In silico screening and evaluation of the anticonvulsant activity of docosahexaenoic acid-like molecules in experimental models of seizures

Background: Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid [DHA] make it as a good candidate for designing and development of the new anticonvulsant medications

Methods: Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole [PTZ, 60 mg/kg, i.p.] and tonic seizures induced by maximal electroshock [MES, 50 mA, 50 Hz, 1 ms duration] by intracerebroventricular [i.c.v.] injection of the screened compounds to mice

Results: Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED[50] values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED[50] values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM

Conclusion: Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA

Anticonvulsant effect of cicer arietinum seed in animal models of epilepsy: introduction of an active molecule with novel chemical structure

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. 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 nhexane 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. 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. 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.

effect of the flavonoid quercetin on pain sensation in diabetic rats

Introduction: Hyperalgesia is considered as one of the marked signs of subchronic diabetes mellitus in patients that could affect their lifestyle. This study was designed to investigate the anti-nociceptive effect of chronic administration of quercetin in streptozotocin [STZ]-diabetic rats using formalin and hot tail immersion tests. Methods: Rats were divided into control, control or diabetic groups receiving sodium salicylate, untreated diabetic, and quercetin-treated control and diabetic groups. The treatment groups received i.p. administration of quercetin at a dose of 10 mg/kg for 6 weeks. Finally, hyperalgesia were assessed using standard formalin and hot tail immersion tests. Meanwhile, some markers of oxidative stress were also measured in brain tissue. Results: Quercetin or SS treatment of diabetic rats significantly reduced pain score in chronic phase of formalin test [p<0.05]. Regarding hot tail immersion test, diabetic rats showed a significant reduction in tail flick latency as compared to control ones [p<0.05] and quercetin treatment of diabetic rats did significantly increase this latency relative to untreated diabetics [p<0.05]. Quercetin treatment of diabetic rats also significantly decreased brain level of malondialdehyde [MDA] [p<0.05] and nitrite [p<0.05] and slightly increased activity of superoxide dismutase [SOD] relative to diabetics. Discussion: Taken together, chronic administration of quercetin could attenuate nociceptive score in chronic phase of formalin test in streptozotocin-diabetic rats and could also increase threshold of thermal nociception