Biomedical subjects

Carina Mallard

Publications and source records attributed to Carina Mallard.

At least 19 recordsLinked to original sources

PubMed2006

Deletion of the c-Jun N-terminal kinase 3 gene protects neonatal mice against cerebral hypoxic-ischaemic injury.

c-Jun N-terminal kinase 3 (JNK3) is a member of the stress-activated group of mitogen-activated protein kinases. c-Jun N-terminal kinase 3 is a potent mediator of apoptosis and the use of JNK inhibitors or jnk3 gene deletion each protect against brain injury in adults. However, little is known about the role of JNK3 or its mechanism of action in neonatal brain injury. The aim of the present study was to compare the vulnerability of neonatal JNK3 knockout (JNK3 KO) mice and wild-type (WT) mice to cerebral hypoxic-ischaemic injury (HII) using unilateral-carotid occlusion combined with transient hypoxia. The degree of neural tissue loss in JNK3 KO mice was substantially reduced compared with WT mice (JNK3 KO 27.8%+/-2.8% versus WT 48.3%+/-2.0%, P<or=0.0001) after HII. Significant attenuation of injury was observed in the cerebral cortex, hippocampus, striatum, and thalamus of JNK3 KO compared with WT mice. Hypoxic-ischaemic injury increased JNK phosphorylation and activity, with JNK3 as the major isoform. Significantly, in JNK3 KO animals there was no difference in the activation of the upstream kinases mitogen-activated protein kinase kinase (MKK4) or MKK7. Downstream of JNK3, HII lead to increased phosphorylation of the transcription factors c-Jun and adenovirus transcription factor-2 (ATF-2), which was attenuated in JNK3 KO mice. c-Jun N-terminal kinase 3 deletion also decrease caspase-3 cleavage and Bim/PUMA expression, coupled with a upregulation of AKT/FOXO3a levels, linking JNK3 to apoptosis. These findings implicate JNK3 involvement in neural cell loss resulting from cerebral HII in the developing brain.

Activating Transcription Factor 2↗

PubMed2006

Vascular response to hypoxic preconditioning in the immature brain.

We hypothesized that hypoxic preconditioning (PC) modifies the microvasculature in the immature brain and thereby affects the cerebral blood flow (CBF) during a subsequent hypoxic-ischemic (HI) insult. On postnatal day 6 rats were exposed to hypoxia (36 degrees C, 8.0% O2) or normoxia for 3 h. Unilateral HI (unilateral carotid ligation and 8% hypoxia) was induced 24 h later. Cortical CBF was measured with the 14C-iodoantipyrine technique (at the end of HI) or with laser Doppler flowmetry (Perimed PF5001) before and during HI. At 0, 2, 8, and 24 h cerebral cortex was sampled and analyzed with gene arrays (Affymetrix 230 2.0). L-nitroarginine or vehicle was administrated before hypoxic PC or 30 mins before HI followed by CBF measurement (laser Doppler) during subsequent HI. Twenty-four hours after PC animals were perfusion-fixed and brains immunolabeled for von Willebrand factor and vascular density was determined by stereological quantification. The decrease in CBF during HI was attenuated significantly in PC versus control animals (P<0.01), as detected by both techniques. Several vascular genes (Angpt2, Adm, Apln, Vegf, Flt1, Kdr, Pdgfra, Agtrap, Adora2a, Ednra, serpine1, caveolin, Id1, Prrx1, Ero1l, Acvrl1, Egfl7, Nudt6, Angptl4, Anxa2, and NOS3) were upregulated and a few (Csrp2, Adora2b) were downregulated after PC. A significant increase in vascular density (P<0.05) was seen after PC. Nitric oxide synthase inhibition did not affect CBF during HI after PC. In conclusion, hypoxic PC upregulates vascular genes, increases vascular density and attenuates the decrease of CBF during a subsequent HI, which could contribute to tolerance.

Animals↗

PubMed2006

Lipopolysaccharide-induced inflammation and perinatal brain injury.

