Chronic Fetal Hypoxia Produces Selective Brain Injury Associated With Altered Nitric Oxide Synthases

Abstract

OBJECTIVE-The impact of chronic hypoxia on the nitric oxide synthase isoenzymes (NOSs) in specific brain structures is unknown. STUDY DESIGN-Time-mated pregnant guinea pigs were exposed to 10.5% O 2 for 14d (HPX) or room air (NMX); L-NIL (an iNOS inhibitor, 1mg/kg/day) was administered to HPX animals for 14d (L-NIL+HPX). Fetal brains were harvested at term. Multi-labeled immunofluorescence was used to generate a brain injury map. Laser capture microdissection and quantitative PCR were applied and cell injury markers, apoptosis activation, neuron loss, total NO, and the levels of individual NOSs quantified. RESULTS-Chronic hypoxia causes selective fetal brain injury rather than globally. Injury is associated with differentially affected NO synthases in both neurons and glial cells, with iNOS up regulated at all injury sites. L-NIL attenuated the injury despite continued hypoxia. CONCLUSIONS-These studies demonstrate chronic hypoxia selectively injures the fetal brain in part by the differential regulation of NOSs in an anatomic and cell specific manner.

Chronic fetal hypoxia affects axonal maturation in guinea pigs during development: A longitudinal diffusion tensor imaging and T2 mapping study

“…These findings are consistent with the demonstration of significant neuronal loss and reactive gliosis in those areas of the guinea pig neonates in this study as well as in previous findings. 18 A limitation of this study is that analysis of other brain structures such as the striatum was not feasible due to the use of a surface coil to increase the sensitivity of MR measurement. A whole-brain acquisition strategy with a volume coil could help to assess the global effects of chronic fetal hypoxia.…”

“…Chronic fetal hypoxia was induced in guinea pigs during 13-21 days before birth (or 45-53 days of fetal life), which was at 46-49 days of gestation (about 0.7 gestation, term 65 days), according to an established hypoxic model. 18 A total of 14 newborn guinea pigs (7 HPX and 7 NMX; 2 males in each group) from four litters were used in the longitudinal MR study up to 6 weeks of age. Sixteen guinea pig fetuses (8 HPX and 8 NMX) were used to assess hypoxia-induced neuronal injury and neuronal loss.…”

“…Each stained section was examined by two histology technicians who were with over 10 years' experience using light microscopy and blind to the study, and neuron density in the fetal brain was quantified as previously reported. 18 Quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR)…”

“…In a previous study, a guinea pig model of 14 days of chronic fetal hypoxia, beginning at 46 to 49 days of gestation, resulted in selective brain injury in the cortex, hippocampus, and thalamic nuclei; shorter exposures or milder degrees of hypoxia introduced later in gestation were proven less reliable as fetal brain growth was not altered, although histological damage was observed. 16,18 Magnetic resonance imaging (MRI) relaxation times (especially T 1 and T 2 ), related to tissue structure and the biophysical environment of brain water, have been widely used to characterize microstructural changes of brain tissue in various physiological and pathological conditions including aging, Alzheimer's disease, Parkinson's disease, and stroke. Diffusion tensor imaging (DTI) provides distinctive endogenous contrast for brain tissue delineation as well as information about myelination and axonal integrity.…”

Nitric oxide synthase and changes in oxidative stress levels in embryonic kidney observed in a rabbit model of intrauterine growth restriction

“…5,6 Moreover, numerous studies also suggest a strong association between IUGR and adult diseases such as diabetes, 7,8 hypercholesterolemia, 9 and cardiovascular diseases and hypertension. 10,11 The Fetal Programming Theory is explained by changes observed in proliferation, differentiation, and gene expression in organs such as the brain, [12][13][14] heart, [15][16][17][18][19] liver, 16,20,21 and kidney 21,22 induced by the IUGR condition.…”