Role of mitochondrial permeability transition in fetal brain damage in rats.

Recirculation after transient in utero ischemia has previously been found to be accompanied by delayed deterioration of cellular bioenergetic state and of mitochondrial function in the fetal rat brain. Our objective was to assess whether the delayed deterioration is a result of the activation of mitochondrial permeability transition which is observed ultrastructurally as mitochondrial swelling. The respiratory activities and ultrastructure of isolated mitochondria and the cellular bioenergetic state in fetal rat brain were examined at the end of 30 minutes of in utero ischemia and after 1, 2, 3 and 4 hours of recirculation. Cyclosporin A, a potent and virtually specific mitochondrial permeability transition blocker, or vehicle was administered 1 hour after recirculation. In the vehicle-treated animals, the transient ischemia was associated with a delayed deterioration of cellular bioenergetic state and mitochondrial activities at 4 hours of recirculation. The number of swollen mitochondria increased markedly after 4 hours of recirculation. The deterioration and the swelling were prevented by cyclosporin A. The present study indicates that cyclosporin A treatment improves recovery of fetal brain energy metabolism and inhibits the mitochondrial swelling after transient in utero ischemia. The results suggest that mitochondria and mitochondrial permeability transition may be involved in the development of ischemic brain damage in the immature rat.

Vitamins ameliorate secondary mitochondrial failure in neonatal rat brain.

Recirculation after transient intrauterine ischemia has previously been found to be accompanied by secondary mitochondrial dysfunction in the immature rat brain. This study was performed to assess the efficacy of combined treatment with ascorbic acid and alpha-tocopherol in improving secondary brain damage. On the 17th day of gestation, transient intrauterine ischemia was induced by 30 minutes of uterine artery occlusion. Either vehicle, ascorbic acid, alpha-tocopherol, or combination of ascorbic acid and alpha-tocopherol was randomly administered to pregnant rats before and after occlusion. The pups were delivered by cesarean section at 21 days of gestation, and cerebral neocortical tissue was sampled. The mitochondrial respiration was measured polarographically in homogenates. In the ischemia uterine horn, mitochondrial activity of the vehicle treatment decreased significantly to 56% of nonischemic controls. Treatment with ascorbic acid or alpha-tocopherol alone demonstrated a moderate improvement of the secondary mitochondrial dysfunction to 64% and 62% of nonischemic controls, respectively. The combined treatment caused a normalization of mitochondrial activity to 91% of nonischemic controls. These results indicate that combined treatment with ascorbic acid and alpha-tocopherol has a more protective effect against secondary mitochondrial dysfunction after transient intrauterine ischemia compared with the administration of ascorbic acid or alpha-tocopherol alone.

Short therapeutic window for nifedipine in transient intrauterine ischemia in fetal rat brain.

The aim of this study was to explore whether nifedipine influences the secondary deterioration of cerebral mitochondrial function after transient intrauterine ischemia in fetal rats. Intrauterine ischemia was induced by a 30-min occlusion of the right uterine artery at 20 days of gestation in Wistar rats. Nifedipine (1 mg kg(-1)) or vehicle was injected subcutaneously before the onset of ischemia or 1 h after the start of recirculation. Fetuses were delivered by cesarean section at the end of ischemia (n=6 with vehicle; n=6 with nifedipine pretreatment) or at 4 h of recirculation (n=6 with vehicle; n=6 with nifedipine pretreatment; n=6 with nifedipine posttreatment), and the cerebral mitochondrial respiration was measured polarographically. Tissue oxygen tension was evaluated in placental and fetal cerebral tissues (n=5 with vehicle; n=5 with nifedipine pretreatment). The vehicle treated animals showed a significant decrease in mitochondrial activities at the end of ischemia and 4 h of recirculation. Nifedipine attenuates the secondary deterioration at 4 h of recirculation when given just prior to ischemia, but had no neuroprotective activity when given 1 h after the start of recirculation. Nifedipine pretreatment had no influence on oxygen delivery in placenta and fetal cerebrum during and after ischemia. Despite the short therapeutic window, the treatment of nifedipine attenuates the secondary deterioration of cerebral mitochondrial function after transient intrauterine ischemia in fetal rats when given just prior to ischemia.

Effect of dexamethasone on mitochondrial maturation in the fetal rat brain.

OBJECTIVE: The objective of the present study was to explore whether prenatal dexamethasone treatment influences mitochondrial maturation in the fetal rat brain. STUDY DESIGN: Mitochondrial respiration was measured polarographically with homogenates of fetal cerebral cortical tissues on day 16 (with saline solution, n = 8; with dexamethasone, n = 8), day 18 (with saline solution, n = 8; with dexamethasone, n = 8), and day 20 (with saline solution, n = 8; with dexamethasone,n = 8) of gestation. Four doses of dexamethasone (0.1 mg small middle dot kg) or vehicle (saline solution) were given, with an interval of 12 hours, until 12 hours before each measurement. RESULTS: In the vehicle-treated animals, mitochondrial respiratory activity was increased significantly after day 18 of gestation. Dexamethasone-treated animals showed a significant increase in mitochondrial activity at day 16 of gestation compared with vehicle-treated animals. CONCLUSION: The results indicate that prenatal dexamethasone treatment contributes to the precocious maturation of mitochondrial activity in the fetal rat brain. Because acceleration in cerebral mitochondrial activities is required immediately after birth to maintain high-energy phosphate levels, the precocious maturation may be crucial for the successful outcome of the preterm infant.