position of the substituents is important in the intensity of activities and that the absence of toxicity and the action of these compounds in the CNS, shows the pharmacological potential of these molecules, and, therefore, the insights are designed for the development of new drugs.

Synthesis, in vivo anticonvulsant testing, and molecular modeling studies of new nafimidone derivatives.

An estimated 50 million people suffer epilepsy worldwide and 30% of the cases do not respond to current antiepileptic drugs (AEDs). Here, we report synthesis and anticonvulsant screening of new derivatives of nafimidone, a well-known member of (arylakyl)azole anticonvulsants. The compounds showed promising protection against maximal electroshock (MES)-induced seizures in mice and rats when administered via intraperitoneal (ip) and oral route. Especially, 5b, 5c, and 5i displayed outstanding activity in rats in MES test when given ip (ED50 : 16.0, 15.8, and 11.8 mg/kg, respectively). Additionally, 5l was active against 6 Hz and corneal-kindled mice models. Behavioral toxicity of the compounds was very low and their therapeutic indexes were high compared to some currently available AEDs. A number of pharmaceutically relevant descriptors and properties were predicted for the compounds in silico in comparison with a set of known drugs. Favorable results were obtained such as good blood-brain barrier permeability and high oral absorption, as well as drug-likeness. 5l was found to show affinity to the benzodiazepine binding site of A-type GABA receptor via molecular docking simulations.

Synthesis and Anticonvulsant Activity of α-Amino Acid Amide Derivatives

Background: Epilepsy is a disease of the central nervous system that affects approximately 50 million individuals worldwide. Although several new drugs have been marketed in the last 25 years, almost one-third of patients are not protected. In many cases, currently available drugs produce undesirable side effects. As a result, a need exists for novel anticonvulsants with unique mechanisms of action and minimal side effects. Methods: A mixed anhydride coupling procedure and standard deprotection procedures were utilized to prepare 36 α-amino acid amides. All final products were evaluated in mice and rats utilizing a standard battery of anticonvulsant tests. Results: α-Amino acids containing a 2,6-dimethylanilide group exhibited anticonvulsant activity in the maximal electroshock seizure test and 6 Hz test in mice and rats. A small, branched-chain on the α- carbon generally maintained or enhanced anticonvulsant activity in the maximal electroshock seizure test. The (R)-α-amino acid amides were typically more potent and slightly more neurotoxic than the corresponding (S)-enantiomers. The valine dimethylanilide (R)-42 was highly active in the MES test in mice (ED50 = 3.6mg/kg) and rats (ED50 = 3.8 mg/kg). (R)-42 also demonstrated excellent anticonvulsant activity in the 6 Hz, picrotoxin, and corneal kindled mouse tests. Furthermore, (R)-42 did not lower seizure threshold when evaluated in the intravenous metrazol seizure test. Conclusion: α-Amino acid 2,6-dimethylanilides exhibited potent activity in a variety of anticonvulsant tests in mice and rats. The valine derivative (R)-42 represents a promising compound for potential use in complex partial seizures.

Epilepsy-on-a-Chip System for Antiepileptic Drug Discovery.

Hippocampal slice cultures spontaneously develop chronic epilepsy several days after slicing and are used as an in vitro model of post-traumatic epilepsy. Here, we describe a hybrid microfluidic-microelectrode array (μflow-MEA) technology that incorporates a microfluidic perfusion network and electrodes into a miniaturized device for hippocampal slice culture based antiepileptic drug discovery. Field potential simulation was conducted to help optimize the electrode design to detect a seizure-like population activity. Epilepsy-on-a-chip model was validated by chronic electrical recording, neuronal survival quantification, and anticonvulsant test. To demonstrate the application ofμflow-MEA in drug discovery, we utilized a two-stage screening platform to identify potential targets for antiepileptic drugs. In Stage I, lactate and lactate dehydrogenase biomarker assays were performed to identify potential drug candidates. In Stage II, candidate compounds were retested withμflow-MEA-based chronic electrical assay to provide electrophysiological confirmation of biomarker results. We screened 12 receptor tyrosine kinases inhibitors, and EGFR/ErbB-2 and cFMS inhibitors were identified as novel antiepileptic compounds. This epilepsy-on-a-chip system provides the means for rapid dissection of complex signaling pathways in epileptogenesis, paving the way for high-throughput antiepileptic drug discovery.

