title: Microarray profile of seizure damage-refractory hippocampal CA3 in a mouse model of epileptic preconditioning.
abstract: A neuroprotected state can be acquired by preconditioning brain with a stimulus that is subthreshold for damage (tolerance). Acquisition of tolerance involves coordinate, bi-directional changes to gene expression levels and the re-programmed phenotype is determined by the preconditioning stimulus. While best studied in ischemic brain there is evidence brief seizures can confer tolerance against prolonged seizures (status epilepticus). Presently, we developed a model of epileptic preconditioning in mice and used microarrays to gain insight into the transcriptional phenotype within the target hippocampus at the time tolerance had been acquired. Epileptic tolerance was induced by an episode of non-damaging seizures in adult C57Bl/6 mice using a systemic injection of kainic acid. Neuron and DNA damage-positive cell counts 24 h after status epilepticus induced by intraamygdala microinjection of kainic acid revealed preconditioning given 24 h prior reduced CA3 neuronal death by approximately 45% compared with non-tolerant seizure mice. Microarray analysis of over 39,000 transcripts (Affymetrix 430 2.0 chip) from microdissected CA3 subfields was undertaken at the point at which tolerance was acquired. Results revealed a unique profile of small numbers of equivalently up- and down-regulated genes with biological functions that included transport and localization, ubiquitin metabolism, apoptosis and cell cycle control. Select microarray findings were validated post hoc by real-time polymerase chain reaction and Western blotting. The present study defines a paradigm for inducing epileptic preconditioning in mice and first insight into the global transcriptome of the seizure-damage refractory brain.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Hatazaki
authors.forename: C
authors.initials: C
authors.lastname: Bellver-Estelles
authors.forename: E M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.forename: R
authors.initials: R
authors.lastname: Meller
authors.forename: C
authors.initials: C
authors.lastname: Bonner
authors.forename: N
authors.initials: N
authors.lastname: Murphy
authors.forename: S
authors.initials: S
authors.lastname: Matsushima
authors.forename: W
authors.initials: W
authors.lastname: Taki
authors.forename: J H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: R P
authors.initials: RP
authors.lastname: Simon
authors.forename: D C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D001925:Brain Damage, Chronic / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy*; D003292:Convulsants / Q000627:therapeutic use; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004827:Epilepsy / Q000150:complications / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use; D015870:Gene Expression / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D019194:Ischemic Preconditioning / Q000379:methods; D007608:Kainic Acid / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D013226:Status Epilepticus / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D016896:Treatment Outcome; D015854:Up-Regulation / Q000235:genetics
chemical_list: D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D007608:Kainic Acid