title: Neuronal deletion of caspase 8 protects against brain injury in mouse models of controlled cortical impact and kainic acid-induced excitotoxicity.
abstract: BACKGROUND
  Acute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8(-/-)), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system.
  
  
  RESULTS
  Caspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNFα (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8(-/-) mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging.
  
  
  CONCLUSIONS
  Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Zerong
authors.initials: Z
authors.lastname: You
authors.forename: Juan
authors.initials: J
authors.lastname: Rong
authors.forename: Christina
authors.initials: C
authors.lastname: Kress
authors.forename: Xianshu
authors.initials: X
authors.lastname: Huang
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Yang
authors.forename: Tiffany
authors.initials: T
authors.lastname: Kyoda
authors.forename: Ricardo
authors.initials: R
authors.lastname: Leyva
authors.forename: Steven
authors.initials: S
authors.lastname: Banares
authors.forename: Yue
authors.initials: Y
authors.lastname: Hu
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Sze
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Whalen
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004622:Embryo, Mammalian; D017353:Gene Deletion; D005911:Gliosis / Q000150:complications; D007249:Inflammation / Q000150:complications; D007608:Kainic Acid / Q000633:toxicity*; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000150:complications; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D009498:Neurotoxins; D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8; D007608:Kainic Acid