Discovery of potent anti-convulsant carbonic anhydrase inhibitors: Design, synthesis, in vitro and in vivo appraisal

We report the design, synthesis and pharmacological assessment of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the synthesized compounds were screened for their CA inhibitory action against four isoforms of human origin (h), i.e. hCA I, hCA II, hCA VII and hCA IX. In-vitro carbonic anhydrase inhibition studies have shown that first series, 4-(2-(4-(4-substitutedpiperazin-1-yl)benzylidene)hydrazinyl)benzenesulfonamides (4a- 4i) bestowed low nanomolar range to medium nanomolar range inhibitors against hCA II and hCA VII, effectively involved in epileptogenesis. Furthermore, compounds belonging to the second series, 4-(2-(4-(4-substitutedpiperazin-yl)benzylidene)hydrazinecarbonyl)benzenesulfonamides (8a-8k) showed effective inhibition against hCA VII, being less effective against other hCA isoforms. Inspiring with obtained CA inhibition results, we have chosen some of the potent hCA II and hCA VII inhibitors (4g, 4i and 8d) to test their anti-convulsant efficacy in MES and sc-PTZ seizure tests in Swiss Albino male mice. In result, these compounds significantly attenuated both electrical (MES) as well as chemical (sc-PTZ) induced seizures. Next, in advance anticonvulsant tests, compound 8d displayed long duration of action in time course study and successfully attenuated MES induced seizure in mice up to 6 h after drug administration without showing neurotoxicity in rotarod test. Moreover, this compound was also found to be orally active and effectively abolished generalized tonic-clonic seizures in male Wistar rats upon oral administration, being non-toxic in sub acute toxicity studies.

Design, synthesis, molecular modeling and biological evaluation of novel 2,3-dihydrophthalazine-1,4-dione derivatives as potential anticonvulsant agents

In view of their expected anticonvulsant activity, some novel derivatives of 2,3-dihydrophthalazine-1,4-dione 4–22 were designed, synthesized and evaluated using pentylenetetrazole (PTZ) and picrotoxin as convulsion-inducing models. Moreover, the most active compounds were tested against electrical induced convulsion using maximal electroshock (MES) models of seizures. Most of the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 13 and 14g were proved to be the most potent compounds of this series with relatively low toxicity in the median lethal dose test when compared with the reference drug. Molecular modeling studies were done to verify the biological activity. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogues.

Anticonvulsant mechanism of saponins fraction from adventitious roots of Ficus religiosa: possible modulation of GABAergic, calcium and sodium channel functions

In our previous studies, quantified saponins-rich fraction from adventitious root extract of Ficus religiosa L., Moraceae, showed anticonvulsant effect in acute, as well as chronic mice models of epilepsy. The present study was designed to reveal putative anticonvulsant mechanism of quantified saponins-rich fraction using target specific animal models. The anticonvulsant effect of quantified saponins-rich fraction was initially studied in maximal electroshock and pentylenetetrazol test at 1, 2 and 4mg/kg; i.p. doses. Based on the results of initial anticonvulsant testing, different groups of mice were injected with vehicle or quantified saponins-rich fraction (4mg/kg; i.p.), 30min prior to an injection of N-methyl-d-aspartic acid (100mg/kg; s.c.), bicuculline (5mg/kg; i.p.), strychnine hydrochloride (2mg/kg; i.p.), BAY k-8644 (37.5μg; i.c.v.), veratridine (500μg/kg; i.p.) and the convulsive episodes were studied. Treatment with the extract (1, 2 and 4mg/kg) showed significant protection in maximal electroshock and pentylenetetrazol-induced convulsion tests, in a dose-dependent manner. Moreover, quantified saponins-rich fraction at 4mg/kg dose showed significant increase in latency to clonic convulsions, decrease in seizure severity and increase in average wave amplitude in bicuculline, BAY k-8644 and veratridine tests, respectively, as compared to vehicle control. However, SRF treatment failed to abolish N-methyl-d-aspartic acid and strychnine-induced convulsions, indicated by insignificant change in the appearance of turning behavior and onset of tonic extension, respectively, as compared to vehicle control. From the results of present study, it is concluded that quantified saponins-rich fraction suppress maximal electroshock, pentylenetetrazol, bicuculline, BAY k-8644 and veratridine-induced convulsions, indicating its GABAergic, Na+ and Ca2+ channel modulatory effects. Further it can be correlated that quantified saponins-rich fraction causes deactivation of voltage-gated Na+ and Ca2+ channels, without effecting ligand-gated Na+ and Ca2+ channels. More studies are required at molecular levels using in vitro techniques to understand the exact molecular interactions of quantified saponins-rich fraction with these pathways.