Both energy failure and infections are important risk factors for brain injury in term and preterm infants. In this review we focus on recent experimental studies that have examined the effects of lipopolysaccharide (LPS) exposure to the fetus or neonate and the interaction of LPS with other events. Intracerebral LPS injections induce a marked cerebral cytokine response and prominent white matter lesions. LPS administered intravenously to the fetus also induces gross lesions, which are mainly localised to the white matter and are accompanied by activation of inflammatory cells. Cerebral effects following fetal LPS exposure via more distant routes, such as intracervical, intrauterine or maternal LPS administration, are characterised by reductions in oligodendrocyte or myelin markers without macroscopic lesions being evident. Both antenatal and neonatal LPS exposures increase the sensitivity of the brain to subsequent hypoxic/ischaemic events, even in adulthood. These studies suggest that fetal inflammation is the strongest predictor of brain lesions.

Animals↗

PubMed2006

Effect of lipopolysaccharide on global gene expression in the immature rat brain.

To improve the understanding of the molecular mechanisms whereby lipopolysaccharide (LPS) affects the immature brain, global gene expression following LPS exposure was investigated in neonatal rats. Brains (n = 5/time point) were sampled 2, 6, and 72 h after LPS and compared with age-matched controls. The mRNA from each brain was analyzed separately on Affymextrix GeneChip Rat Expression Set 230. The number of genes regulated after LPS were 847 at 2 h, 1564 at 6 h, and 1546 genes at 72 h. Gene ontology analysis demonstrated that, at both 2 and 6 h after LPS, genes associated with protein metabolism, response to external stimuli and stress (immune and inflammatory response, chemotaxis) and cell death were overrepresented. At 72 h, the most strongly regulated genes belonged to secretion of neurotransmitters, transport, synaptic transmission, cell migration, and neurogenesis. Several pathways associated with cell death/survival were identified (caspase-tumor necrosis factor alpha [TNF-alpha]-, p53-, and Akt/phosphatidylinositol-3-kinase (PI3 K)-dependent mechanisms). Caspase-3 activity increased and phosphorylation of Akt decreased 8 h after peripheral LPS exposure. These results show a complex cerebral response to peripheral LPS exposure. In addition to the inflammatory response, a significant number of cell death-associated genes were identified, which may contribute to increased vulnerability of the immature brain to hypoxia-ischemia (HI) following LPS exposure.

Animals↗

PubMed2006

Fetal brain injury in experimental intrauterine asphyxia and inflammation in Göttingen minipigs.

OBJECTIVE: To examine fetal brain injury in the Göttingen minipig following intrauterine asphyxia and infection/inflammation induced at 3/4 of gestational length. METHODS: We performed laparotomy after anesthesia in six pregnant sows. We randomized 29 fetuses to one of four groups: pretreatment with saline or endotoxin followed by 30 min of umbilical cord occlusion or no occlusion. After 48 h we performed a re-laparotomy and examined the fetal brains. RESULTS: After total asphyxia, brain stem injury was present in the group pretreated with saline (P < 0.01 vs. controls) and with endotoxin (P < 0.005 vs. controls). Microglia activation was more marked in the brain stem (P < 0.05) and posterior white matter (P < 0.05) in the asphyxia group than in controls. Two of five fetuses in the asphyxia group had white matter injury, while no white matter lesions were found in the asphyxia/inflammation or endotoxin only groups. CONCLUSIONS: In this Göttingen minipig model, a species closer to humans than animals commonly used in experimental studies of perinatal brain injuries, intrauterine asphyxia following pretreatment with saline caused brain stem and white matter injury. This model can be further developed to study the impact of other intrauterine exposures on brain injury.

Animals↗

PubMed2006

Disruption of interleukin-18, but not interleukin-1, increases vulnerability to preterm delivery and fetal mortality after intrauterine inflammation.

Preterm birth is a major contributor of adverse perinatal outcome. Clinical data suggest that an inflammatory response is important in the process leading to preterm labor. By using a recently introduced mouse model of localized intrauterine lipopolysaccharide-induced inflammation, the effect of interleukin (IL)-18 gene disruption and/or IL-18 neutralization as well as combined IL-1alpha/beta gene disruption on inflammation-induced fetal loss was investigated. The frequency of preterm fetal loss was significantly higher in IL-18 knockout mice (58.9%) and in mice administered IL-18-binding protein (59.7%) compared to wild-type controls (34.7%). The rate of fetal loss was not affected by IL-1alpha/beta gene deficiency (38.7%). Decreased IL-18 protein expression combined with elevated IL-12 protein expression in uterine tissue of IL-18 knockout mice and IL-18-binding protein-treated animals was noticed. These data demonstrate that preterm pregnancy loss in response to intrauterine inflammation was enhanced by disruption of the IL-18 gene and/or IL-18 neutralization, events that may relate to exaggerated Th1 responses because of an increased IL-12/IL-18 ratio.

