title: Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma.
abstract: The functional significance of neuronal death for pathogenesis of epilepsy and the underlying molecular mechanisms thereof remain incompletely understood. The p53 transcription factor has been implicated in seizure damage, but its target genes and the influence of cell death under its control on epilepsy development are unknown. In the present study, we report that status epilepticus (SE) triggered by intra-amygdala kainic acid in mice causes rapid p53 accumulation and subsequent hippocampal damage. Expression of p53-up-regulated mediator of apoptosis (Puma), a proapoptotic Bcl-2 homology domain 3-only protein under p53 control, was increased within a few hours of SE. Induction of Puma was blocked by pharmacologic inhibition of p53, and hippocampal damage was also reduced. Puma induction was also blocked in p53-deficient mice subject to SE. Compared to Puma-expressing mice, Puma-deficient mice had significantly smaller hippocampal lesions after SE. Long-term, continuous telemetric EEG monitoring revealed a approximately 60% reduction in the frequency of epileptic seizures in the Puma-deficient mice compared to Puma-expressing mice. These are the first data showing genetic deletion of a proapoptotic protein acting acutely to influence neuronal death subsequently alters the phenotype of epilepsy in the long-term, supporting the concept that apoptotic pathway activation is a trigger of epileptogenesis.-Engel, T., Murphy, B. M., Hatazaki, S., Jimenez-Mateos, E. M., Concannon, C. G., Woods, I., Prehn, J. H. M., Henshall, D. C. Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma.
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.forename: Brona M
authors.initials: BM
authors.lastname: Murphy
authors.forename: Seiji
authors.initials: S
authors.lastname: Hatazaki
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.forename: Caoimhin G
authors.initials: CG
authors.lastname: Concannon
authors.forename: Ina
authors.initials: I
authors.lastname: Woods
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D052160:Benzothiazoles / Q000494:pharmacology; D015153:Blotting, Western; D004827:Epilepsy / Q000378:metabolism / Q000473:pathology*; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013226:Status Epilepticus / Q000378:metabolism / Q000503:physiopathology*; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D052160:Benzothiazoles; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014050:Toluene; C121565:pifithrin