Design, synthesis, anticonvulsant, and antiarrhythmic properties of novel N-Mannich base and amide derivatives of β-tetralinohydantoin.

5,5-Diphenylhydantoin (Phenytoin) is a well-known anticonvulsant and antiarrhythmic drug which may cause unwanted side effects. In order to avoid the adverse effects of phenytoin, especially on the central nervous and cardiovascular systems, two small series of amine derivatives (Mannich bases) and amide ones were designed containing β-tetralinohydantoin system. In preliminary studies, some of arylpiperazinylmethyl derivatives with a β-tetralinohydantoin moiety were effective in screening anticonvulsant tests in mice. These new amine and amide derivatives of β-tetralinohydantoin were evaluated in standard anticonvulsant screens (maximal electroshock (MES) or pentylenetetrazole (scPTZ) seizure tests) and their neurotoxicity was assessed in standardized rotarod tests. Additionally, due to structural features (a hydantoin ring), influence on antiarrhythmic activity, electrocardiogram components and blood pressure was tested in rats. The new N-Mannich bases were effective in maximal electroshock or pentylenetetrazole seizures screens; and the most interesting compound 4 (1-{[4-(1-phenyethyl)-piperazin-1-yl]methyl}-3',4'-dihydro-1'H,2H,5H-spiro[imidazolidine-4,2'-naphthalene]-2,5-dione) displayed anticonvulsant activity in both the aforementioned tests. Furthermore, compound 6, an amide derivative of β-tetralinohydantoin, displayed significant antiarrhythmic activity in a barium chloride-induced arrhythmia model (ED50 16.3mg/kg), but it was devoid of anticonvulsant protection. None of the tested compounds affected the electrocardiogram components or blood pressure in normotensive rats. All new N-Mannich bases containing the β-tetralinohydantoin system and 1-phenylalkylpiperazine were classified to Anticonvulsant Screening Program 1st class. In contrast, our results suggested that the introduction of an amide bond in the alkyl side chain of the β-tetralinohydantoin system abolished the anticonvulsant activity, but not the antiarrhythmic one. However, further studies are required for a definitive conclusion.

Comparative Anticonvulsant Study of Epoxycarvone Stereoisomers.

Stereoisomers of the monoterpene epoxycarvone (EC), namely (+)-cis-EC, (−)-cis-EC, (+)-trans-EC, and (−)-trans-EC, were comparatively evaluated for anticonvulsant activity in specific methodologies. In the pentylenetetrazole (PTZ)-induced anticonvulsant test, all of the stereoisomers (at 300 mg/kg) increased the latency to seizure onset, and afforded 100% protection against the death of the animals. In the maximal electroshock-induced seizures (MES) test, prevention of tonic seizures was also verified for all of the isomers tested. However, the isomeric forms (+) and (−)-trans-EC showed 25% and 12.5% inhibition of convulsions, respectively. In the pilocarpine-induced seizures test, all stereoisomers demonstrated an anticonvulsant profile, yet the stereoisomers (+) and (−)-trans-EC (at 300 mg/kg) showed a more pronounced effect. A strychnine-induced anticonvulsant test was performed, and none of the stereoisomers significantly increased the latency to onset of convulsions; the stereoisomers probably do not act in this pathway. However, the stereoisomers (+)-cis-EC and (+)-trans-EC greatly increased the latency to death of the animals, thus presenting some protection. The four EC stereoisomers show promise for anticonvulsant activity, an effect emphasized in the isomers (+)-cis-EC, (+)-trans-EC, and (−)-trans-EC for certain parameters of the tested methodologies. These results serve as support for further research and development of antiepileptic drugs from monoterpenes.

Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models

It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models.Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the ‘classical’ models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety.

Design, synthesis, and biological evaluation studies of novel quinazolinone derivatives as anticonvulsant agents

In view of their expected anticonvulsant activity, some novel derivatives of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones (4–14) were synthesized, evaluated for their anticonvulsant activity by the maximal electroshock-induced seizure and subcutaneous pentylenetetrazole tests. The neurotoxicity was assessed using rotorod test. All the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 5, 6, and 8 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test when compared with the reference drugs. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogs.

Some Novel Anticonvulsant Agents Derived from Phthalazinedione

A series of phthalazinedione bearing substituted oxadiazole moiety derivatives X(1-7) were synthesized in good yield and evaluated for their possible anticonvulsant activity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their anticonvulsant activities were evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. All the tested compounds showed considerable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results,[3-)2-Alkoxycarbonylmethylthioxadiozol-5-yl)methyl -6-Iodophthalazine - 1,4- (2H,3H)-1,4-dion] (X1-7) derivatives could be recommended as novel structures of broad spectrum anticonvulsants.

Design and pharmacological activity of glycinamide and N-methoxy amide derivatives of analogs and constitutional isomers of valproic acid

A series of glycinamide conjugates and N-methoxy amide derivatives of valproic acid (VPA) analogs and constitutional isomers were synthesized and evaluated for anticonvulsant activity. Of all compounds synthesized and tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following anticonvulsant tests: maximal electroshock, subcutaneous metrazol, and 6-Hz (32-mA) seizure tests. In mice, the ED50 values of N-methoxy-VCD were 142mg/kg (maximal electroshock test), 70mg/kg (subcutaneous metrazol test), and 35mg/kg (6-Hz test), and its neurotoxicity TD50 was 118mg/kg. In rats, the ED50 of N-methoxy-VCD in the subcutaneous metrazol test was 36mg/kg and its protective index (PI=TD50/ED50) was >5.5. In the rat pilocarpine-induced status epilepticus model, N-methoxy-VCD demonstrated full protection at 200mg/kg, without any neurotoxicity. N-Methoxy-VCD was tested for its ability to induce teratogenicity in a mouse strain susceptible to VPA-induced teratogenicity and was found to be nonteratogenic, although it caused some resorptions. Nevertheless, a safety margin was still maintained between the ED50 values of N-methoxy-VCD in the mouse subcutaneous metrazol test and the doses that caused the resorptions. On the basis of these results, N-methoxy-VCD is a good candidate for further evaluation as a new anticonvulsant and central nervous system drug.

Evaluation of cytotoxicity and anticonvulsant activity of some Iranian medicinal Ferula species

