Olivetolic acid, a cannabinoid precursor in Cannabis sativa, but not CBGA methyl ester exhibits a modest anticonvulsant effect in a mouse model of Dravet syndrome

Objective Cannabigerolic acid (CBGA), a precursor cannabinoid in Cannabis sativa, has recently been found to have anticonvulsant properties in the Scn1a+/- mouse model of Dravet syndrome. Poor brain penetration and chemical instability of CBGA limits its potential as an anticonvulsant therapy. Here, we examined whether CBGA methyl ester, a more stable analogue of CBGA, might have superior pharmacokinetic and anticonvulsant properties. In addition, we examined whether olivetolic acid, the biosynthetic precursor to CBGA with a truncated (des-geranyl) form, might possess minimum structural requirements for anticonvulsant activity. We also examined whether olivetolic acid and CBGA methyl ester retain activity at the epilepsy-relevant drug targets of CBGA: G-protein-coupled receptor 55 (GPR55) and T-type calcium channels. Methods The brain and plasma pharmacokinetic profiles of CBGA methyl ester and olivetolic acid were examined following 10 mg/kg intraperitoneal (i.p.) administration in mice (n = 4). The anticonvulsant potential of each was examined in male and female Scn1a+/- mice (n = 17–19) against hyperthermia-induced seizures (10–100 mg/kg, i.p.). CBGA methyl ester and olivetolic acid were also screened in vitro against T-type calcium channels and GPR55 using intracellular calcium and ERK phosphorylation assays, respectively. Results CBGA methyl ester exhibited relatively limited brain penetration (13%), although somewhat superior to that of 2% for CBGA. No anticonvulsant effects were observed against thermally induced seizures in Scn1a+/- mice. Olivetolic acid also showed poor brain penetration (1%) but had a modest anticonvulsant effect in Scn1a+/- mice increasing the thermally induced seizure temperature threshold by approximately 0.4°C at a dose of 100 mg/kg. Neither CBGA methyl ester nor olivetolic acid displayed pharmacological activity at GPR55 or T-type calcium channels. Conclusions Olivetolic acid displayed modest anticonvulsant activity against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome despite poor brain penetration. The effect was, however, comparable to the known anticonvulsant cannabinoid cannabidiol in this model. Future studies could explore the anticonvulsant mechanism(s) of action of olivetolic acid and examine whether its anticonvulsant effect extends to other seizure types.

Evaluation of Antiepileptic Activity of Flowers of Cocos nucifera L. Against Experimentally Induced Convulsions in Rats

The report used to be planned to analyze the antiepileptic activity of Cocos nucifera flowers against special experimentally induced convulsions in rats. In the present study, antiepileptic activity was assessed by following experimental models. Anti-convulsant in vivo models: Maximal electroshocks (MES) induced models in rats, Pentylenetetrazole (PTZ) induced in rats. Pretreatment of animals with Cocos nucifera flowers extract has reduced by half the general continuance of tonic hind leg extension, the most commonly used endpoint in assessing clonic convulsions. MES provokes repetitive neuronal firing indicates epileptic neurons. MES is the widely accepted model to demonstrate the antiepileptic property of a drug. This property is antagonistic of the plant extract could flow from to blockade of voltage-gated sodium channel or due to effect on NMDA receptors. The Cocos nucifera flowers extract was also demonstrated potential anticonvulsant activity in PTZ induced convulsions and this may be due to its agonistic activity on the GABAA receptor. This is further supported by an elevated level of GABA by the plant extract in the PTZ model. Methanolic extract of Cocos nucifera flowers has shown significant anticonvulsant activity against MES and Pentlylenetetrazole induced convulsion models. This observed activity could also be the referable presence of flavonoids and other phytochemical constituents found in the powerful extract. Keywords: Cocos nucifera, antiepileptic activity, Maximal electroshock, Pentlylenetetrazole, Flavonoids,

Synthesis, in silico Studies, and Anticonvulsant Activity of 1,3,4-Oxadiazole Derivatives

