Biomedical subjects

Henrik Hagberg

Publications and source records attributed to Henrik Hagberg.

At least 19 recordsLinked to original sources

PubMed2007

Sex and the pathogenesis of cerebral palsy.

Cerebral palsy (CP) and related developmental disorders are more common in males than in females, but the reasons for this disparity are uncertain. Males born very preterm also appear to be more vulnerable to white matter injury and intraventricular hemorrhage than females. Experimental studies in adult animals and data from adult patients with stroke indicate that sex hormones such as estrogens provide protection against hypoxic-ischemic injury, and the neonatal brain is also influenced by these hormones. However, hormonal influences on the fetus and neonates are substantially different from those on adults. Recent data from neonatal rodents subjected to hypoxia-ischemia also demonstrate differences between males and females. Knockout of the gene for poly (ADP-ribose) polymerase (PARP-1), a major step in the cascade of injury, protected male but not female mouse pups from hypoxic-ischemic injury. Other reports demonstrated major differences between male and female neurons grown separately in cell culture, suggesting that sex differences in the fetal or neonatal period result from intrinsic differences in cell death pathways. This new information indicates that there are important neurobiological differences between males and females with respect to their response to brain injuries. This information is relevant to understanding the pathogenesis of CP as well as to the design of future clinical trials of potential neuroprotective strategies.

Animals↗

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

The dynamics of the LPS triggered inflammatory response of murine microglia under different culture and in vivo conditions.

Overall, the inflammatory potential of lipopolysaccharide (LPS) in vitro and in vivo was investigated using different omics technologies. We investigated the hippocampal response to intracerebroventricular (i.c.v) LPS in vivo, at both the transcriptional and protein level. Here, a time course analysis of interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) showed a sharp peak at 4 h and a return to baseline at 16 h. The expression of inflammatory mediators was not temporally correlated with expression of the microglia marker F4/80, which did not peak until 2 days after LPS injection. Of 480 inflammation-related genes present on a microarray, 29 transcripts were robustly up-regulated and 90% of them were also detected in LPS stimulated primary microglia (PM) cultures. Further in vitro to in vivo comparison showed that the counter regulation response observed in vivo was less evident in vitro, as transcript levels in PM decreased relatively little over 16 h. This apparent deficiency of homeostatic control of the innate immune response in cultures may also explain why a group of genes comprising tnf receptor associated factor-1, endothelin-1 and schlafen-1 were regulated strongly in vitro, but not in vivo. When the overall LPS-induced transcriptional response of PM was examined on a large Affymetrix chip, chemokines and cytokines constituted the most strongly regulated and largest groups. Interesting new microglia markers included interferon-induced protein with tetratricopeptide repeat (ifit), immune responsive gene-1 (irg-1) and thymidylate kinase family LPS-inducible member (tyki). The regulation of the former two was confirmed on the protein level in a proteomics study. Furthermore, conspicuous regulation of several gene clusters was identified, for instance that of genes pertaining to the extra-cellular matrix and enzymatic regulation thereof. Although most inflammatory genes induced in vitro were transferable to our in vivo model, the observed discrepancy for some genes potentially represents regulatory factors present in the central nervous system (CNS) but not in vitro.

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

STAN in clinical practice--the outcome of 2 years of regular use in the city of Gothenburg.

OBJECTIVE: The purpose of this study was to monitor the introduction of the STAN-methodology (Noventa Medical, Moelndal, Sweden). STUDY DESIGN: This was a prospective observational study covering the total population of deliveries at term during 2 years. Four thousand eight hundred and thirty out of 14,687 term pregnancies were monitored using the STAN S 21 fetal heart monitor and the associated clinical guidelines. Cord artery metabolic acidosis, neonatal outcome, and rates of operative deliveries for fetal distress were assessed. RESULTS: The annual rate of STAN usage increased from 28.1% to 37.7% and was associated with a significant reduction in metabolic acidosis rate in the total population from 0.76% to 0.44% (P < .05). The compliance with the clinical guidelines increased in cases requiring intervention. The rates for moderate/severe hypoxic neonatal encephalopathy were consistently low, 0.55 and 0.68 per 1000 deliveries, respectively, and corresponding to previous findings. The rate of operative delivery did not change during the 2 years in the total population. CONCLUSION: Increasing STAN usage provided consistent improvements in fetal outcome equalling those noted in the Swedish randomized controlled trial (RCT) without increasing operative interventions for fetal distress.

Acidosis↗

PubMed2006

Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia.

Sex-related brain injury was evaluated after unilateral hypoxia-ischaemia (HI) in C57/BL6 mice on postnatal day (P) 5, 9, 21 or 60, corresponding developmentally to premature, term, juvenile and adult human brains. There was no sex difference in brain injury when the insult was severe, as evaluated by pathological scoring or tissue loss, but when the insult was moderate, adult (P60) females displayed less injury. In the immature (P9) male brains, neurones displayed a more pronounced translocation of apoptosis-inducing factor (AIF) (loss of AIF from the mitochondrial fraction and increase in nuclear AIF) after HI, whereas the female brain neurones displayed a stronger activation of caspase 3 (more pronounced loss of pro-caspase 3, increase in cleaved caspase 3 and increase in caspase 3 enzymatic activity). Two other mechanisms of injury, peroxynitrite-induced formation of nitrotyrosine and autophagy, were no different between males and females at P9. These data show that the CNS is more resistant to HI in adult females compared with males, whereas no sex differences were found in the extent of injury in neonatal mice. However, critical sex-dependent differences were demonstrated in vivo with regard to cellular, apoptosis-related mechanisms.

