title: Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.
abstract: Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy. A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim. Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro. Inhibition of Akt increased the FKHR/Bim response and DNA fragmentation within the normally resistant cortex. Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures. We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy.
authors.affiliation: Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Shinoda
authors.forename: Clara K
authors.initials: CK
authors.lastname: Schindler
authors.forename: Robert
authors.initials: R
authors.lastname: Meller
authors.forename: Norman K
authors.initials: NK
authors.lastname: So
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Araki
authors.forename: Akitaka
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Jing-Quan
authors.initials: JQ
authors.lastname: Lan
authors.forename: Waro
authors.initials: W
authors.lastname: Taki
authors.forename: Roger P
authors.initials: RP
authors.lastname: Simon
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D004827:Epilepsy / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017207:Rats, Sprague-Dawley; D013702:Temporal Lobe / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C491073:BCL2L2 protein, human; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; C491072:Bcl2l2 protein, rat; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt