Caspase Inhibitors Prevent Endothelial Apoptosis and Cerebral Vasospasm in Dog Model of Experimental Subarachnoid Hemorrhage

Changman Zhou, Mitsuo Yamaguchi, Gen Kusaka, Claudio Schonholz, Anil Nanda, John H. Zhang

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

Apoptosis in the endothelium of major cerebral arteries may play a role in the initiation and maintenance of cerebral vasospasm after subarachnoid hemorrhage (SAH). We tested the therapeutic effect of caspase inhibitors on endothelial apoptosis and on cerebral vasospasm in an established dog double-hemorrhage model. Thirty-one mongrel dogs were divided into five groups: control; SAH; SAH treated with vehicle [DMSO]; SAH treated with Ac-DEVD-CHO [a specific caspase-3 inhibitor]; and SAH treated with Z-VAD-FMK [a broad caspase inhibitor]. The inhibitors (100 μM) were injected into the cisterna magna daily from Day 0 through Day 3. Angiography was performed on Day 0 and Day 7. Histology, TUNEL staining, and immunohistochemistry were conducted on basilar arteries collected on Day 7 after SAH. Positive staining of TUNEL, poly(ADP)-ribose polymerase (PARP), caspase-3, and caspase-8 was observed in the endothelial cells of the spastic arteries. Double fluorescence labeling demonstrated colocalization of TUNEL with caspase-3 and TNFα-receptor-1 (TNFR1). Ac-DEVD-CHO and Z-VAD-FMK prevented endothelial apoptosis and reduced angiographic vasospasm. The mechanism of apoptosis in endothelial cells involves TNFR1 and the caspase-8 and caspase-3 pathways. Caspase inhibitors may have potential in the treatment of cerebral vasospasm.

Original languageEnglish (US)
Pages (from-to)419-431
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume24
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Keywords

  • Apoptosis
  • Caspase inhibitor
  • Cerebral vasospasm
  • Subazachnoid hemorrhage

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