Partial neuroprotection by nNOS inhibition during profound asphyxia in preterm fetal sheep

- The first large animal study of selective nNOS inhibition during asphyxia
- nNOS inhibition delayed the onset of post-asphyxial seizures.
- nNOS inhibition attenuated secondary mitochondrial deterioration.
- nNOS inhibition improved striatal neuronal survival after 7 days recovery.
- nNOS inhibition increased mature oligodendroglia in white matter tracts.

Preterm brain injury is partly associated with hypoxia-ischemia starting before birth. Excessive nitric oxide production during HI may cause nitrosative stress, leading to cell membrane and mitochondrial damage. We therefore tested the hypothesis that therapy with a new, selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10 (0.022 mg/kg bolus, n = 8), given 30 min before 25 min of complete umbilical cord occlusion was protective in preterm fetal sheep at 101-104 day gestation (term is 147 days), compared to saline (n = 8). JI-10 had no effect on fetal blood pressure, heart rate, carotid and femoral blood flow, total EEG power, nuchal activity, temperature or intracerebral oxygenation on near-infrared spectroscopy during or after occlusion. JI-10 was associated with later onset of post-asphyxial seizures compared with saline (p < 0.05), and attenuation of the subsequent progressive loss of cytochrome oxidase (p < 0.05). After 7 days recovery, JI-10 was associated with improved neuronal survival in the caudate nucleus (p < 0.05), but not the putamen or hippocampus, and more CNPase positive oligodendrocytes in the periventricular white matter (p < 0.05). In conclusion, prophylactic nNOS inhibition before profound asphyxia was associated with delayed onset of seizures, slower decline of cytochrome oxidase and partial white and gray matter protection, consistent with protection of mitochondrial function.