Biomedical subjects

Frances J Northington

Publications and source records attributed to Frances J Northington.

6 recordsLinked to original sources

PubMed2006

Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70.

BACKGROUND AND PURPOSE: Caspase-8 and caspase-9 are essential proteases of the extrinsic and intrinsic apoptotic pathways, respectively. We investigated whether neuroprotection associated with overexpression of heat-shock protein 70 (Hsp70), a natural cellular antiapoptotic protein, is mediated by caspase-8 and caspase-9 signaling in the neonatal mouse brain after hypoxia/ischemia (H/I) injury. METHODS: Postnatal day 7 transgenic mice overexpressing rat Hsp70 (Hsp70 Tg) and their wild-type (Wt) littermates underwent unilateral common carotid artery ligation followed by 30 minutes of exposure to 8% O2. The expression of apoptotic proteins was quantified by Western blot analysis, and the specific interaction between Hsp70 and apoptotic protease activating factor 1 (Apaf-1) was determined by coimmunoprecipitation. RESULTS: Hsp70 overexpression reduced cytosolic translocation of cytochrome c without affecting the levels of Apaf-1 and pro-caspase-9 24 hours after H/I. The expression of these apoptotic proteins in the naïve neonatal brains was also not affected by Hsp70 overexpression. Reduced caspase-9 cleavage occurred in Hsp70 Tg mice compared with Wt littermates 24 hours after H/I and correlated with increased binding of Hsp70 and Apaf-1. Increased cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP) expression and decreased caspase-8 cleavage were also observed in Hsp70 Tg compared with Wt mice 24 hours after H/I. CONCLUSIONS: Our results suggest that the extrinsic and intrinsic apoptotic pathways mediate the neuroprotective effects of Hsp70 overexpression in neonatal H/I, specifically by upregulating FLIP and sequestering Apaf-1, leading to reduced cleavage of caspase-8 and caspase-9.

Animals↗

PubMed2006

Brief update on animal models of hypoxic-ischemic encephalopathy and neonatal stroke.

The discovery of safe and effective therapies for perinatal hypoxia ischemia (HI) and stroke remains an unmet goal of neonatal-perinatal medicine. Because of the many developmental and functional differences between the neonatal brain and the adult brain, the ability to extrapolate adult data to the neonatal condition is very limited. For this reason, it is incumbent on scientists in the field of neonatal brain injury to address the questions of therapeutic efficacy of an array of potential therapies in a developmentally appropriate model. Toward that end, a number of new models of neonatal HI and stroke have been introduced recently. Additionally, some of the established models have been adapted to different species and different ages, giving scientists a greater choice of models for the study of neonatal HI and stroke. Many of these models are now also being used for functional and behavioral testing, an absolute necessity for preclinical therapeutic trials. This review focuses primarily on the newly developed models, recent adaptations to established models, and the studies of functional outcome that have been published since 2000.

Animals↗

PubMed2005

Apoptosis in perinatal hypoxic-ischemic brain injury: how important is it and should it be inhibited?

The discovery of safe and effective therapies for perinatal hypoxia-ischemia (HI) and stroke remains an unmet goal of perinatal medicine. Hypothermia and antioxidants such as allopurinol are currently under investigation as treatments for neonatal HI. Drugs targeting apoptotic mechanisms are currently being studied in adult diseases such as cancer, stroke, and trauma and have been proposed as potential therapies for perinatal HI and stroke. Before developing antiapoptosis therapies for perinatal brain injury, we must determine whether this form of cell death plays an important role in these injuries and if the inhibition of these pathways promotes more benefit than harm. This review summarizes current evidence for apoptotic mechanisms in perinatal brain injury and addresses issues pertinent to the development of antiapoptosis therapies for perinatal HI and stroke.

Animals↗

PubMed2004

Neonatal mice lacking functional Fas death receptors are resistant to hypoxic-ischemic brain injury.

Neonatal hypoxia-ischemia (HI) upregulates Fas death receptor expression in the brain, and alterations in expression and activity of Fas signaling intermediates occur in neonatal brain injury. B6.MRL-Tnfrsf6(lpr) mice lacking functional Fas death receptors are protected from HI brain damage in cortex, striatum, and thalamus compared to wild-type mice. Expression of Fas death receptor and active caspases increase in the cortex after HI. In wild-type mice, the hippocampus is most severely injured, and the hippocampus is the only region not protected in the B6.MRL-Tnfrsf6(lpr) mice. The selective vulnerability of the hippocampus to injury correlates with (1) lower basal expression of [Fas-associated death-domain-like IL-1beta-converting enzyme]-inhibitory protein (FLIP), (2) increased degradation of spectrin to its 145 or 150 kDa breakdown product, and (3) a higher percentage of non-apoptotic cell death following neonatal HI. We conclude that Fas signaling via both extrinsic and intrinsic caspase cascades causes brain injury following neonatal HI in a region-dependent manner. Basal levels of endogenous decoy proteins may modulate the response to Fas death receptor signaling and provide a novel approach to understanding mechanisms of neonatal brain injury.

