Anticonvulsant activity of some semicarbazone and thiosemicarbazone derivatives of isatin on PTZ induced seizure
Abstract
Epilepsy is a syndrome characterized by excessive discharge of many neurons. In spite of the optimal use of available antiepileptic drugs; seizures in lots of patients fail to be controlled. On the other hand many patients experience side effects which can limit the use of these drugs. Hence, investigation on chemicals with anticonvulsant properties and lower side effects are a valuable task. Isatin is a heterocyclic compound with different biological properties. We synthesized 14 isatinsemicarbazone and thiosemicarbazone derivatives (a-n) in our previous study. Here we are going to evaluate these compounds for their anticonvulsant effects.
We performed Pentylenetetrazole (PTZ) model (acute) in male mice (85mg/kg) and chemical kindling model (chronic) in male rats (37.5 mg/kg each 48 h for 14-20 days). Intraperitoneal injection was used to induce seizures in rodents.
In the acute test, compounds b, d, f, I, j, k, l, m and n, with 3 doses of 10, 20 and30 mg/kg showed significant anticonvulsant effects in comparison to the control group and increase the seizure onsets and the time of death (p<0.05). In the kindling model, derivatives k and n were selected as effective compounds with doses of 10, 30 mg/kg. These derivatives significantly prevented the epileptogenesis and improved motor coordination in Rotarod test. In conclusion, these compounds seem to be potential anticonvulsant agents with low side effects.
Keywords:
Epilepsy,, Isatin, PTZ, Animal models
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References
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26. Dhir A, Naidu PS, Kulkarni SK. Neuroprotective effect of nimesulide, a preferential COX-2 inhibitor, against pentylenetetrazol (PTZ)-induced chemical kindling and associated biochemical parameters in mice. Seizure 2007; 16(8):691-7.
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28. Mathur G, Nain S. Recent advancement in synthesis of isatin as anticonvulsant agents: a review. Med Chem. 2014; 4(4):417-27.
29. Yogeeswari P, Sriram D, Thirumurugan R, Raghavendran JV, Sudhan K, Pavana RK, et al. Discovery of N-(2,6-dimethylphenyl)-substituted semicarbazones as anticonvulsants: hybrid pharmacophore-based design. Journal of medicinal chemistry 2005; 48(20):6202-11.
30. Gupta Y, Sharma M, Chaudhary G. Antiepileptic activity of Panax ginseng against pentylenetetrazole induced kindling in rats. Indian journal of physiology and pharmacology 2001; 45(4):502-6.
31. Deka S, Mohan S, Saravanan J, Kakati M, Talukdar A, Sahariah BJ, et al. Syntheses, characterization and in-vitro anti-Inflammatory activity of some novel thiophenes. Macedonian Journal of Medical Sciences 2012; 5(2):159-63.
32. Rauca C, Zerbe R, Jantze H. Formation of free hydroxyl radicals after pentylenetetrazol-induced seizure and kindling. Brain research 1999; 847(2):347-51.
33. Sun J-P, Hendsbee AD, Dobson AJ, Welch GC, Hill IG. Perylene diimide based all small-molecule organic solar cells: Impact of branched-alkyl side chains on solubility, photophysics, self-assembly, and photovoltaic parameters. Organic Electronics 2016; 35:151-7.
2. Abdel-Rahman LH, Abu-Dief AM, Mostafa H, Hamdan SK. Ni (II) and Cu (II) complexes with ONNO asymmetric tetradentate Schiff base ligand: synthesis, spectroscopic characterization, theoretical calculations, DNA interaction and antimicrobial studies. Appl Organomet Chem. 2017; 31:e3555.
3. Beauchard A, Ferandin Y, Frère S, Lozach O, Blairvacq M, Meijer L, et al. Synthesis of novel 5-substituted indirubins as protein kinases inhibitors. Bioorganic & medicinal chemistry 2006; 14(18):6434-43.
4. Van Mierlo P, Papadopoulou M, Carrette E, Boon P, Vandenberghe S, Vonck K, et al. Functional brain connectivity from EEG in epilepsy: Seizure prediction and epileptogenic focus localization. Progress in Neurobiology 2014; 121:19-35.
5. Moezi L, Pirsalami F, Inaloo S. Constipation enhances the propensity to seizure in pentylenetetrazole-induced seizure models of mice. Epilepsy & behavior : E&B. 2015;44:200-6.
6. Sharma CS, Verma T, Singh HP, Kumar N. Synthesis, characterization and preliminary anticonvulsant evaluation of some flavanone incorporated semicarbazides. Medicinal Chemistry Research 2014; 23(11):4814-24.
7. Sardari S, Amiri M, Rahimi H, Kamalinejad M, Narenjkar J, Sayyah M. 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.
8. Aboul-Fadl T, Bin-Jubair FA. Anti-tubercular activity of isatin derivatives. Int J Res Pharm Sci. 2010; 1(2):113-26.
9. Sridhar SK, Saravanan M, Ramesh A. Synthesis and antibacterial screening of hydrazones, Schiff and Mannich bases of isatin derivatives. Eur J Med Chem. 2001; 36(7-8):615-25.
10. Hossain MM, Islam N, Khan R, Islam MR. Cytotoxicity study of dimethylisatin and its heterocyclic derivatives. Bangladesh Journal of Pharmacology 2007; 2(2):5.