Animals↗

PubMed2005

Endotoxin-induced hypoxic-ischemic tolerance is mediated by up-regulation of corticosterone in neonatal rat.

Previous studies suggest that the endotoxin lipopolysaccharide (LPS) may have dual effects on brain damage induced by hypoxia-ischemia (HI) in 7-d-old rats, depending on the exposure paradigm. Although a 4-h interval between LPS administration and HI results in sensitization to HI brain injury, tolerance is observed when LPS is administered 24 h before HI. Our hypothesis is that endogenous corticosteroids are important in acquiring tolerance to HI. Neonatal rats received a single injection of LPS (1.0 mg/kg) either 4 h or 24 h before HI, or two LPS injections (4 h and 24 h) before HI. Increased brain injury was seen in animals subjected to a single LPS injection made 4 h before HI. In contrast, both the single 24-h exposure and the double injections of LPS resulted in tolerance to HI brain damage. To study the effects of corticosteroids on HI tolerance, RU486, a glucocorticoid receptor blocker, was subcutaneously injected at the same time as LPS (1.0 mg/kg), 24 h before HI stress. RU486-LPS treatment counteracted the LPS-induced tolerance effect, and aggravated the HI-induced brain injury compared with the vehicle-LPS-treated group. RU486 did not aggravate the HI-induced brain injury produced 24 h later in saline-injected animals. LPS (1.0 mg/kg) injected into 6-d-old rats transiently up-regulated serum corticosterone levels (119.6, 57.9, 56.8, and 28.3 ng/mL at 6, 12, 24, and 48 h after the LPS injection, respectively). We conclude that endotoxin-induced up-regulation of endogenous corticosterone appears to be critical for acquiring endotoxin-induced HI tolerance.

Animals↗

PubMed2005

Neurokinin 1 receptor signaling affects the local innate immune defense against genital herpes virus infection.

We show that genital infection with neurotropic HSV type 2 (HSV-2) induced a significant increase of the neuropeptide substance P (SP) within the genital tract of mice. SP was shown to weakly interfere with the HSV-2 replication. Furthermore, lack of SP signaling through the use of mice deficient in the SP receptor, neurokinin 1 receptor (NK1R), revealed an important role for SP in the innate defense against HSV-2. NK1R-deficient mice had significantly enhanced levels of HSV-2 in the genital tract and in the CNS following infection and a significantly accelerated disease progression, which was associated with an impaired NK cell activity locally in the vagina. Lack of NK1R signaling did, however, not impair the animals' ability to mount a protective immune response to HSV-2 following vaccination with an attenuated virus. Both NK1R+/+ and NK1R-/- mice developed strong HSV-2-specific Th1 T cell responses following vaccination. No genital viral replication was observed in either vaccinated NK1R-deficient or NK1R+/+ control animals following a genital HSV-2 challenge, and all of these animals survived without any symptoms of disease. In conclusion, the present results indicate that SP and NK1R signaling contributes to the innate resistance against HSV-2 infection in mice.

Animals↗

PubMed2005

Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3beta phosphorylation.

Hexarelin (HEX) is a peptide GH secretagogue with a potent ability to stimulate GH secretion and recently reported cardioprotective actions. However, its effects in the brain are largely unknown, and the aim of the present study was to examine the potential protective effect of HEX on the central nervous system after injury, as well as on caspase-3, Akt, and extracellular signal-regulated protein kinase (ERK) signaling cascades in a rat model of neonatal hypoxia-ischemia. Hypoxic-ischemic insult was induced by unilateral carotid ligation and hypoxic exposure (7.7% oxygen), and HEX treatment was administered intracerebroventricularly, directly after the insult. Brain damage was quantified at four coronal levels and by regional neuropathological scoring. Brain damage was reduced by 39% in the treatment group, compared with vehicle group, and injury was significantly reduced in the cerebral cortex, hippocampus, and thalamus but not in the striatum. The cerebroprotective effect was accompanied by a significant reduction of caspase-3 activity and an increased phosphorylation of Akt and glycogen synthase kinase-3beta, whereas ERK was unaffected. In conclusion, we demonstrate for the first time that HEX is neuroprotective in the neonatal setting in vivo and that increased Akt signaling is associated with downstream attenuation of glycogen synthase kinase-3beta activity and caspase-dependent cell death.

