title: Effect of the calcineurin inhibitor FK506 on K+-Cl- cotransporter 2 expression in the mouse hippocampus after kainic acid-induced status epilepticus.
abstract: Calcineurin (CaN)-mediated excitotoxicity impairs γ-aminobutyric acid (GABA) transmission and induces neuronal apoptosis. Ca(2+)-dependent K(+)-Cl(-) cotransporter 2 (KCC2) participates in GABAergic inhibitory transmission. However, the mechanism by which CaN mediates GABA receptor-mediated KCC2 in seizures is not fully understood. In the present study, we investigated the altered expression of KCC2 and the effects of the CaN inhibitor FK506 on KCC2 expression in the mouse hippocampus following kainic acid (KA) treatment. FK506 was injected twice 24 h and 30 min before KA treatment and then mice were treated with KA and killed 2 days later. FK506 had anticonvulsant effect on KA-induced seizure activities. CaN cleavage was evident in the hippocampus 24 h after KA treatment. FK506 pretreatment blocked the truncation of CaN in the KA-treated hippocampus. Cresyl violet and TUNEL staining showed that FK506 prevented KA-induced hippocampal cell death. In particular, Western blot analysis showed that KCC2 expression was time dependent, with a peak at 6 h and a return to decreased levels at 48 h, whereas FK506 pretreatment inhibited the KA-induced decrease in KCC2 expression in the hippocampus. Immunofluorescence showed that FK506 pretreatment protected the loss of inhibitory GABAergic KCC2-expressing neurons following KA treatment. Taken together, these results provide evidence that altered KCC2 expression may be associated with Ca(2+)-mediated seizure activity and indicate that neuron-specific KCC2 may be involved in neuroprotection after seizures.
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Health Sciences, Medical Research Center for Neural Dysfunction, School of Medicine, Gyeongsang National University, 816 Beongil 15 Jinju-daero, Jinju, Gyeongnam 660-290, Republic of Korea.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Shin
authors.forename: Byeong Tak
authors.initials: BT
authors.lastname: Jeon
authors.forename: Jungmee
authors.initials: J
authors.lastname: Kim
authors.forename: Eun Ae
authors.initials: EA
authors.lastname: Jeong
authors.forename: Myeung Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Lee
authors.forename: Hyun Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.forename: Wan Sung
authors.initials: WS
authors.lastname: Choi
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D065095:Calcineurin Inhibitors; D016923:Cell Death / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D027981:Symporters / Q000096:biosynthesis*; D016559:Tacrolimus / Q000494:pharmacology*; D000096922:K Cl- Cotransporters
chemical_list: D065095:Calcineurin Inhibitors; D018690:Excitatory Amino Acid Agonists; D007166:Immunosuppressive Agents; D007608:Kainic Acid; D027981:Symporters; D016559:Tacrolimus; D000096922:K Cl- Cotransporters