Attenuation of experimental subarachnoid hemorrhage-induced increases in circulating intercellular adhesion molecule-1 and cerebral vasospasm by the endothelin-converting enzyme inhibitor CGS 26303.

Abstract

OBJECT:

Adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, are important mediators of inflammation, and their levels are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The investigators previously found that CGS 26303 is effective in preventing and reversing arterial narrowing in a rabbit model of SAH. The purpose of the present study was to examine whether levels of adhesion molecules are altered after treatment with CGS 26303 in this animal model.

METHODS:

New Zealand White rabbits were each injected with 3 ml of autologous blood in the cisterna magna, and intravenous treatment with CGS 26303 (30 mg/kg) was initiated 1 hour later. The compound was subsequently administered at 12, 24, and 36 hours post-SAH. Blood samples were collected at 48 hours post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. After the rabbits had been killed by perfusion-fixation, the basilar arteries (BAs) were removed and sliced, and their cross-sectional areas were measured. Treatment with CGS 26303 attenuated arterial narrowing after SAH. Morphologically, corrugation of the internal elastic lamina of BAs was prominently observed in the SAH only and vehicle-treated SAH groups, but not in the CGS 26303-treated SAH group or in healthy controls. There were no significant differences in the levels of VCAM-1 among the four groups. The levels of E-selectin were increased in all animals subjected to SAH (those in the SAH only, SAH plus vehicle, and SAH plus CGS 26303 groups) compared with healthy controls (no SAH); however, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and treatment with CGS 26303 reduced ICAM-1 to control levels following SAH.

CONCLUSIONS:

These results show that ICAM-1 may play a role in mediating SAH-induced vasospasm and that a reduction of ICAM-1 levels after SAH may partly contribute to the antispastic effect of CGS 26303.

• Authors: Chih-Lung Lin, Aij-Lie Kwan, Aaron S Dumont, Yu-Feng Su, Neal F Kassell, Chih-Jen Wang, Shu-Chuan Wu, Ching-Ling Kuo, Ching-Shan Huang, Arco Y Jeng, Chin-San Liu
• Journal: Journal of neurosurgery (J Neurosurg) Vol. 106 Issue 3 Pg. 442-8 (Mar 2007) ISSN: 0022-3085 [Print] United States
• PMID: 17367067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• E-Selectin
• Organophosphonates
• Tetrazoles
• Vascular Cell Adhesion Molecule-1
• Intercellular Adhesion Molecule-1
• CGS 26303
• Aspartic Acid Endopeptidases
• Metalloendopeptidases
• Endothelin-Converting Enzymes

Topics

• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors)
• Disease Models, Animal
• E-Selectin (blood)
• Endothelin-Converting Enzymes
• Intercellular Adhesion Molecule-1 (blood)
• Male
• Metalloendopeptidases (antagonists & inhibitors)
• Organophosphonates (therapeutic use)
• Rabbits
• Subarachnoid Hemorrhage (blood, complications)
• Tetrazoles (therapeutic use)
• Vascular Cell Adhesion Molecule-1 (blood)
• Vasospasm, Intracranial (blood, etiology, prevention & control)