Short communicationAntiepileptogenic and anticonvulsive actions of levetiracetam in a pentylenetetrazole kindling model
Introduction
Levetiracetam (LEV) is a unique antiepileptic drug (AED) which preferentially interacts with synaptic vesicle protein 2A (SV2A) without affecting activities of neurotransmitter receptors or ion channels (Lynch et al., 2004, Sasa, 2006, Kaminski et al., 2008). Unlike conventional AEDs, LEV is not active in the classical convulsion tests (i.e., maximal electroshock- and maximal pentylenetetrazole (PTZ)-evoked seizures) (Löscher and Hönack, 1993, Klitgaard et al., 1998, Bastlund et al., 2005), but it inhibits seizures in various animal models including kindled animals (e.g., corneal- and amygdala kindling) (Löscher and Hönack, 1993, Klitgaard et al., 1998, Löscher et al., 1998) and genetically defined animal models of epilepsy (Gower et al., 1995, Bouwman and van Rijn, 2004, Yan et al., 2005, Ji-qun et al., 2005). In addition, previous studies demonstrated that LEV can inhibit the development of amygdala kindling in rats, suggesting that LEV has antiepileptogenic activities (Löscher et al., 1998, Husum et al., 2004, Gu et al., 2004). Nonetheless, a recent study by Matveeva et al. (2008) showed that LEV retarded the development of amygdala kindling, but could not prevent kindling acquisition. Studies using animals with spontaneous recurrent seizures after status epilepticus also demonstrated the lack of effectiveness of LEV against the epileptogenesis (Brandt et al., 2007). Thus, the antiepileptogenic potential of LEV is still unclear and remains to be verified using different animal models.
In order to address this question further, we studied the effects of LEV on the development and acquisition of PTZ-induced kindling in mice, and compared them with those of the typical AED sodium valproate (VPA).
Section snippets
Methods
Male ddY mice (Japan SLC, Shizuoka, Japan) weighing 20–25 g were used. Animals were housed in air-conditioned rooms under a 12-h light/dark cycle (light on: 7:00 a.m.) and allowed ad libitum access to food and water. The housing conditions of the mice and animal care methods complied with NIH guide for the care and use of laboratory animals. The experimental protocols of this study were approved by the Experimental Animal Research Committee at Osaka University of Pharmaceutical Sciences.
In order
Results
In naïve animals, LEV did not affect PTZ seizures even at high doses up to 300 mg/kg (i.p.) while VPA inhibited the seizures with an ED50 value of 229 mg/kg (i.p.) (Table 1). We therefore set the test doses of LEV and VPA at 30 and 100 mg/kg (i.p.), and these doses were repeatedly administered to the animals 30 min before PTZ (40 mg/kg, i.p.) injection for 12 days.
Repeated administration of sub-convulsive PTZ (40 mg/kg, i.p.) progressively increased seizure susceptibility in mice during the 12-day
Discussion
The present study demonstrated that repeated treatments with LEV effectively inhibited development and acquisition of PTZ kindling. In addition, LEV showed a significant ability to inhibit PTZ-evoked seizures specifically in kindled animals while being inactive in naïve animals. These characteristics are different from those of VPA, which failed to prevent the development of PTZ kindling and inhibited PTZ seizures in fully kindled and naïve animals at equipotent doses. Our results revealed that
Acknowledgments
This work was partly supported by the Japan Epilepsy Research Foundation. We thank UCB Japan (Tokyo, Japan) for kindly donating a sample of LEV.
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