Lubeluzole Pretreatment Does Not Provide Neuroprotection Against Transient Global Cerebral Ischemia in Fetal Sheep Near Term

The aim of the present study was to test the neuroprotective effect of the novel benzothiazol compound lubeluzole on neuronal cell damage in fetal sheep arising from global cerebral ischemia. Thirteen fetal sheep were prepared at a mean gestational age of 127 ± 1 d (term is at 147 d). Six fetuses were treated with lubeluzole (0.33 mg/kg estimated body weight) before induction of global cerebral ischemia (−90, −60, and −30 min), while the remainder (n = 7) received solvent. Cerebral ischemia was induced by occluding both carotid arteries for 30 min. Cerebral blood flow was measured by injecting radio-labeled microspheres before (−90 min), during (+3 min and +27 min), and after (+40 min, +3 h, and +72 h) cerebral ischemia. Neuronal cell damage was assessed in the cerebrum and deeper brain structures by light microscopy. Values are given as means ± SD. In control fetuses, blood flow to the cerebrum was reduced from 100 ± 25 mL·100 g−1 min−1 to less than 20 mL·100 g−1 min−1 during ischemia. Shortly after ischemia, hyperperfusion occurred (217 ± 66 mL·100 g−1min−1) followed by a tendency toward hypoperfusion (72 ± 17 mL·100 g−1 min−1) later on (+3 h). Significant differences in blood flow to the various brain structures between the control and study groups could not be observed. Neuronal cell damage was concentrated in the parasagittal regions of the cerebrum. Preischemic application of lubeluzole did not have any effect on the extent of neuronal cell damage. From these results, we conclude that pretreatment with lubeluzole fails to protect the brain of fetal sheep near term from injury after transient global cerebral ischemia. However, because the observation period lasted only 3 d, a possible effect of lubeluzole on pathophysiological mechanisms inducing delayed neuronal cell death cannot be fully excluded.