Neuropharmacology and Analgesia
Osthole suppresses seizures in the mouse maximal electroshock seizure model

https://doi.org/10.1016/j.ejphar.2009.02.022Get rights and content

Abstract

The aim of this study was to determine the anticonvulsant effects of osthole {[7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one] – a natural coumarin derivative} in the mouse maximal electroshock-induced seizure model. The antiseizure effects of osthole were determined at 15, 30, 60, and 120 min after its systemic (i.p.) administration. Time course of anticonvulsant action of osthole revealed that the natural coumarin derivative produced a clear-cut antielectroshock activity in mice and the experimentally-derived ED50 values for osthole ranged from 259 to 631 mg/kg. In conclusion, osthole suppresses seizure activity in the mouse maximal electroshock-induced seizure model. It may become a novel treatment option following further investigation in other animal models of epilepsy and preclinical studies.

Introduction

Osthole {[7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one], a natural coumarin derivative (Fig. 1)}, is extracted from many medicinal plants, such as Angelica pubescens, Cnidium monnieri and Peucedanum ostruthium (Teng et al., 1994, Chen et al., 2000, Cisowski et al., 2001, Chou et al., 2007). Previous experimental studies have shown that osthole exerts a broad spectrum of pharmacological activities due to its antiproliferative, vasorelaxing, anti-hepatitis, anti-inflammatory, antiaggregatory and anti-allergic effects (Ko et al., 1989, Ko et al., 1992, Huang et al., 1996, Liu et al., 1998, Chiou et al., 2001, Matsuda et al., 2002, Yang et al., 2003).

Accumulating evidence indicates that imperatorin {[9-(3-methylbut-2-enyloxy)-7H-furo[3,2-g]chromen-7-one], a natural furanocoumarin derivative (Fig. 1)} possesses the anticonvulsant activity in preclinical studies by elevating the threshold for electroconvulsions (Luszczki et al., 2007a) and enhancing the antielectroshock action of carbamazepine, phenobarbital, phenytoin (Luszczki et al., 2007b), and lamotrigine (Luszczki et al., 2008) in mice.

Since osthole and imperatorin (two naturally occurring coumarin derivatives) have similar chemical structures (Fig. 1), we expected that osthole would also exert the anticonvulsant action in mice. Therefore, we examined the dose–response relationship and time course of action of osthole against maximal electroshock-induced seizures in mice. Generally, the maximal electroshock-induced seizure test in rodents is considered as a valid experimental model to detect the anticonvulsant action of drugs against generalized tonic–clonic seizures and partial convulsions with or without secondary generalization in humans (Fisher, 1989, Löscher et al., 1991). Moreover, this experimental model of epilepsy is widely used for an investigation of the new drugs and for preselection of the agents with antiseizure activity in vivo (Fisher, 1989, Löscher et al., 1991).

Section snippets

Materials and methods

Adult male Swiss mice (weighing 22–26 g) that were kept in colony cages (20 per cage) with free access to food and tap water, under standardized housing conditions (12 h light–dark cycle, temperature of 23 ± 1°C, relative humidity of 55 ± 5%), were used. After 7 days of adaptation to laboratory conditions, the animals were randomly assigned to experimental groups comprising of 8 mice. Each mouse was used only once and all tests were performed between 08:00 a.m. and 03:00 p.m. Procedures involving

Results

Osthole administered systemically (i.p.), at 15, 30, 60 and 120 min before the test, produced a clear-cut anticonvulsant activity in the mouse maximal electroshock-induced seizure test and the experimentally-derived ED50 values for the natural coumarin derivative were 266, 259, 443, and 631 mg/kg, respectively (Fig. 2). Considering dose–response relationship and time course of anticonvulsant action of osthole in the maximal electroshock-induced seizure test and comparing the ED50 values for

Discussion

Results indicate that osthole administered systemically (i.p.), at various pretreatment times (15, 30, 60 and 120 min) before the maximal electroshock-induced seizure test, produced a clear-cut antielectroshock action in mice. The maximum anticonvulsant activity of osthole (at 15 and 30 min after its i.p. administration) was similar to that as documented earlier for imperatorin (Luszczki et al., 2007a). Moreover, the systemic (i.p.) administration of osthole, at various pretreatment times and

Disclosure of conflicts of interest

The authors have no conflicts of interest to disclose.

Acknowledgement

This study was supported by a grant from the Medical University of Lublin (Lublin, Poland). The authors express their thanks to Miss K. Tejchman for her technical assistance.

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    Accumulated evidence demonstrates that Chinese herbal agents provide a new hope for effective cancer treatments [18] and some agents show promise in the treatment of HNSCC [19,20]. Osthole, an active ingredient of Cnidium monnieri (L.), has been widely applied as an anti-allergic, anti-osteoporotic, anti-inflammatory, and anti-seizure agent [8–10,12]. Recent literature suggests that osthole exerts anticancer effects by inhibiting cell growth through induced cell cycle arrest and apoptosis [21,22].

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