Preliminary study of the effects of caspase inhibitors on vasospasm in dog penetrating arteries.
This preliminary study was undertaken to explore the possible protective effect of caspase inhibitors Z-VDVAD-FMK and Z-DEVD-FMK in apoptosis and vasospasm in penetrating arteries during cerebral vasospasm. Experimental subarachnoid hemorrhage (SAH) was induced in 16 dogs by an intracisternal injection of autologous arterial blood (0.4 ml/kg) on Day 0 and Day 2. The dogs were then randomly divided into four groups: control-SAH, vehicle-control, and two treatment groups. In the treatment groups, caspase inhibitors (10 microM) were intracisternally injected each day beginning on Day 2 until Day 6. Effects of the inhibitors were analyzed utilizing angiography, the clinical status of the dogs (activity, appetite, and neurological deficits), and transmission electron microscopy of the penetrating arteries. All the dogs were sacrificed on Day 7. In control-SAH and vehicle-control groups, severe angiographic vasospasm, poor clinical status, and penetrating vasospasm were registered in all the dogs. In the treatment groups, all the dogs developed angiographic vasospasm and vasospasm in penetrating arteries, however, with benign clinical statues. The occurrence of apoptosis in endothelial cells was reduced by caspase-2 but not by caspase-3 inhibitor. Caspase inhibitors failed to prevent vasospasm either in major or in penetrating arteries. The improvement of clinical scores by the caspase inhibitors may be related to their protection of the endothelial cells. Further investigations using more rigorous clinical scoring system and quantitative information on the degree of apoptosis in the vessels, as well as in the brain parenchyma are recommended.
Departments of Neurology, University of Mississippi Medical Center, Jackson, MI 39216, USA.
Alexander Y
AY
Zubkov
Kazuya
K
Aoki
Andrew D
AD
Parent
John H
JH
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D061945:Caspase Inhibitors; D002533:Cerebral Angiography; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D020301:Vasospasm, Intracranial
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