title: Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death.
abstract: Prolonged seizures (status epilepticus, SE) can cause neuronal death within brain regions such as the hippocampus. This may contribute to impairments in cognitive functioning and trigger or exacerbate epilepsy. Seizure-induced neuronal death is mediated, at least in part, by apoptosis-associated signaling pathways. Indeed, mice lacking certain members of the potently proapoptotic BH3-only subfamily of Bcl-2 proteins are protected against hippocampal damage caused by status epilepticus. The recently identified BH3-only protein Bcl-2-modifying factor (Bmf) normally interacts with the cytoskeleton, but upon certain cellular stresses, such as loss of extracellular matrix adhesion or energy crisis, Bmf relocalizes to mitochondria, where it can promote Bax activation and mitochondrial dysfunction. Although Bmf has been widely reported in the hematopoietic system to exert a proapoptotic effect, no studies have been undertaken in models of neurological disorders. To examine whether Bmf is important for seizure-induced neuronal death, we studied Bmf induction after prolonged seizures induced by intra-amygdala kainic acid (KA) in mice, and examined the effect of Bmf-deficiency on seizures and damage caused by SE. Seizures triggered an early (1-8 h) transcriptional activation and accumulation of Bax in the cell death-susceptible hippocampal CA3 subfield. Bmf mRNA was biphasically upregulated beginning at 1 h after SE and returning to normal by 8 h, while again being found elevated in the hippocampus of epileptic mice. Bmf upregulation was prevented by Compound C, an inhibitor of adenosine monophosphate-activated protein kinase, indicating Bmf expression may be induced in response to bioenergetic stress. Bmf-deficient mice showed normal sensitivity to the convulsant effects of KA, but, surprisingly, displayed significantly more neuronal death in the hippocampal CA1 and CA3 subfields after SE. These are the first studies investigating Bmf in a model of neurologic injury, and suggest that Bmf may protect neurons against seizure-induced neuronal death in vivo.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: Moran
authors.forename: A
authors.initials: A
authors.lastname: Sanz-Rodriguez
authors.forename: A
authors.initials: A
authors.lastname: Jimenez-Pacheco
authors.forename: J
authors.initials: J
authors.lastname: Martinez-Villareal
authors.forename: R C
authors.initials: RC
authors.lastname: McKiernan
authors.forename: E M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.forename: C
authors.initials: C
authors.lastname: Mooney
authors.forename: I
authors.initials: I
authors.lastname: Woods
authors.forename: J H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: D C
authors.initials: DC
authors.lastname: Henshall
authors.forename: T
authors.initials: T
authors.lastname: Engel
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C435486:Bmf protein, mouse; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; C516138:dorsomorphin; D055372:AMP-Activated Protein Kinases; D007608:Kainic Acid