title: Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage.
abstract: OBJECTIVE
  Inflammation in the subarachnoid space and apoptosis of arterial endothelial cells have been implicated in the development of delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). The authors investigated mechanisms of possible antivasospastic effects of N-benzyl-oxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), a caspase inhibitor that can inhibit both inflammatory and apoptotic systems, in animal models of SAH.
  
  
  METHODS
  Rabbits were assigned to three groups of eight animals each and were subjected to SAH by injection of blood into the cisterna magna. The experiments were performed in the following groups: SA only, SAH + vehicle, and SAH + Z-VAD-FMK. The Z-VAD-FMK (1 mg) or vehicle (5% dimethyl sulfoxide) was intrathecally administered before SAH induction. Diameters of the basilar artery (BA) were measured on angiograms obtained before and 2 days after SAH. The BA diameter on Day 2 was expressed as a percentage of that before SAH. Interleukin (IL)-1 in the cerebrospinal fluid (CSF) was examined using Western blotting, and brains were immunohistochemically examined for caspase-1 and IL-1beta. In a separate experiment, 20 rats were subjected to SAH and their brains were immunohistochemically assessed for caspase-1, IL-1beta, and macrophages. RESULTS. In rabbits, Z-VAD-FMK significantly attenuated cerebral vasospasm (the BA diameter on Day 2 in SAH-only, SAH + vehicle, and SAH + Z-VAD-FMK groups was 66.6 +/- 3.2%, 66.3 +/- 3.7%, and 82.6 +/- 4.9% of baseline, respectively), and suppressed IL-1beta release into the CSF and also suppressed immunoreactivities of caspase-1 and IL-1P in macrophages infiltrating into the subarachnoid space. Immunoreactivities for caspase-1 and IL-1P were observed in immunohistochemically proven infiltrating macrophages in rats.
  
  
  CONCLUSIONS
  These results indicate that caspase activation may be involved in the development of SAH-induced vasospasm through inflammatory reaction.
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. keiiseda@pop21.odn.ne.jp
authors.forename: Keiichi
authors.initials: K
authors.lastname: Iseda
authors.forename: Shigeki
authors.initials: S
authors.lastname: Ono
authors.forename: Keisuke
authors.initials: K
authors.lastname: Onoda
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Satoh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Manabe
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Nishiguchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Koji
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugiu
authors.forename: Isao
authors.initials: I
authors.lastname: Date
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D000818:Animals; D001488:Basilar Artery / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology; D020170:Caspase 1 / Q000276:immunology*; D061945:Caspase Inhibitors; D002533:Cerebral Angiography; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D053583:Interleukin-1beta / Q000276:immunology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020170:Caspase 1