Several Ferula (Umbelliferae) species have been used in Iranian traditional medicine as antiflatulent, antispasmodic, anticonvulsant, expectorant, etc. In the present study, cytotoxicity and anticonvulsant activity of the methanol extracts from several Ferula species were evaluated. Air-dried samples of different parts of these plants (Ferula diversivittata Regel & Schmalh. (roots), Ferula persica Willd. (aerial parts), Ferula ovina (Boiss.) Boiss. (roots), Ferula badrakema Kos.-Pol. (roots), Ferula diversivittata (flowers), Ferula latisecta Rech. F. & Aell. (roots), and Ferula badrakema (fruits)) were macerated with methanol for 3 days. The mixtures were then filtered, concentrated and dried. For determination of the cytotoxicity of the extracts and also the oleo-gum-resin of F. assafoetida L., the brine shrimp (Artemia salina) was employed as a model assay system since it provides a convenient in-house pre-screening method for evaluating general cytotoxicity. The methanol extracts of different Ferula species and the oleo-gum-resin of F. assafoetida exhibited cytotoxic effect with LC50 values in the range of 6-321 μg/mL. For the anticonvulsant testing, seizure was induced by injection of pentylenetetrazole (PTZ), 90 mg/kg intraperitoneally (i.p.). This dose was given to 10 groups, each consisting of 6 mice, which were pretreated i.p. with the extracts (300 mg/kg), Diazepam (10 mL/kg) or saline (10 mL/kg). The results showed that none of the tested Ferula species can prevent PTZ-induced seizure at the used dose. In conclusion, all of the extracts and the oleo-gum resin of F. assafoetida showed dose-dependent cytotoxicity which was highest in F. badrakema fruits and lowest in F. badrakema roots. Our findings also revealed that the methanol extracts and F. assafoetida oleo-gum resin do not possess anticonvulsant activity.

Synthesis, Anticonvulsant Evaluation of 2,3,4,5-Tetrahydro-7-alkoxy-1H-2-benzazepin-1-ones

A series of novel 2,3,4,5-tetrahydro-7-alkoxy-1H-2-benzazepin-1-ones derivatives was synthesized and screened for its anticonvulsant activities by the maximal electroshock (MES) test and its neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The MES is the most commonly used method of screening antiepileptic drugs. 2,3,4,5-tetrahydro-7-heptyloxy-1H-2-benzazepin-1-one 4e, revealed as the best anticonvulsant activity, exhibited median effective dose (ED50) of 39.4 mg/kg, and median toxicity dose (TD50) of 392.9 mg/kg, resulting in a protective index (PI) of 10.0, which is a little higher than the PI of the marked antiepileptic drug carbamazepine (PI=6.4). Comound 4e also underwent further anticonvulsant tests evaluating its activity in some chemically induced seizure models, including pentylenetetrazole (PTZ), isoniazid, 3-mercaptopropionic acid (3-MP), and thiosemicarbazide. Keywords: Anticonvulsant, Benzo[c]azepinone, Synthesis

Design and synthesis of 6-amino-1,4-oxazepane-3,5-dione derivatives as novel broad spectrum anticonvulsants

Based on the structural estimations of the typical anticonvulsant drugs, a series of 6-amino-1,4-oxazepane-3,5-dione derivatives, novel structures of 7-membered heterocyclic imides, which were hybridized with pharmacophores such as cyclic imide and N-CO-C-N group in their molecule were designed and synthesized. Their anticonvulsant activities were evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. Almost all the designed compounds except 1c and 1f showed comparable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results, 6-amino-1,4-oxazepane-3,5-dione derivatives could be recommended as novel structures of broad spectrum anticonvulsants.

Anticonvulsant Effect of Glyphaea Brevis (Speng) Moraches Leaf Extracts in Mice and Preliminary Phytochemical Tests

The anticonvulsant activities of an aqueous ethanol (70%) extract of Glyphaea brevis leaves were studies in mice to evaluate this aspect of the folkloric use of the plant. Two anticonvulsant evaluation tests, namely the strychnine and pentylenetetrazole (PTZ) test were used for the assessment of anti-seizure effects. The results showed that a non-lethal dose of 400mg kg-1 body weight of the extract offered 60% protection to the animals against strychnine-induced convulsion. In PTZ – induced convulsion non-lethal doses of 400 mg and 800 mg kg-1 body weight of the extract offered the same degree of protection to the animals but it is interesting to note that a longer seizure onset time obtained with 800 mg kg-1 body weight dose (8.73 ± 0.8) while a shorter seizure onset time was obtained with 400 mg kg-1 body weight does (6.20 ± 1.2 (p # 0.05). Phytochemical tests suggested the presence glyocosides and absence of alkaloids and absence of alkaloids in the extract. NQJHM Vol. 13 (3-4) 2003: pp. 62-64