Neuroscience Letters 461 (2009) 298–301 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Edaravone, a free radical scavenger, retards the development of amygdala kindling in rats Tohru Kamida ∗ , Eiji Abe, Tatsuya Abe, Hiroshi Ooba, Minoru Fujiki, Hidenori Kobayashi Department of Neurosurgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Oita 879-5593, Japan article info Article history: Received 3 May 2009 Received in revised form 3 June 2009 Accepted 15 June 2009 Keywords: Edaravone Free radical scavenger Antiepileptogenic effect Amygdala kindling Rat abstract This study evaluated the antiepileptogenic effects of edaravone, a newly developed radical scavenger, on the amygdala kindling rats. The afterdischarge duration (ADD), AD threshold (ADT), and seizure severity in animals were measured to study the anticonvulsant effects of edaravone (2 mg/kg or 20 mg/kg i.p. for 7 days) on fully kindled seizures. Furthermore, for the study of antiepileptogenesis effects of the drug (2 mg/kg or 20 mg/kg i.p. for 7 days), not only ADD and seizure severity during kindling but also both the pre- and post-kindling ADT were measured. Edaravone neither induces nor inhibits fully kindled seizures regardless of the dose; however high-dose edaravone (20 mg/kg) retarded kindling development together with shortened ADD and elevated ADT. The present data suggest that high-dose edaravone has an antiepileptogenic drug effect for the prevention of epilepsy. However, other chronic models and clinical trials are needed to confirm the effects of edaravone on the prevention of human epilepsy. © 2009 Elsevier Ireland Ltd. All rights reserved. Oxygen free radical species such as nitric oxide (NO) have been implicated in the development of seizures under pathological conditions and linked to seizure-induced neuronal degeneration [2,3,9,13,14]. There are studies showing that scavenging of free radi- cal species has neuroprotective effects on seizure-induced neuronal degeneration [2,5,8]. However, according to a report by Frantseva et al. [2], the neuroprotective effects of free radical scavengers do not always link to antiepileptogenic activities. Whether the scavenging of free radical species is implicated in the development of seizures remains to be elucidated. Edaravone (MCI-186) is a newly developed radical scavenger that protects neurons by ameliorating neuronal damage caused by acute brain ischemia. Edaravone has an antioxidant effect, thereby quenching • OH and preventing both • OH-dependent and • OH- independent lipid peroxidation, and exerting inhibitory effects on both water-soluble and lipid-soluble peroxyl radical-induced peroxidation systems. Furthermore, edaravone has antioxidant activities, quenching not only • OH but also other free radical species such as superoxide and NO radicals [16–18]. No report has focused on the epileptogenecity of edaravone in the previous epilepsy mod- els. The kindling model of temporal lobe epilepsy is widely used for studies on epileptogenic processes and on drug targets by which epilepsy can be prevented or modified. The aim of the present study was to evaluate both the anticonvulsant and ∗ Corresponding author. Tel.: +81 97 586 5862; fax: +81 97 586 5869. E-mail address: kamida@med.oita-u.ac.jp (T. Kamida). antiepileptogenic effects of edaravone on the amygdala kindling rats. Forty-eight adult male Wistar rats (Kyudo Co., Ltd. Kumamoto, Japan) weighing between 200 and 260 g were housed individually and kept on a 12-h light/dark cycle. The rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and placed in a stereotaxic instrument. A Teflon-coated, stainless steel tripolar stimulating electrode (diameter 0.2 mm) was implanted into the right basolat- eral amygdala (2.5 mm posterior and 4.5 mm lateral to the bregma, and 7.5 mm ventral to the dura) for electrical stimulation and elec- troencephalographic (EEG) recording. Stainless steel screw scalp electrodes were implanted in the right upper orbital region as a ground electrode and 1.0mm anterior to the lamboid suture as a reference electrode. The initial (prekindling) afterdischarge threshold (ADT) was determined using an electric stimulator (SEN-7203; Nihon Kohden) 1 week after electrode implantation. The stimulation parameters were a pulse duration of 1.0 ms, frequency of 60 Hz (biphasic square wave pulses), and train duration of 1.0s. The stimulus intensity started at 100 A, and thereafter increased in 40 A increments at 5-min intervals until an afterdischarge (AD) of at least 3s dura- tion was elicited (230–700 A). Animals were kindled by once daily stimulation at 120% of their individual ADT. The kindled seizures were classified according to Racine’s five stages [12]: stage 1, facial twitching, head version or eye closure ipsilateral to stimulation; stage 2, head nodding accompanying mastication; stage 3, clonic forelimb convulsion; stage 4, rearing to a kangaroo-like posture or rearing with clonic forelimb clonus; and stage 5, generalized convulsion, including falling down. Stimulation was repeated for 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.06.039