Animals↗

PubMed2005

White matter injury following prolonged free radical formation in the 0.65 gestation fetal sheep brain.

Free radicals seem to be involved in the development of cerebral white matter damage after asphyxia in the premature infant. The immature brain may be at increased risk of free radical mediated injury, as particularly the preterm infant has a relative deficiency in brain antioxidants systems, such as superoxide dismutase and glutathione peroxidase. In vitro studies show that immature oligodendrocytes express an intrinsic vulnerability to reactive oxygen species and free radical scavengers are able to protect immature oligodendrocytes from injury. The aim of this study was to examine the formation of ascorbyl radicals as a marker of oxidative stress in the preterm brain in association with cerebral white matter injury after intrauterine asphyxia. Fetal sheep at 0.65 gestation were chronically instrumented with vascular catheters and an occluder cuff around the umbilical cord. A microdialysis probe was placed in the periventricular white matter. Fetal asphyxia was induced by occlusion of the umbilical cord for 25 min (n = 10). Microdialysis samples were collected for 72 h and analyzed for ascorbyl radicals using electron spin resonance. Five instrumented fetuses served as controls. Three days after the insult, fetal brains were examined for morphologic injury. Umbilical cord occlusion resulted in prolonged and marked increase in ascorbyl radical production in the brain in connection with white matter injury, with activation of microglia cells in periventricular white matter and axonal injury. These data suggest that reperfusion injury following asphyxia in the immature brain is associated with marked free radical production.

Animals↗

PubMed2005

Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain.

Data indicate that bacterial products in combination with other antenatal or postnatal exposures increase the risk of perinatal brain injury. We have previously shown that administration of lipopolysaccharide (LPS) 4 h before hypoxia-ischemia (HI) increases brain injury in 7-d-old rats. The mechanisms behind such sensitization are unclear, but contrasts against a preconditioning effect of LPS given 1-3 d before ischemia in adult animals. To investigate how the effects of LPS depend on the time interval between administration and HI in the developing brain, we evaluated the effect of varying time interval (2-72 h) between LPS and HI, the duration of HI (20 or 50 min), and age of the rat pups (postnatal d 4 or 7). Outcome was assessed by brain injury scoring of specific regions. We found that LPS reduced brain injury (by 78%) when administered 24 h before 50 min of HI. However, when LPS was administered 6 h before either 20 or 50 min of HI, brain injury was increased by 2026% and 137%, respectively. Even LPS given 72 h before HI increased injury, both when LPS was administered at postnatal d 4 (by 446%) and 7 (by 77%). In conclusion, LPS enhanced vulnerability in the developing brain both in the acute (4-6 h) and the chronic (72 h) phase after administration, whereas an intermediate interval between LPS and HI had the opposite effect. The long-term sensitizing effect of LPS has not been previously described.

Animals↗

PubMed2005

White matter injury in the immature brain: role of interleukin-18.

Inflammation is likely to be important in the pathophysiology of white matter damage in the immature brain. In order to investigate the involvement of interleukin (IL)-18, we subjected 9-day-old IL-18-deficient and wild-type (WT) mice to hypoxia-ischemia (HI) (unilateral carotid ligation and exposure to 10% oxygen) and white matter injury was evaluated after 3 days by immunostaining for myelin basic protein (MBP) and neurofilament (NF). The immunoreactivity of MBP was significantly higher by 92, 49 and 21%, respectively, in subcortical white matter, striatum and thalamus in IL-18-deficient mice versus WT mice following HI. Similarly, there was a more pronounced immunoreactivity of NF by 78% in the subcortical white matter in IL-18 KO versus WT mice. IL-18 was expressed by astrocytes and microglia, whereas the IL-18 receptor was mainly found in astrocytes localized in and around the subventricular white matter. Taken together, these results indicate that release of IL-18 may play an important role in the development of white matter injury in the neonatal brain.

Animals↗

PubMed2005

Effect of inflammation on central nervous system development and vulnerability.

