Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage

Keiichi Iseda, Shigeki Ono, Keisuke Onoda, Motoyoshi Satoh, Hiroaki Manabe, Mitsuhisa Nishiguchi, Kenji Takahashi, Koji Tokunaga, Kenji Sugiu, Isao Date

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Object. 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: SAH 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)-1β in the cerebrospinal fluid (CSF) was examined using Western blotting, and brains were immunohistochemically examined for caspase-1 and IL-1β. In a separate experiment, 20 rats were subjected to SAH and their brains were immunohistochemically assessed for caspase-1, IL-1β, 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-1β release into the CSF and also suppressed immunoreactivities of caspase-1 and IL-1β in macrophages infiltrating into the subarachnoid space. Immunoreactivities for caspase-1 and IL-1β 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.

Original languageEnglish
Pages (from-to)128-135
Number of pages8
JournalJournal of Neurosurgery
Volume107
Issue number1
DOIs
Publication statusPublished - Jul 2007

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Caspase Inhibitors
Subarachnoid Hemorrhage
Anti-Inflammatory Agents
Interleukin-1
Caspase 1
Basilar Artery
Intracranial Vasospasm
Subarachnoid Space
Macrophages
Cerebrospinal Fluid
Cisterna Magna
Rabbits
Brain
Caspases
Dimethyl Sulfoxide

Keywords

  • Caspase inhibitor
  • Cerebral vasospasm
  • Inflammation
  • Macrophage
  • Subarachnoid hemorrhage

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage. / Iseda, Keiichi; Ono, Shigeki; Onoda, Keisuke; Satoh, Motoyoshi; Manabe, Hiroaki; Nishiguchi, Mitsuhisa; Takahashi, Kenji; Tokunaga, Koji; Sugiu, Kenji; Date, Isao.

In: Journal of Neurosurgery, Vol. 107, No. 1, 07.2007, p. 128-135.

Research output: Contribution to journalArticle

Iseda, K, Ono, S, Onoda, K, Satoh, M, Manabe, H, Nishiguchi, M, Takahashi, K, Tokunaga, K, Sugiu, K & Date, I 2007, 'Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage', Journal of Neurosurgery, vol. 107, no. 1, pp. 128-135. https://doi.org/10.3171/JNS-07/07/0128
Iseda, Keiichi ; Ono, Shigeki ; Onoda, Keisuke ; Satoh, Motoyoshi ; Manabe, Hiroaki ; Nishiguchi, Mitsuhisa ; Takahashi, Kenji ; Tokunaga, Koji ; Sugiu, Kenji ; Date, Isao. / Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage. In: Journal of Neurosurgery. 2007 ; Vol. 107, No. 1. pp. 128-135.
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abstract = "Object. 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: SAH 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)-1β in the cerebrospinal fluid (CSF) was examined using Western blotting, and brains were immunohistochemically examined for caspase-1 and IL-1β. In a separate experiment, 20 rats were subjected to SAH and their brains were immunohistochemically assessed for caspase-1, IL-1β, 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-1β release into the CSF and also suppressed immunoreactivities of caspase-1 and IL-1β in macrophages infiltrating into the subarachnoid space. Immunoreactivities for caspase-1 and IL-1β 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.",
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author = "Keiichi Iseda and Shigeki Ono and Keisuke Onoda and Motoyoshi Satoh and Hiroaki Manabe and Mitsuhisa Nishiguchi and Kenji Takahashi and Koji Tokunaga and Kenji Sugiu and Isao Date",
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AU - Iseda, Keiichi

AU - Ono, Shigeki

AU - Onoda, Keisuke

AU - Satoh, Motoyoshi

AU - Manabe, Hiroaki

AU - Nishiguchi, Mitsuhisa

AU - Takahashi, Kenji

AU - Tokunaga, Koji

AU - Sugiu, Kenji

AU - Date, Isao

PY - 2007/7

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N2 - Object. 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: SAH 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)-1β in the cerebrospinal fluid (CSF) was examined using Western blotting, and brains were immunohistochemically examined for caspase-1 and IL-1β. In a separate experiment, 20 rats were subjected to SAH and their brains were immunohistochemically assessed for caspase-1, IL-1β, 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-1β release into the CSF and also suppressed immunoreactivities of caspase-1 and IL-1β in macrophages infiltrating into the subarachnoid space. Immunoreactivities for caspase-1 and IL-1β 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.

AB - Object. 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: SAH 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)-1β in the cerebrospinal fluid (CSF) was examined using Western blotting, and brains were immunohistochemically examined for caspase-1 and IL-1β. In a separate experiment, 20 rats were subjected to SAH and their brains were immunohistochemically assessed for caspase-1, IL-1β, 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-1β release into the CSF and also suppressed immunoreactivities of caspase-1 and IL-1β in macrophages infiltrating into the subarachnoid space. Immunoreactivities for caspase-1 and IL-1β 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.

KW - Caspase inhibitor

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KW - Inflammation

KW - Macrophage

KW - Subarachnoid hemorrhage

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