11. Selvam P, Chandramohan M, De Clercq E, Witvrouw M, Pannecouque C. Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives. European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 2001; 14(4):313-6.
12. Pajouhesh H, Parson R, Popp FD. Potential anticonvulsants VI: condensation of isatins with cyclohexanone and other cyclic ketones. Journal of pharmaceutical sciences 1983; 72(3):318-21.
13. Kumar N, Sharma P, Garg V, Singh P. Synthesis and anticonvulsant activity of novel substituted phenyl indoloimidazole derivatives. 2011.
14. Pandeya SN, Raja AS, Stables JP. Synthesis of isatin semicarbazones as novel anticonvulsants--role of hydrogen bonding. Journal of pharmacy & pharmaceutical sciences: a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 2002; 5(3):266-71.
15. Popp FD. Potential anticonvulsants. IX. Some isatin hydrazones and related compounds. Journal of Heterocyclic Chemistry 1984; 21(6):1641-5.
16. Prakash CR, Raja S, Saravanan G. Synthesis, characterization and anticonvulsant activity of novel Schiff base of isatin derivatives. Int J Pharm Pharm Sci. 2010; 2:177-81.
17. Divar M. A: Synthesis of Some Novel Isatin Derivatives including Semicarbazone and Thiosemicarbazone B: Application of Some Novel lewis Acids in Protective Chemistry 2009.
18. Palizvan M, Ghaznavi-Rad E. Naloxane enhanced inhibitory effect of verapamil on seizure induced by pentylenetetrazol in male rats. Research in pharmaceutical sciences 2014; 9(4):295.
19. Jing X, Liu X, Wen T, Xie S, Yao D, Liu X, et al. Combined effects of epileptic seizure and phenobarbital induced overexpression of P‐glycoprotein in brain of chemically kindled rats. British journal of pharmacology 2010; 159(7):1511-22.
20. Singh S, Trigun SK. Low grade cirrhosis induces cognitive impairment and motor dysfunction in rats: could be a model for minimal hepatic encephalopathy. Neuroscience letters 2014; 559:136-40.
21. Shannon HE, Love PL. Effects of antiepileptic drugs on learning as assessed by a repeated acquisition of response sequences task in rats. Epilepsy & behavior : E&B 2007; 10(1):16-25.
22. Ali A, Rao NV, Shalam M, Gouda TS, Shantakumar S. Anticonvulsive effect of seed extract of Caesalpinia bonducella (Roxb.). Iranian Journal of Pharmacology & Therapeutics 2009; 8(2):51-5.
23. Loscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 2011; 20(5):359-68.
24. Mussulini BHM, Leite CE, Zenki KC, Moro L, Baggio S, Rico EP, et al. Seizures induced by pentylenetetrazole in the adult zebrafish: a detailed behavioral characterization. PloS one. 2013; 8(1):e54515.
25. Sayyah M, Moaied S, Kamalinejad M. Anticonvulsant activity of Heracleum persicum seed. Journal of ethnopharmacology 2005; 98(1): 209-11.
26. Dhir A, Naidu PS, Kulkarni SK. Neuroprotective effect of nimesulide, a preferential COX-2 inhibitor, against pentylenetetrazol (PTZ)-induced chemical kindling and associated biochemical parameters in mice. Seizure 2007; 16(8):691-7.
27. Loscher W, Rundfeldt C. Kindling as a model of drug-resistant partial epilepsy: selection of phenytoin-resistant and nonresistant rats. The Journal of pharmacology and experimental therapeutics 1991; 258(2):483-9.
28. Mathur G, Nain S. Recent advancement in synthesis of isatin as anticonvulsant agents: a review. Med Chem. 2014; 4(4):417-27.
29. Yogeeswari P, Sriram D, Thirumurugan R, Raghavendran JV, Sudhan K, Pavana RK, et al. Discovery of N-(2,6-dimethylphenyl)-substituted semicarbazones as anticonvulsants: hybrid pharmacophore-based design. Journal of medicinal chemistry 2005; 48(20):6202-11.
30. Gupta Y, Sharma M, Chaudhary G. Antiepileptic activity of Panax ginseng against pentylenetetrazole induced kindling in rats. Indian journal of physiology and pharmacology 2001; 45(4):502-6.
31. Deka S, Mohan S, Saravanan J, Kakati M, Talukdar A, Sahariah BJ, et al. Syntheses, characterization and in-vitro anti-Inflammatory activity of some novel thiophenes. Macedonian Journal of Medical Sciences 2012; 5(2):159-63.
32. Rauca C, Zerbe R, Jantze H. Formation of free hydroxyl radicals after pentylenetetrazol-induced seizure and kindling. Brain research 1999; 847(2):347-51.
33. Sun J-P, Hendsbee AD, Dobson AJ, Welch GC, Hill IG. Perylene diimide based all small-molecule organic solar cells: Impact of branched-alkyl side chains on solubility, photophysics, self-assembly, and photovoltaic parameters. Organic Electronics 2016; 35:151-7.
Published
30/09/2017
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Masoumeh Divar1M., Yeganeh, Y., Jamshidzadeh, A., Khabnadideh, S., & Heidari, R. (2017). Anticonvulsant activity of some semicarbazone and thiosemicarbazone derivatives of isatin on PTZ induced seizure. Journal of Innovations in Applied Pharmaceutical Science (JIAPS), 2(3), 04-14. Retrieved from https://www.saapjournals.org/index.php/jiaps/article/view/190
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