The title compounds 1,3,4-oxadiazole derivatives (C1-5) were synthesized by the cyclization of 4-hydroxy benzhydrazide (1) with various substituted aromatic aldehydes (2) in the presence of ceric ammonium nitrate. The structures of the newly synthesized compounds were established based on FT-IR, 1H-NMR, and Mass spectral data. In silico analysis was carried out using the Schrodinger 2018-3 suite device Maestro and docked to the binding site of the Human GABAA receptor (PDB ID:4COF). The toxicity of the compounds was predicted using the LAZAR (Lazy structure-activity relationship) program. The invivo anticonvulsant study was performed by means of a maximal electroshock test and pentylenetetrazole (PTZ)-induced seizures. Compounds C4&C5 showed the highest docking score of −5.676 and −5.277, respectively, and compounds C4&C5 showed the most increased in vivo anticonvulsant activity when compared with the reference drugs in both the PTZ and MES test methods. HIGHLIGHTS A new series of 1,3,4-oxadiazoles (C1-C5) were synthesized by reacting aromatic aldehydes and 4-hydroxy benzhydrazide using cerric ammonium nitrate as (CAT) catalyst and characterized by spectral data All the new compounds were subjected for In-silico analysis and docked to Human GABAA receptor (PDB ID:4COF) In-vivo anticonvulsant activity was carried out for all the new compounds by using maximal electroshock (MES) and pentylenetetrazole (PTZ) models Some of the tested compounds C4&C5 displayed promising anticonvulsant activity GRAPHICAL ABSTRACT

EVALUATION OF ANTICONVULSANT ACTIVITY OF CALLISTEMON CITRINUS (CURTIS) SKEELS (MYRTACEAE) VOLATILE OIL

The use of medicinal plants is on the rise due to the increase of various diseases and shortcomings of orthodox medicine. For many ailments including convulsion, conventional medicine has not been able to find a lasting solution. This study was directed towards assessing the ethnomedicinal use of Callistemon citrinus leaves in the management of convulsion. The volatile oil of the leaves was extracted and an acute toxicity test was carried out following Lorke’s description. Maximal electroshock (MES), strychnine and pentylenetetrazol anticonvulsant methods were used. Separate groups of albino mice were given 200, 400 and 800 mg/kg doses of the volatile oil. Drug solutions; 30 mg/kg phenobarbitone for MES and 2 mg/kg diazepam for strychnine and pentylenetetrazol models were administered as a positive control. The start of tonic leg extension, duration and percentage mortality was recorded. Doses of 200 and 400 mg/kg significantly (P<0.05) inhibited seizure in the mice with scores of 40 % each in the MES model. There was a dose-dependent reduction in the duration of seizures with 68.47, 70.27 and 81.08 % reductions in the pentylenetetrazol model. No significant coverage was given in the strychnine model. C. citrinus oil protected the mice against pentylenetetrazol and maximal electroshock-induced convulsion hence could contribute to the medical treatment of epilepsy.

Anticonvulsant Activity of Elaesis guineensis (Jacq) Oil in Pentylenetetrazol-Induced Seizure in Drosophila melanogaster

Elaesis guineensis, a plant whose oil extract (palm kernel oil) is medicinal, is reported to treat a wide range of disorders, including seizures. However, the anticonvulsant activity of this oil extract has not been exhaustively studied. This study aimed at evaluating the anticonvulsant activity of Elaesis guineensis oil in pentylenetetrazol-induced seizure in Drosophila melanogaster (fruit-fly). Pentylenetetrazol (50 mg/5 g diet) was used to induce seizure in Drosophila melanogaster. Flies were exposed to different concentrations (0.5-5%) of the oil and phenytoin for 28 days in a survival assay to determine the safety in the fruit flies. Five replicate of fifty files each were exposed to diet containing the LC50 of phenytoin and other groups were exposed to different concentrations of the extract for 7 days. Seizure was then induced with Pentylenetetrazol. The Trikinetic system was used to monitor activity and the DAMSystem3 data collection program to collect, process and store data. The results showed that the extract increased the latency of seizures and improved survival in the flies and suggest that the extract possesses anticonvulsant properties.