PURPOSE OF REVIEW: Preterm infants are at high risk for neurological sequelae and cognitive dysfunction. These problems have been attributed to a high occurrence of central nervous system (CNS) lesions, but suboptimal brain development appears to be just as important. In this brief review we present the hypothesis that systemic infection/inflammation can severely interfere with normal CNS function and development. RECENT FINDINGS: We focus on the effects of lipopolysaccharide because it is often used to model the systemic inflammatory response induced by infections. The inflammatory signals are propagated across the intact or ruptured blood-brain barrier to the CNS by proinflammatory cytokines, prostaglandins, or lipopolysaccharide. Subsequently, microglia are triggered to release cytokines, oxygen free radicals and trophic factors, which will influence the CNS in various ways. Cognition, dendritic length and spine density, dopaminergic cells, neurogenesis and glial proliferation will be affected. Furthermore, CNS vulnerability and, in some instances, cerebral anomalies and white matter damage are produced. SUMMARY: Hypothetically, all of these effects on the CNS triggered by inflammation may have severe consequences for the individual's ability to cope with environmental exposures during childhood and adulthood.

Brain Diseases↗

PubMed2005

Electrocardiographic changes following umbilical cord occlusion in the midgestation fetal sheep.

BACKGROUND: Clinical studies show that analysis of the fetal electrocardiographic (FECG) ST waveform at term gives important information on the myocardial response to intrapartum asphyxia. However, it is not known whether the preterm fetus responds in a similar fashion. The objective of the present study was to evaluate the FECGST response to umbilical cord occlusion in the preterm fetal sheep. METHODS: Fetal sheep at midgestation were subjected to 25 min umbilical cord occlusion (n = 7) and compared to controls (n = 5). Changes in the FECGST waveform were recorded together with arterial blood pressure, heart rate, and acid base status during the occlusion and for 3 days afterward. RESULTS: Umbilical cord occlusion resulted in immediate bradycardia (control: 187 +/- 7 bpm versus occlusion: 102 +/- 7 bpm), hypertension (control: 43.2 +/- 1.1 mmHg versus occlusion: 59.8 +/- 2.2 mmHg), and an initial increase in the T/QRS ratio (control: 0.10 +/- 0.02 versus occlusion: 0.60 +/- 0.10, P < 0.001), followed by hypotension (21.7 +/- 1.2 mmHg), normalization of the T/QRS ratio, and in some cases the development of negative T waves toward the end of the occlusion. CONCLUSIONS: These studies show that the midgestation fetal sheep has the capacity to react to umbilical cord occlusion with a significant increase in the amplitude of the ST waveform together with an augmentation of blood pressure, which then subsides as the occlusion continues. The appearance of negative ST segment appears to signify significant cardiac dysfunction. The characteristic progression of ST-waveform changes in response to umbilical cord occlusion in midgestation fetal sheep, suggests that monitoring the ST waveform may contribute clinically important information also in the preterm individual.

Animals↗

PubMed2005

IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta?

Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and/or IGF-I on the serine/threonine kinases Akt and glycogen synthase kinase 3beta (GSK3beta) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3beta (pGSK3beta) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3beta remained low 4 h after HI. Administration of IGF-I (50 microg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3beta decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3beta in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3- and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3beta, may explain the attenuated activation of caspases and reduction of injury in the immature brain.

Animals↗

PubMed2005

Role of cytokines in preterm labour and brain injury.

Intrauterine infection induces an intra-amniotic inflammatory response involving the activation of a number of cytokines and chemokines which, in turn, may trigger preterm contractions, cervical ripening and rupture of the membranes. Infection and cytokine-mediated inflammation appear to play a prominent role in preterm birth at early gestations (<30 weeks). The role of infection/inflammation in preterm birth in Europe has been incompletely characterised. The rate of preterm birth in Sweden is lower, and the rate of chorioamnionitis, bacterial vaginosis (BV), neonatal sepsis, and urinary tract infections during pregnancy is lower compared with the USA. In a Swedish population of women with preterm labour or preterm premature rupture of the membranes (PPROM) <34 weeks of gestation, microorganisms were detected in the amniotic fluid in 25% of women with PPROM and in 16% of those in preterm labour. Nearly half of these women had intra-amniotic inflammation defined as elevated interleukin-6 (IL-6) and IL-8, and there was a high degree of correlation between cytokine levels and preterm birth or the presence of microbial colonisation. These data do not support the hypothesis that infection-related preterm birth is less frequent in northern Europe than elsewhere. The intra-amniotic inflammatory response has also been associated with white matter injury and cerebral palsy. We find that in experimental models, induction of a systemic inflammatory response using lipopolysaccharide activates toll-like receptors (TLRs), which produce either white matter lesions or increase brain susceptibility to secondary insults. Recently, IL-18 in umbilical blood was shown to correlate with brain injury in preterm infants and IL-18 deficiency in mice decreases CNS vulnerability.

