Intrauterine infection and inflammation have been linked to preterm birth and brain damage. We hypothesized that recombinant human erythropoietin (rhEPO) would ameliorate brain damage in anovine model of fetal inflammation. At 107 +/- 1 day of gestational age (DGA), chronically catheterized fetal sheep received on 3 consecutive days 1) an intravenous bolus dose of lipopolysaccharide ([LPS] approximately 0.9 microg/kg; n = 8); 2) an intravenous bolus dose of LPS, followed at 1 hour by 5,000 IU/kg of rhEPO (LPS + rhEPO, n = 8); or 3) rhEPO (n = 5). Untreated fetuses (n = 8) served as controls. Fetal physiological parameters were monitored, and fetal brains and optic nerves were histologically examined at 116 +/- 1 DGA. Exposure to LPS, but not to rhEPO alone or saline, resulted in fetal hypoxemia, hypotension (p < 0.05), brain damage, including white matter injury, and reductions in numbers of myelinating oligodendrocytes in the corticospinal tract and myelinated axons in the optic nerve (p < 0.05 for both). Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but reduced brain injury and was beneficial to myelination in the corticospinal tract and the optic nerve. This is the first study in a long-gestation species to demonstrate the neuroprotective potential of rhEPO in reducing fetal brain and optic nerve injury after LPS exposure.

Premature infants now have an improved chance of survival but the impact of respiratory therapies on the brain, particularly the cerebellum, remains unclear. We examined the effects of early nasal continuous positive airway pressure (EnCPAP) ventilation and delayed (Dn) CPAP on the development of the cerebellum in prematurely delivered baboons. The baboons were delivered at 125 ± 2 days of gestation and ventilated for 28 days with either EnCPAP commencing at 24 hours (n = 5) or DnCPAP commencing at 5 days (n = 5). Gestational controls (n = 4) were delivered at 153 days. Cerebella were assessed histologically and an ontogeny study (90 days to term) was performed to establish values for key cerebellar developmental indicators. Cerebellar weight was reduced in DnCPAP but not EnCPAP animals vs. controls; cerebellar/total brain weight ratio was increased in EnCPAP (p < 0.05) vs. control and DnCPAP animals. There was no overt damage in the cerebella of any animals, but a microstructural alteration index based on morphologic developmental parameters and microglial immunoreactivity was increased in both prematurely delivered cohorts vs. controls (p < 0.001) and was higher in DnCPAP than EnCPAP animals (p < 0.05). These results indicate that respiratory regimens can influence cerebellar development and that early compared to delayed extubation to nCPAP appears to be beneficial.

High-frequency oscillatory ventilation (HFOV) may improve pulmonary outcome in very preterm infants, but the effects on the brain are largely unknown. We hypothesized that early prolonged HFOV compared with low volume positive pressure ventilation (LV-PPV) would not increase the risk of delayed brain growth or injury in a primate model of neonatal chronic lung disease. Baboons were delivered at 127 Ϯ 1 d gestation (dg; term ϳ185 dg), ventilated for 22-29 d with either LV-PPV (n ϭ 6) or HFOV (n ϭ 5). Gestational controls were delivered at 153 dg (n ϭ 4). Brains were assessed using quantitative histology. Body, brain, and cerebellar weights were lower in both groups of prematurely delivered animals compared with controls; the brain to body weight ratio was higher in HFOV compared with LV-PPV, and the surface folding index was lower in the LV-PPV compared with controls. In both ventilated groups compared with controls, there was an increase in astrocytes and microglia and a decrease in oligodendrocytes (p Ͻ 0.05) in the forebrain and a decrease in cerebellar granule cell proliferation (p Ͻ 0.01); there was no difference between ventilated groups. LV-PPV and HFOV ventilation in prematurely delivered animals is associated with decreased brain growth and an increase in subtle neuropathologies; HFOV may minimize adverse effects on brain growth. (Pediatr Res 66: 545-550, 2009) A dvances in prenatal and neonatal care, including respiratory support, have significantly improved survival rates for prematurely delivered infants in recent years. These infants, however, still have a higher incidence of poor neurodevelopmental outcome than full-term infants with approximately 10% at risk of developing cerebral palsy and 10 -20% likely to have some form of developmental delay or sensory or motor impairment (1,2). Thus, it is critical to understand the effects of postnatal intervention on the developing brain and, in particular, to determine whether specific modes of respiratory support and other postnatal treatments influence the nature and severity of cerebral injury.High-frequency oscillatory ventilation (HFOV) is used in the neonatal setting as both primary and rescue therapy, because it is believed to cause less trauma to the immature lungs compared with other forms of mechanical ventilation. In models of neonatal lung injury, HFOV has been shown to improve pulmonary outcome (3,4). Recent meta-analyses in human studies have cast some doubt on whether there is a better prognosis for chronic lung disease (CLD) after HFOV compared with an optimized protocol of conventional mechanical ventilation (5,6). The effects on the brain are also controversial with some studies suggesting an increased risk of both intracranial hemorrhage and periventricular leucomalacia (7,8) and others reporting that there is no difference in neonatal associated morbidity, including hemorrhage (9). Long-term neurodevelopmental (10) and neuromotor (11) outcomes do not seem to be worse in infants ventilated with HFOV compared with conventional ve...

Intrauterine growth restriction (IUGR) can lead to adverse neurodevelopmental sequelae in postnatal life. However, the effects of IUGR on the cerebellum are still to be fully elucidated. A major determinant of growth and development of the cerebellum is proliferation and subsequent migration of cerebellar granule cells. Our objective was to determine whether IUGR, induced by chronic placental insufficiency (CPI) in guinea pigs, results in abnormal cerebellar development due to deficits suggestive of impaired granule cell proliferation and/or migration. CPI was induced by unilateral ligation of the uterine artery at mid-gestation, producing growth-restricted (GR) foetuses at 52 and 60 days of gestation (dg), and neonates at 1 week postnatal age (term approx. 67 dg). Controls were from sham-operated animals. In GR foetuses compared with controls at 52 dg, the external granular layer (EGL) width and internal granular layer (IGL) area were similar. In GR foetuses compared with controls at 60 dg: (a) the EGL width was greater (p < 0.005); (b) the IGL area was smaller (p < 0.005); (c) the density of Ki67-negative (postmitotic) granule cells in the EGL was greater (p < 0.01); (d) the somal area of Purkinje cells was reduced (p < 0.005), and (e) the linear density of Bergmann glia was similar. The EGL width in GR foetuses at 60 dg was comparable to that of 52 dg control and GR foetuses. The pattern of p27-immunoreactivity in the EGL was the inverse of Ki67-immunoreactivity at both foetal ages; there was no difference between control and GR foetuses at either age in the width of p27-immunoreactivity, or in the percentage of the EGL width that it occupied. In the molecular layer of GR neonates compared with controls there was an increase in the areal density of granule cells (p < 0.05) and in the percentage of migrating to total number of granule cells (p < 0.01) at 1 week but not at 60 dg (p > 0.05). Thus, we found no specific evidence that IUGR affects granule cell proliferation, but it alters the normal program of migration to the IGL and, in addition, the development of Purkinje cells. Such alterations will likely affect the development of appropriate circuitry and have implications for cerebellar function.