Pharm Sci. 2018;24(4):250-256.
doi: 10.15171/PS.2018.37
  Abstract View: 139
  PDF Download: 178

Research Article

Benzylidene Barbituric Acid Derivatives Shown Anticonvulsant Activity on Pentylenetetrazole-Induced Seizures in Mice: Involvement of Nitric Oxide Pathway

Shabnam Mahernia 1, Niusha Sharifi 2, Malihe Hassanzadeh 2 * , Nastaran Rahimi 3,4, Nastaran Pourshadi 1, Arash Amanlou 5, Ahmad Reza Dehpour 3,4, Massoud Amanlou 1,2 * ORCiD

1 The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
2 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
3 Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran.
4 Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
5 Faculty of Specialized Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran.

Abstract

ABSTRACT

Background: Barbituric acid derivatives have long been used as central nervous system (CNS) suppressants, such as sedatives, hypnotics and anticonvulsants. In addition, previous studies have implicated the involvement of nitric oxide (NO) in the anticonvulsive effects of barbiturates in CNS. Therefore, the purpose of this study was to figure out the effects of a novel class of barbituric acid derivatives on pentylenetetrazole (PTZ)-induced seizures in male mice. Methods: Thirteen synthesized barbituric acid derivatives (a-m) and phenobarbital were administered intraperitoneally (i.p.) 30 min before induction of seizures by PTZ administration. The mechanisms of PTZ-induced seizures in the mice was evaluated using a non-selective nitric oxide synthase (NOS) inhibitor, selective inducible NOS (iNOS) inhibitor, a selective neuronal NOS (nNOS) inhibitor, and NO substrate. Results: Administration of most of the above mentioned derivatives significantly increased the seizures threshold (P<0.001). The most potent derivative (compound a), was chosen in order to investigate the mechanism of action involving in anticonvulsant activity. Administration of a non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) and a selective nNOS inhibitor, 7-nitroindazole (7-NI) reversed anticonvulsant activity of compound a. However, injection of the nitric oxide precursor, L-arginine (L-Arg) and a selective iNOS inhibitor, aminoguanidine (AG), did not change anticonvulsant activity of the mentioned compound. Conclusion: These results indicated that the NO system, specifically nNOS may contribute to the anticonvulsant activity of benzylidene barbituric acid derivative a. Therefore, this compound is a good candidate in order to designing new anticonvulsant medications

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Submitted: 21 Jul 2018
Revised: 06 Sep 2018
Accepted: 09 Sep 2018
First published online: 30 Dec 2018
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