title: Deletion of the BH3-only protein Noxa alters electrographic seizures but does not protect against hippocampal damage after status epilepticus in mice.
abstract: Several members of the Bcl-2 gene family are dysregulated in human temporal lobe epilepsy and animal studies show that genetic deletion of some of these proteins influence electrographic seizure responses to chemoconvulsants and associated brain damage. The BH3-only proteins form a subgroup comprising direct activators of Bax-Bak that are potently proapoptotic and a number of weaker proapoptotic BH3-only proteins that act as sensitizers by neutralization of antiapoptotic Bcl-2 family members. Noxa was originally characterized as a weaker proapoptotic, 'sensitizer' BH3-only protein, although recent evidence suggests it too may be potently proapoptotic. Expression of Noxa is under p53 control, a known seizure-activated pathway, although Noxa has been linked to energetic stress and autophagy. Here we characterized the response of Noxa to prolonged seizures and the phenotype of mice lacking Noxa. Status epilepticus induced by intra-amygdala kainic acid caused a rapid increase in expression of noxa in the damaged CA3 subfield of the hippocampus but not undamaged CA1 region. In vivo upregulation of noxa was reduced by pifithrin-α, suggesting transcription may be partly p53-dependent. Mice lacking noxa developed less severe electrographic seizures during status epilepticus in the model but, surprisingly, displayed equivalent hippocampal damage to wild-type animals. The present findings indicate Noxa does not serve as a proapoptotic BH3-only protein during seizure-induced neuronal death in vivo. This study extends the comprehensive phenotyping of seizure and damage responses in mice lacking specific Bcl-2 gene family members and provides further evidence that these proteins may serve roles beyond control of cell death in the brain.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.|Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ichikawa
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Mariana
authors.initials: M
authors.lastname: Alves
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Shona
authors.initials: S
authors.lastname: Pfeiffer
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Elena
authors.initials: E
authors.lastname: Langa
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Yasmina E
authors.initials: YE
authors.lastname: Hernández-Santana
authors.affiliation: Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Jochen Hm
authors.initials: JH
authors.lastname: Prehn
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D017353:Gene Deletion; D006624:Hippocampus / Q000293:injuries / Q000473:pathology; D006801:Humans; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D013226:Status Epilepticus / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C581062:RTL10 protein, human; D016159:Tumor Suppressor Protein p53