Effects of GYKI 52466 on early vasospasm in rats

The pathogenesis and treatment of cerebral vasospasm (CV) after subarachnoid hemorrhage (SAH) remains a matter of discussion. The authors investigated the efficacy of GYKI 52466, a 2,3-benzodiazepine that is a selective and potent alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist, in a rat femoral artery vasospasm model.

Twenty-seven Wistar albino rats were used in this study. The animals were divided into 3 groups of 9 animals each: sham-operated control (group 1), vasospasm group (group 2), and vasospasm-plus-treatment group (group 3). In groups 2 and 3, autologous blood (0.1 mL) was applied to a 1-cm segment of the femoral artery, which was then wrapped with a silicone cuff. One minute after blood application, the rats in group 3 received an intraperitoneal injection of 15 mg/kg GYKI 52466 every 12 h for 24 h. Responses to blood application and treatment were evaluated with light and electron microscopy examinations of femoral artery specimens at 72 h.

On light microscope examination, the mean diameters of the arterial lumens in groups 1, 2, and 3 were 514.47+/-15.3, 317.63+/-12.1, and 503.91+/-9.6 microm, respectively. At 24 h, the mean arterial wall thickness in group 1 was 77.69+/-4.2 microm. This mean thickness in group 2 increased to 164.82+/-9.1 microm. After GYKI treatment in group 3, the mean arterial wall thickness measured 95.37+/-5.3 microm. In group 2 rats, electron microscopy demonstrated various changes including marked luminal narrowing and increased wall thickness in the femoral arterial wall. The most striking finding were the degenerative changes in the endothelium, which presented as a corrugated appearance of the internal elastic lamina. Rats in group 3 had endothelia that were slightly constricted and smooth muscle cells that were relaxed; changes in the vessel wall and internal elastic lamina were less prominent in these rats than in the rats of group 2.

The results of the present study suggest that GYKI 52466 inhibited AMPA receptors and induced relaxation of smooth muscle cells in the wall of the femoral artery in a rat model. This substance may be a protective and therapeutic agent in the treatment of cerebral vasospasm.