title: Therapeutic effect of caspase inhibitors in the prevention of apoptosis and reversal of chronic cerebral vasospasm.
abstract: One of the important histological changes in cerebral vasospasm after subarachnoid hemorrhage (SAH) is endothelial cell damage, which involves apoptosis. The current study was undertaken to determine whether anti-apoptosis therapy prevents apoptosis and reverses vasospasm in a dog SAH model. Twenty-three mongrel dogs of either sex, weighing 17-25 kg, were subjected to autologous arterial blood injection into the cisterna magna on day 0 and day 2, and sacrificed on day 7. Angiography was performed on day 0 before blood injection and on day 7 before sacrifice. Caspase-2 (Z-VDVAD-FMK, 10 microM) inhibitor, caspase-3 (Z-DEVD-FMK, 10 microM) inhibitor, or vehicle (DMSO) were injected intrathecally from day 2 to day 6. The effects of caspase inhibitors on apoptosis and vasospasm were evaluated by angiography and transmission electron microscopy. The residual diameter of the basilar artery on day 7 in SAH dogs without treatment was 53.4+/-5.5% of the day 0 diameter. Marked damage to the endothelial cells, including apoptotic like changes, was observed in these arteries. Both caspase inhibitors prevented apoptosis in the endothelial cells. Only caspase-3 inhibitor, however, had a near-significant effect on reducing 13.3% of angiographic vasospasm. Higher doses and early treatment, as well as other more potent apoptosis inhibitors, are recommended for future studies.
authors.affiliation: Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Aoki
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Zubkov
authors.forename: Ian B
authors.initials: IB
authors.lastname: Ross
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002533:Cerebral Angiography; D002908:Chronic Disease; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D005260:Female; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C427308:benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone