Reduced nitric oxide is involved in prenatal ischemia-induced tolerance toneonatal hypoxic-ischemic brain injury in rats

To explore the role of nitric oxide (NO) in the hypoxic-ischemic (HI) toler ance phenomenon, NO production and brain injury following neonatal hypoxia- ischemia (induced by unilateral common carotid artery ligation followed by hypoxic exposure) were assessed in rat pups with or without HI precondition ing. A previously demonstrated prenatal HI rat model of preconditioning was used in this study. On G17, rat fetuses were subjected to either HI in ute ro (PreHI) for 30 min or a sham operation (SH). The PreHI treatment provide d significant protection against neonatal HI-induced brain injury, as indic ated by decreased ipsilateral brain weight reduction, less severe tissue da mage, and decreased activation of caspase-3. Concomitant with the protectiv e effect of prenatal HI preconditioning, elevation of nitrite/nitrate conte nt in the ipsilateral cortex of the brain, as an indirect measure of NO pro duction, was significantly lower in the PreHI group than in the SH group fo llowing neonatal HI. The protective effect of prenatal HI preconditioning c ould be reversed by sodium nitroprusside (SNP), a spontaneous NO donor, whi le SNP had no effect on neonatal HI-induced brain injury in the SH group. I ntraperitoneal administration of SNP to pups from the PreHI group (2 mg/kg, 24 and 1.5 h before neonatal HI) increased neonatal HI-induced brain injur y similar to that observed in the SH group. On the other hand, L-NG-nitroar ginine (2 mg/kg, i.p., 1.5 h before the hypoxic exposure), an NO synthase i nhibitor, significantly attenuated neonatal HI-induced brain injury in the SH group. The overall results indicate that reduced NO production in the pr econditioned rat brain contributes to prenatal HI-induced tolerance to neon atal HI brain injury. (C) 2000 Elsevier Science Ireland Ltd. All rights res erved.