Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog model of experimental subarachnoid hemorrhage.
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 microM) 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 co-localization of TUNEL with caspase-3 and TNFalpha 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.
Zhou
Changman
C
Department of Neurosurgery, Louisiana State University Health Sciences Center-Shreveport, 71130-3932, USA.
Yamaguchi
Mitsuo
M
Kusaka
Gen
G
Schonholz
Claudio
C
Nanda
Anil
A
Zhang
John H
JH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001488:Basilar Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3; D053181:Caspase 8; D061945:Caspase Inhibitors; D002533:Cerebral Angiography; D004195:Disease Models, Animal; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014665:Vasodilator Agents / Q000627:therapeutic use*; D020301:Vasospasm, Intracranial / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D014665:Vasodilator Agents; D053148:Caspase 3; D053181:Caspase 8