Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage.
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.
Iseda
Keiichi
K
Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. keiiseda@pop21.odn.ne.jp
Ono
Shigeki
S
Onoda
Keisuke
K
Satoh
Motoyoshi
M
Manabe
Hiroaki
H
Nishiguchi
Mitsuhisa
M
Takahashi
Kenji
K
Tokunaga
Koji
K
Sugiu
Kenji
K
Date
Isao
I
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*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020170:Caspase 1