Therapeutic effect of caspase inhibitors in the prevention of apoptosis and reversal of chronic cerebral vasospasm

• Published in: Journal of clinical neuroscience 2002-11, Vol.9 (6), p.672-677
• Main Authors: Aoki, Kazuya, Zubkov, Alexander Y., Ross, Ian B., Zhang, John H.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; apoptosis, caspase inhibitors, endothelium, vasospasm; Biological and medical sciences; Caspase Inhibitors; Cerebral Angiography; Chronic Disease; Cysteine Proteinase Inhibitors - pharmacology; Dogs; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Female; Male; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Vascular diseases and vascular malformations of the nervous system; Vasospasm, Intracranial - drug therapy; Vasospasm, Intracranial - metabolism; Vasospasm, Intracranial - pathology
• ISSN: 0967-5868; 1532-2653
• DOI: 10.1054/jocn.2002.1088

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 17–25kg, 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, 10μM) inhibitor, caspase-3 (Z-DEVD-FMK, 10μM) 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.