Brain Diseases↗

PubMed2005

Maturational effects of lipopolysaccharide on white-matter injury in fetal sheep.

White-matter damage has been associated with the development of cerebral palsy in children born both prematurely and at term, and it has been suggested that intrauterine infection can contribute to the brain injury. However, the relative importance of age on white-matter injury following infectious exposure in utero remains unclear. In this study, fetal sheep were exposed to systemic endotoxemia by administration of Escherichia coli lipopolysaccharide (88.7 +/- 7.7 ng/kg) at 65% or 85% of gestation. These gestational ages approximately correspond to human brain development in preterm and near-term infants respectively. White-matter injury was evaluated 3 days after lipopolysaccharide exposure with regard to microglia activation and loss of neurofilament and myelin basic protein. The expression of oligodendrocytes at different maturational stages was demonstrated in preterm and near-term fetuses with the oligodendroglial markers O4 and 2 ,3 -cyclic nucleotide 3 -phospodiesterase. Forty percent of the fetuses in the preterm group and 22% in the near-term group died within 8 hours of the endotoxin exposure. Three of six preterm and two of seven near-term surviving fetuses demonstrated pathologic changes in the brain with regard to increased microglia activation and loss of neurofilament staining. The number of activated microglia was enhanced in the subcortical white matter in both the preterm lipopolysaccharide-exposed fetuses (lipopolysaccharide: 235 +/- 64 cells/mm2; control: 72 +/- 28 cells/mm2; P = .0374) and the near-term fetuses (lipopolysaccharide: 180 +/- 40 cells/mm2; control 23 +/- 16 cells/mm2; P = .0152). There was a loss of neurofilament staining in both preterm fetuses (lipopolysaccharide: 2.20 +/- 0.77 pixel units; control: 0.20 +/- 0.10 pixel units; P = .0306) and near-term fetuses (lipopolysaccharide: 1.15 +/- 0.48 pixel units; control: 0.06 +/- 0.06 pixel units; P = .0285). O4-positive cells were detected at both gestational ages, whereas 2,3-cyclic nucleotide 3-phospodiesterase-positive cells and myelin basic protein staining were mainly detected in the near-term fetuses. In summary, we found white-matter injury in a proportion of both preterm and near-term fetuses after administration of lipopolysaccharide. These results are in agreement with clinical evidence suggesting that both preterm and term infants are at risk of periventricular leukomalacia in association with intrauterine infection.

Animals↗

PubMed2004

Hypoxic preconditioning confers long-term reduction of brain injury and improvement of neurological ability in immature rats.

Exposure to preconditioning (PC) hypoxia 24 h before a severe hypoxic-ischemic (HI) insult reduces development of injury in the immature brain. Several protective regimens have proved effective in the short-term but not in the long-term perspective. The aim of the present study, therefore, was to evaluate the PC effect on long-term morphologic and neurologic outcome in the developing brain. Six-day-old rats were subjected to hypoxia (36 degrees C, 8.0% O2; PC/HI group) and sham controls to normoxia (36 degrees C; HI group) for 3 h. Twenty-four hours later, all rats were exposed to cerebral HI produced by unilateral carotid artery occlusion combined with 1 h, 15 min of hypoxia (36 degrees C, 7.7% O2). A cylinder test was used to evaluate forelimb asymmetry to determine sensorimotor function at 4, 6, and 8 wk of age. Spatial/cognitive ability was assessed by Morris water maze trials at 7 wk of recovery. Neuropathologic analysis was performed 8 wk after insult. Brain damage was reduced (p<0.0001) in PC/HI (45.0+/-11.1 mm3) in comparison with HI (159.3+/-12.2 mm3) rats. A bias for using the ipsilateral forelimb in wall movements was observed in the cylinder test in HI compared with PC/HI rats at 4 (p<0.001), 6 (p<0.01), and 8 (p<0.0001) wk of age. Results of the Morris water maze test revealed differences (p<0.0001) in average path length between groups on the third and fourth day of trials. Hypoxic PC before HI reduced brain injury by 72% at 8 wk after the insult and provided long-term improvement of sensorimotor and spatial/cognitive functions.

Animals↗