title: Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade.
abstract: Necrotic and apoptotic cell death both play a role mediating tissue injury following brain trauma. Caspase-1 (interleukin-1beta converting enzyme) is activated and oligonucleosomal DNA fragmentation is detected in traumatized brain tissue. Reduction of tissue injury and free radical production following brain trauma was achieved in a transgenic mouse expressing a dominant negative inhibitor of caspase-1 in the brain. Neuroprotection was also conferred by pharmacological inhibition of caspase-1 by intracerebroventricular administration of the selective inhibitor of caspase-1, acetyl-Tyr-Val-Ala-Asp-chloromethyl-ketone or the non-selective caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. These results indicate that inhibition of caspase-1-like caspases reduces trauma-mediated brain tissue injury. In addition, we demonstrate an in vivo functional interaction between interleukin-1beta converting enyzme-like caspases and free radical production pathways, implicating free radical production as a downstream mediator of the caspase cell death cascade.
authors.affiliation: Stroke and Neurovascular Regulation, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Fink
authors.forename: L J
authors.initials: LJ
authors.lastname: Andrews
authors.forename: W E
authors.initials: WE
authors.lastname: Butler
authors.forename: V O
authors.initials: VO
authors.lastname: Ona
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Bogdanov
authors.forename: M
authors.initials: M
authors.lastname: Endres
authors.forename: S Q
authors.initials: SQ
authors.lastname: Khan
authors.forename: S
authors.initials: S
authors.lastname: Namura
authors.forename: P E
authors.initials: PE
authors.lastname: Stieg
authors.forename: M F
authors.initials: MF
authors.lastname: Beal
authors.forename: M A
authors.initials: MA
authors.lastname: Moskowitz
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.forename: R M
authors.initials: RM
authors.lastname: Friedlander
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000235:genetics / Q000473:pathology*; D020170:Caspase 1 / Q000502:physiology; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation; D017665:Hydroxyl Radical / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D017665:Hydroxyl Radical; D020170:Caspase 1