Evaluation of anticonvulsant activity of 2-aryl-3-triazolylindole derivatives in mice

Evaluation of anticonvulsant activity of 2-aryl-3-triazolylindole derivatives in mice
Patrick Honarchian Masihi,¹ Aidin Shakiba,² Saeed Emami,³ Seyedeh Mahdieh Hashemi,⁴ Nematollah Ahangar,^5,*
1. Doctor of Pharmacy, Student Researches Committee, Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
2. Doctor of Pharmacy, Student Researches Committee, Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
3. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
4. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
5. Department of Pharmacology, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
Introduction: Epilepsy is a common disorder in the central nervous system. Almost one percent of the world's population suffers from seizures. Epilepsy is a disorder with a complicated nature that various factors play roles in it. Pharmacotherapy with new antiepileptic drugs (AEDs) is the first way to treat epilepsy. In 70% of patients, their seizure is controlled by taking one to three AEDs, about 60% of patients experience adverse effects and 33% of patients have to change their drugs. Side effects and teratogenicity of newer AEDs have made them more commonly used in the treatment of resistant epilepsy. Given the importance of discovering new AEDs with better efficacy and fewer side effects, this study with the purpose of evaluating the anticonvulsant effects of new triazolylindole derivatives, which differ in their substituents on benzene and indole rings, was done by PTZ and MES methods.
Methods: Male NMRI mices (20-25g, n=4 heads) were selected. The compounds were injected intraperitoneally (IP) to each animal group in both MES and PTZ methods at doses of 30 and 100 mg/kg. In the PTZ method, 0.5 hour after the injection of the compounds, PTZ was injected intraperitoneally at a dose of 100 mg/kg, and the animals were observed for 0.5 hour and deaths from tonic-colonic seizures were recorded. In the MES method, 0.5 hour and 4 hours after the injection of the compounds, the animal was stimulated by an electrical current stimulator (f: 60 Hz, I: 50 mA, T: 0.2 sec) through the ear electrodes and the occurrence or absence of seizures incidentally Hind Limb Tonic Extension (HLTE) was recorded as the response. Also in both methods, a group as a positive control received standard drug (diazepam, 2 mg/kg) and a group as a negative control received solvent (DMSO, 5 ml/kg).
Results: Among the compounds studied, none of them had a protective effect on the PTZ method. In the MES method, at a dose of 100 mg/kg, compounds containing fluorine substituents at para- and ortho positions of the benzene ring and fluorine substituent at position 5 of indole ring (compound A), chlorine substituents at the para- and ortho positions of the benzene ring and chlorine substituent at position 7 of indole ring (compound B), and fluorine substituent at the para position of the benzene ring and chlorine at position 5 of indole ring (compound C), had the highest protective effect (50%) at 0.5 h after injection and compounds containing fluorine substituents at para- and ortho positions of the benzene ring and chlorine substituent at position 7 or 5 of indole ring (compounds D and E), had the highest protective effect (50%) at 4 hours after injection. At a dose of 30 mg/kg, compounds containing chlorine substituents at para- and ortho positions of the benzene ring and fluorine substituent at position 5 of indole ring (compound F), and compound C had the highest protective effect (25%) at 0.5 h after injection, and compounds C and E had the highest protective effects (25%) at 4 hours after injection.
Conclusion: Generally, the compounds studied had moderate anticonvulsant effects. The studied compounds showed the highest anticonvulsant activity in the MES method and were not effective in the PTZ method. Since the model of MES in animals is a measure of the effectiveness of the drug in generalized tonic-colonic epilepsy in humans, therefore, these compounds have the potential for further studies and more detailed evaluations to determine the exact mechanism of action by docking and molecular modeling studies, as well as toxicity tests to calculate LD50 and Rota-rod test to evaluating neurotoxicity. The results also indicate that the type and position of substituents of the indole ring are more effective than substituents of a benzene ring on the compound’s anticonvulsant effects.
Keywords: Epilepsy, Pentylentetrazole, Maximal electroshock seizure, Triazole, Indole