Premature babies are at high risk for both infantile apnea and long-term neurobehavioral deficits. Recent studies suggest that diffuse structural changes in brain white matter are a positive predictor of poor cognitive outcomes. Since oligodendrocyte maturation, myelination, axon development and synapse formation mainly occur in the 3rd trimester of gestation and 1st postnatal year, infantile apnea could lead to and/or exaggerate white matter impairments in preterm neonates. Therefore, we investigated oligodendroglia and axon development in a neonatal mouse model of intermittent hypoxia between postnatal days 2 to 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix and cerebellum, but not the pons or spinal cord. Intermittent hypoxia-elicited alterations in myelin-forming processes were reflected by decreased expression of myelin proteins, including MBP, PLP, MAG and CNPase, possibly due to arrested maturation of oligodendrocytes. Ultra-structural abnormalities were apparent in the myelin sheath and axon. Immature oligodendrocytes were more vulnerable to neonatal intermittent hypoxia exposures than developing axons, suggesting that hypomyelination may contribute, at least partially, to axonal deficits. Insufficient neurofilament synthesis with anomalous components of neurofilament subunits, β-tubulin and MAP2 isoforms indicated immaturity of axons in intermittent hypoxia-exposed mouse brains. In addition, down-regulation of Synapsin I, Synaptophysin and Gap-43 phosphorylation suggested a potential stunt in axonogenesis and synaptogenesis. The region-selective and complex impairment in brain white matter induced by intermittent hypoxia was further associated with electrophysiological changes that may underlie long-term neurobehavioral sequelae.

A neonatal mouse model of intermittent hypoxia (IH) simulating the recurring hypoxia/reoxygenation episodes of apnea of prematurity (AOP) was developed. C57BL/6 P2 pups were culled for exposure to either intermittent hypoxia or intermittent air as control. The IH paradigms consisted of alternation cycles of 20.9% O2 and either 8.0% or 5.7% O2 every 120 or 140 seconds for 6 hours a day during daylight hours from day 2 to day 10 postnatally, i.e., roughly equivalent to human brain development in the perinatal period. IH exposures elicited modest to severe decrease in oxygen saturation along with bradycardia in neonatal mice, which were severity-dependent. Hypomyelination in both central and peripheral nervous systems was observed despite the absence of visible growth retardation. The neonatal mouse model of IH in this study partially fulfills the current diagnostic criteria with features of AOP, and provides opportunities to reproduce in rodents some of the pathophysiological changes associated with this disorder, such as alterations in myelination.

The SO bridge of the complex, [Mo(2)(NTo)(2)(S(2)P(OEt)(2))(2)(mu-O(2)CMe)(mu-SBn)(mu-SO)], 1, displayed nucleophilicity at O, giving alkylation products [Mo(2)(NTo)(2)(S(2)P(OEt)(2))(2)(mu-O(2)CMe)(mu-SBn)(mu-SOR)](+), 4(+), which contained the thioperoxide bridge. These cations were then subject to nucleophilic attack by two pathways. Debenzylation of the bridge thiolate in 4(+) afforded neutral [Mo(2)(NTo)(2)(S(2)P(OEt)(2))(2)(mu-O(2)CMe)(mu-S)(mu-SOR)], 5; de-esterification of a dithiophosphate ligand in 4(+) gave [Mo(2)(NTo)(2)(S(2)P(O)(OEt))(S(2)P(OEt)(2))(mu-O(2)CMe)(mu-SBn)(mu-SO)], 6, which contained a monoester, dithiophosphate ligand. Complex 1 gave a slow and clean reaction in the crystalline state, further demonstrating its nucleophilicity by attacking a neighboring molecule in its lattice. X-ray crystallography confirmed the thioperoxide linkage and revealed structural similarities of the Mo(2)(mu-SOR) unit to sulfenate esters (RSOR) and related derivatives.