title: Prevention of status epilepticus-induced brain edema and neuronal cell loss by repeated treatment with high-dose levetiracetam.
abstract: The management of status epilepticus (SE) is important to prevent mortality and the development of post-SE symptomatic epilepsy. Acquired epilepsy after an initial brain insult by SE can be experimentally reproduced in the murine model of SE induced by pilocarpine. In the present study, we evaluated the possibility of treatment with a high-dose of levetiracetam in this model. Repeated treatment with high-dose levetiracetam after termination of SE by diazepam significantly prevented the incidence of spontaneous recurrent seizures and mortality for at least 28 days. To determine the brain alterations after SE, magnetic resonance imaging was performed. Both T2-weighted imaging and diffusion-weighted imaging showed changes in the limbic regions. These changes in the limbic regions demonstrated the development of cytotoxic edema three hours after SE, followed by the development of vasogenic edema two days after SE. In the pilocarpine-SE model, the incidence of spontaneous recurrent seizures after SE was strongly associated with neuronal damage within a few hours to days after SE by the development of vasogenic edema via the breakdown of the blood-brain barrier in the limbic regions. High-dose levetiracetam significantly suppressed the parameters in the limbic areas. These data indicate that repeated treatment with high-dose levetiracetam for at least two days after SE termination by diazepam is important for controlling the neuronal damage by preventing brain edema. Therefore, these findings suggest that early treatment with high-dose levetiracetam after SE termination by diazepam may protect against adverse sequelae via the inhibition of neurotoxicity induced by brain edema events.
authors.affiliation: Laboratory for Pharmacotherapy and Experimental Neurology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan. Electronic address: itoh@kph.bunri-u.ac.jp.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Laboratory for Pharmacotherapy and Experimental Neurology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.
authors.forename: Moriyoshi
authors.initials: M
authors.lastname: Inamine
authors.affiliation: Laboratory for Pharmacotherapy and Experimental Neurology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Oshima
authors.affiliation: Department of Molecular and Cellular Biology, Faculty of Pharmaceutical Science, Ohu University, Koriyama, Fukushima 963-8611, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kotani
authors.affiliation: Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Chiba
authors.affiliation: Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima 739-8521, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D000077287:Levetiracetam; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018721:Muscarinic Agonists; D009474:Neurons / Q000473:pathology*; D010862:Pilocarpine / Q000633:toxicity; D010889:Piracetam / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D018721:Muscarinic Agonists; D010862:Pilocarpine; D000077287:Levetiracetam; D010889:Piracetam
keywords: Brain edema; Epileptogenesis; Levetiracetam; MRI; Pilocarpine; Status epilepticus