Animals↗

PubMed2004

Increased morbidity in severe early intrauterine growth restriction.

OBJECTIVE: To determine the relative frequencies of complications in severe early intrauterine growth-restricted (IUGR) infants. METHODS: All infants 32 weeks gestation or less with birth weight less than the fifth percentile admitted from January 1991 to December 1998 were identified retrospectively. Two infants were identified for each IUGR case: the subsequent admission with birth weight +/-100 g of the case, and the subsequent admission with the same gestational age. Infants with multiple congenital anomalies, congenital infections or admission after 48 hours of age were excluded. Maternal and neonatal demographic data, neonatal morbidity and mortality until discharge were gathered by chart review. RESULTS: A total of 39 IUGR identified infants met criteria, with 41 gestational age infants and 33 birth weight infants. Mean birth weights and gestational ages for the IUGR group, gestational age group, and birth weight group were 744 g and 29.6 weeks, 1370 g and 29.7 weeks, and 781 g and 25.5 weeks respectively. Mortality was higher for IUGR infants than gestational age infants (20.5 vs 0%), but less than the birth weight infants (30%). In surviving infants, total ventilator days, total oxygen days, days to full feeds, and patent ductus arteriosis, were higher for IUGR infants than gestational age infants, but less than birth weight infants. Hypoglycemia, direct hyperbilirubinemia, necrotizing enterocolitis (NEC), thrombo-cytopenia, chronic lung disease and feeding difficulties occurred more frequently in IUGR infants than in both other groups. Length of stay for survivors and incidence of retinopathy of prematurity (ROP) was similar for the IUGR and birth weight infants. CONCLUSIONS: Infants born prematurely who are also severely IUGR have higher neonatal morbidity and mortality when compared to infants of similar gestational age. The surviving IUGR infants had less intraventricular hemorrhage and periventricular leukomalacia than less mature infants of comparable birth weight, but a similar incidence of ROP and length of stay. They had a higher incidence of NEC, direct hyperbilirubinemia and chronic lung disease, probably due to end-organ damage in utero from chronic placental insufficiency. These findings highlight the unique pattern of mortality and morbidity seen in infants with severe early IUGR.

Birth Weight↗

PubMed2004

Cannabinoid receptor expression in peripheral arterial chemoreceptors during postnatal development.

Prenatal exposure to tobacco smoke increases risk of sudden infant death syndrome (SIDS). Marijuana is frequently smoked in conjunction with tobacco, and perinatal exposure to marijuana is associated with increased incidence of SIDS. Abnormalities in peripheral arterial chemoreceptor responses during sleep may be operative in infants at risk for SIDS, and nicotine exposure adversely affects peripheral arterial chemoreceptor responses. To determine whether marijuana could potentially affect the activity of peripheral arterial chemoreceptors during early postnatal development, we used in situ hybridization histochemistry to characterize the pattern and level of mRNA expression for cannabinoid type 1 receptor (CB1R) in the carotid body, superior cervical ganglia (SCG), and nodose-petrosal-jugular ganglia (NG-PG-JG) complex in newborn rats. We used immunohistochemistry and light, confocal, and electron microscopy to characterize the pattern of CB1R and tyrosine hydroxylase protein expression. CB1R mRNA expression was intense in the NG-PG-JG complex, low to moderate in the SCG, and sparse in the carotid body. With maturation, CB1R gene expression significantly increased (P < 0.01) in the NG-PG-JG complex. CB1R immunoreactivity was localized to nuclei of ganglion cells in the SCG and NG-PG-JG complex, whereas tyrosine hydroxylase immunoreactivity was localized to the cytoplasm. Exposure to marijuana during early development could potentially modify cardiorespiratory responses via peripheral arterial chemoreceptors. The novel finding of nuclear localization of CB1Rs in peripheral ganglion cells suggests that these receptors may have an, as yet, undetermined role in nuclear signaling in sensory and autonomic neurons.

Animals↗