LOW-DOSE FLUNARIZINE PROTECTS THE FETAL BRAIN FROM ISCHEMIC-INJURY INSHEEP

Flunarizine, a calcium channel blocker, reduced cerebral damage caused by hypoxic-ischemic insults in neonatal rats and in fetal sheep near term. However, the high dose regimen used in these studies produced ca rdiovascular side effects that might have counteracted the neuroprotec tive properties of flunarizine. Therefore, the neuroprotective effect was tested in a low dose protocol (1 mg/kg estimated body weight), Twe lve fetal sheep near term were instrumented chronically, Six fetuses w ere pretreated with 1 mg of flunarizine per kg of estimated body weigh t 1 h before ischemia, whereas the remainder (n = 6) received solvent. Cerebral ischemia was induced by occluding both carotid arteries for 30 min. To exclude the possibility that the neuroprotective effects of flunarizine were caused by cerebrovascular alterations we measured ce rebral blood flow by injecting radiolabeled microspheres before (-1 h) , during (3 min and 27 min) and after (40 min, 3 h, and 72 h) cerebral ischemia. At the end of the experiment (72 h) the ewe was given a let hal dose of sodium pentobarbitone and saturated potassium chloride i.v ., and the fetal brain was perfused with formalin. Neuronal cell damag e was assessed in various brain structures by light microscopy after c resyl violet/fuchsin staining using a scoring system: 1, 0-5% damage; 2, 5-50% damage; 3, 50-95% damage; 4, 95-99% damage; and 5, 100% damag e. In 10 other fetal sheep effects of low dose flunarizine on circulat ory centralization caused by acute asphyxia could be excluded. In the treated group neuronal cell damage was reduced significantly in many c erebral areas to varying degrees (range for control group, 1.03-2.14 v ersus range for treated group, 1.00-1.13; p < 0.05 to p < 0.001, respe ctively). There were only minor differences in blood flow to the vario us brain structures between groups. We conclude that pretreatment with low dose flunarizine protects the brain of fetal sheep near term from ischemic injury. This neuroprotective effect is not mediated by chang es in cerebral blood flow. We further conclude that low dose flunarizi ne may be clinically useful as a treatment providing fetal neuroprotec tion, particularly because the fetal cardiovascular side effects are m inimal.