Levetiracetam treatment influences blood-brain barrier failure associated with angiogenesis and inflammatory responses in the acute phase of epileptogenesis in post-status epilepticus mice.
Our previous study showed that treatment with levetiracetam (LEV) after status epilepticus (SE) termination by diazepam might prevent the development of spontaneous recurrent seizures via the inhibition of neurotoxicity induced by brain edema events. In the present study, we determined the possible molecular and cellular mechanisms of LEV treatment after termination of SE. To assess the effect of LEV against the brain alterations after SE, we focused on blood-brain barrier (BBB) dysfunction associated with angiogenesis and brain inflammation. The consecutive treatment of LEV inhibited the temporarily increased BBB leakage in the hippocampus two days after SE. At the same time point, the LEV treatment significantly inhibited the increase in the number of CD31-positive endothelial immature cells and in the expression of angiogenic factors. These findings suggested that the increase in neovascularization led to an increase in BBB permeability by SE-induced BBB failure, and these brain alterations were prevented by LEV treatment. Furthermore, in the acute phase of the latent period, pro-inflammatory responses for epileptogenic targets in microglia and astrocytes of the hippocampus activated, and these upregulations of pro-inflammatory-related molecules were inhibited by LEV treatment. These findings suggest that LEV is likely involved in neuroprotection via anti-angiogenesis and anti-inflammatory activities against BBB dysfunction in the acute phase of epileptogenesis after SE.
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.
Kouichi
K
Itoh
Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima 739-8521, Japan.
Yasuhiro
Y
Ishihara
Laboratory for Pharmacotherapy and Experimental Neurology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.
Rie
R
Komori
Laboratory for Pharmaceutical Health Sciences, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa 769-2193, Japan.
Hiromi
H
Nochi
Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima 739-8521, Japan.
Ruri
R
Taniguchi
Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Yoichi
Y
Chiba
Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
Masaki
M
Ueno
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Fuyuko
F
Takata-Tsuji
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Shinya
S
Dohgu
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
Yasufumi
Y
Kataoka
D000208:Acute Disease; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000077287:Levetiracetam; D008297:Male; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D013226:Status Epilepticus / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000927:Anticonvulsants; D016207:Cytokines; D000077287:Levetiracetam; D010889:Piracetam
Angiogenesis; Blood-brain barrier; Epileptogenesis; Levetiracetam; Microglia; Status epilepticus