Animals↗

PubMed2006

Cytokines in the placenta of Pakistani newborns with and without intrauterine growth retardation.

Although intrauterine growth retardation (IUGR) is a major risk factor for increased neonatal mortality and morbidity, the mechanisms behind it are not clear. We analyzed cytokine gene expression and gene polymorphisms in infants with and without IUGR in Pakistan, where IUGR is very common. 45 IUGR and 55 control mother/infant pairs were studied. mRNA for IL-10, IL-8, TNF-alpha, TGF-beta, IL-6, IL-4, IL-1beta, IL-12, IFN-gamma and GAPDH was quantified with RT-PCR from placenta. Cytokine and cytokine receptor gene polymorphisms for -1087IL10, -308TNFA, -174IL6, +915TGFB1, intron 2 IL1RN, +36TNFR1, 150V IL4RA and -159CD14 were determined from genomic DNA. The serum levels of IL-1beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha and TGF-beta were measured. There was a significant decrease of IL-10 and IL-12, but increase of TGF-beta in the decidua and similarly decrease of IL-10, but increase of TGF-beta in the trophoblasts of the IUGR placentas compared with the non-IUGR placentas. We found significantly lower levels of IL-1beta in serum from the mothers of the IUGR infants and of TGF-beta in serum of the infants with IUGR compared with the non-IUGR infants. We note that the IL-10 mRNA expression in the decidua was down-regulated, but the TGF-beta mRNA up-regulated in IUGR placentas of mothers from a population with multiple risk factors for IUGR. We propose that the low IL-10 in the placenta may be involved in the pathogenesis of IUGR and might possibly be treatable.

Base Sequence↗

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

Free radicals, mitochondria, and hypoxia-ischemia in the developing brain.

The immature brain is particularly susceptible to free radical injury because of its poorly developed scavenging systems and high availability of iron for the catalytic formation of free radicals. Neurons are more vulnerable to free radical damage than glial cells, but oligodendrocyte progenitors and immature oligodendrocytes in very prematurely born infants are selectively vulnerable to depletion of antioxidants and free radical attack. Reactive oxygen and nitrogen species play important roles in the initiation of apoptotic mechanisms and in mitochondrial permeability transition, and therefore constitute important targets for therapeutic intervention. Oxidative stress is an early feature after cerebral ischemia and experimental studies targeting the formation of free radicals demonstrate various degrees of protection after perinatal insults. Oxidative stress-regulated release of proapoptotic factors from mitochondria appears to play a much more important role in the immature brain. This review will summarize and compare with the adult brain some of the current knowledge of free radical formation in the developing brain and its roles in the pathophysiology after cerebral hypoxia-ischemia.

Animals↗

PubMed2005

Bcl-2 phosphorylation in the BH4 domain precedes caspase-3 activation and cell death after neonatal cerebral hypoxic-ischemic injury.

To date, there are very few in vivo studies addressing the role of Bcl-2 phosphorylation. In a model of neonatal hypoxic-ischemic (HI) brain injury, we characterized the spatial and temporal phosphorylation of Bcl-2 at serine-24 (PS24-Bcl-2), using a site-specific antibody. Very few cells positive for PS24-Bcl-2 were found in control animals, but the number increased during reperfusion in all investigated brain areas in the ipsilateral hemisphere after HI, particularly in the border region between intact and damaged tissue. The highest numbers were encountered 24 h post-HI. Phosphorylation of Bcl-2 at serine-24 coincided with cytochrome c release after hypoxia-ischemia and preceded caspase-3 activation. Injured neurons displayed a predominantly nuclear, but also mitochondrial, localization of PS24-Bcl-2 immunoreactivity. In conclusion, phosphorylation of Bcl-2 at serine 24 was induced by hypoxia-ischemia, presumably resulting in loss of its anti-apoptotic function.

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

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

Effects of acupuncture and stabilising exercises as adjunct to standard treatment in pregnant women with pelvic girdle pain: randomised single blind controlled trial.

OBJECTIVES: To compare the efficacy of standard treatment, standard treatment plus acupuncture, and standard treatment plus stabilising exercises for pelvic girdle pain during pregnancy. DESIGN: Randomised single blind controlled trial. Settings East Hospital, Gothenburg, and 27 maternity care centres in Sweden. PARTICIPANTS: 386 pregnant women with pelvic girdle pain. INTERVENTIONS: Treatment for six weeks with standard treatment (n = 130), standard treatment plus acupuncture (n = 125), or standard treatment plus stabilising exercises (n = 131). MAIN OUTCOME MEASURES: Primary outcome measure was pain (visual analogue scale); secondary outcome measure was assessment of severity of pelvic girdle pain by an independent examiner before and after treatment. RESULTS: After treatment the stabilising exercise group had less pain than the standard group in the morning (median difference = 9, 95% confidence interval 1.7 to 12.8; P = 0.0312) and in the evening (13, 2.7 to 17.5; P = 0.0245). The acupuncture group, in turn, had less pain in the evening than the stabilising exercise group (-14, -18.1 to -3.3; P = 0.0130). Furthermore, the acupuncture group had less pain than the standard treatment group in the morning (12, 5.9 to 17.3; P < 0.001) and in the evening (27, 13.3 to 29.5; P < 0.001). Attenuation of pelvic girdle pain as assessed by the independent examiner was greatest in the acupuncture group. CONCLUSION: Acupuncture and stabilising exercises constitute efficient complements to standard treatment for the management of pelvic girdle pain during pregnancy. Acupuncture was superior to stabilising exercises in this study.

Acupuncture Therapy↗

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↗