Frequent episodes of brief ischemia sensitize the fetal sheep brain to neuronal loss and induce striatal injury.

We examined the neuronal consequences of repeated brief episodes of in utero cerebral hypoxia-ischemia. Chronically instrumented fetal sheep were subjected to three 10-min episodes of reversible cerebral ischemia, repeated at either 1-h (n = 8) or 5-h (n = 5) intervals. Four fetuses were subjected to a single 10-min of ischemia and 17 fetuses to a single 30-min of ischemia. Repeated insults altered the distribution of damage with relatively marked striatal injury compared with isolated episodes of ischemia (p < 0.01). Frequent insults were associated with greater neuronal loss (p < 0.01) and a failure to restore electrocorticographic activity and resolve cortical cytotoxic edema between insults. Intermittent cortical hyperexcitability developed after repeated insults irrespective of the interval between insults. These findings emphasize that repeated brief episodes of ischemia alter the distribution of damage and sensitize the fetal brain to neuronal injury, particularly if the episodes are frequent. Striatal damage may be a feature of multiple but not single insults.