Synthesis and Evaluation of Anticonvulsant Activity of Some Quinazoline Analogues

Aim: A new series of Quinazoline 4(3H)-one derivative were prepared by reacting quinazoline 4(3H)-one hydrazide with substituted aromatic aldehydes. Quinazoline is used as a potent pharmacological agent with various biological activities such as antimicrobial, antiviral, antitumor, convulsion, anxiety, anti-inflammatory, and analgesic. In this background, we have synthesized a series of Quinazoline 4(3H)-one derivatives (4a-4f) and screened for their anticonvulsant activity. Methods: In this work, Schiff bases were prepared by treating quinazoline 4(3H)-one hydrazide with aromatic aldehydes. Six compounds (4a-4f) were screened for anticonvulsant activity by Isoniazid (INH) and Pentylenetetrazole (PTZ) induced convulsions in mice. Results: All the compounds were given satisfactory reaction yields that representing the efficiency of the employed synthetic route. In INH induced convulsion model, delayed the onset of convulsion significantly 4a, 4b, 4d, 4e, 4f when compared to an induction control group. Whereas delayed onset of convulsion was non-significant for 4c. In PTZ induced convulsion model, delayed the onset of convulsion significantly 4a, 4d, 4e, 4f when compared to induction control group. Whereas delayed onset of convulsion was non-significant for 4b and 4c. Conclusion: This indicates the anticonvulsant activity to these derivatives which might be due to potentiating GABA activity in the CNS. This anticonvulsant activity was due to presence of electron-donating group like OH, NH2, OCH3 and electron-withdrawing group like CF3 at 2nd and 4th position of aromatic ring attached to hydrazide.

The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats

The GluN2B subunit of NMDA receptors represents a perspective therapeutic target in various CNS pathologies, including epilepsy. Because of its predominant expression in the immature brain, selective GluN2B antagonists are expected to be more effective early in postnatal development. The aim of this study was to identify age-dependent differences in the anticonvulsant activity of the GluN2B-selective antagonist Ro 25-6981 and assess the safety of this drug for the developing brain. Anticonvulsant activity of Ro 25-6981 (1, 3, and 10 mg/kg) was tested in a pentylenetetrazol (PTZ) model in infantile (12-day-old, P12) and juvenile (25-day-old, P25) rats. Ro 25-6981 (1 or 3 mg/kg/day) was administered from P7 till P11 to assess safety for the developing brain. Animals were then tested repeatedly in a battery of behavioral tests focusing on sensorimotor development, cognition, and emotionality till adulthood. Effects of early exposure to Ro 25-6981 on later seizure susceptibility were tested in the PTZ model. Ro 25-6981 was effective against PTZ-induced seizures in infantile rats, specifically suppressing the tonic phase of the generalized tonic–clonic seizures, but it failed in juveniles. Neither sensorimotor development nor cognitive abilities and emotionality were affected by early-life exposure to Ro 25-6981. Treatment cessation did not affect later seizure susceptibility. Our data are in line with the maturational gradient of the GluN2B-subunit of NMDA receptors and demonstrate developmental differences in the anti-seizure activity of the GluN2B-selective antagonist and its safety for the developing brain.

A Review on Benzoxazole Containing Heterocyclic Compounds as a Wonder Medication for Thousands of Ailments

The benzoxazole is a heterocyclic aromatic organic compound. It is a vital pharmacophore and honoured structure in medicinal chemistry. It plays a very imperative role with quite useful therapeutic activities such as antiulcers, antihypertensives, analgesic, antiinflammatory, anti-virals, antifungals, anticancer, antidepressant activity, antilishmanial activity, anticonvulsant activity, antitubercular activity, antitumor activity, The review of the literature reveals that the benzoxazole derivatives are marvellously effective compounds and a large number of reviews available for biochemical and pharmacological studies established that their molecules are useful against a wide variety of microorganisms. Because of their prominence, the techniques for their synthesis have become an attention of synthetic organic chemists. Therefore, in the contemporary review we tried to assemble the chemistry of different derivative of substituted benzoxazole as well as various pharmacological activities and some of the important methodologies used for the synthesis.