Neuroprotective effect of YM-39558 in focal cerebral ischemia in cats

We studied the effect of YM-39558, orotic acid ethylester, in a focal cerebral ischemia model in anesthetized cats. YM-39558 has good permeability across the blood brain barrier, and in the brain is hydrolyzed to orotic acid, the main active substance. Cats were subjected to permanent occlusion of the middle cerebral artery (MCA) for 6 h, then killed and examined histologically. Treatment with YM-39558 (intravenous infusion of 11.8 mg (10 mg as orotic acid)/6 ml per kg per h) starting 15 min after MCA occlusion markedly reduced the volume of ischemic damage (from 2450 +/- 82 mm3 of the cerebral hemisphere in the saline-treated cats to 1644 +/- 123 mm3 in the YM-39558-treated cats, P < 0.01). In contrast, YM-39558 (2.26 and 1.18 mg/0.8 ml per kg per h) showed no significant protective effect on ischemic damage. No significant differences were observed between saline- and YM-39558-treated cats concerning physiological variables including brain temperature. This evidence for the neuroprotective efficacy of YM-39558 in gyrencephalic species suggests its therapeutic potential in the treatment of stroke in humans.