TNF-α antagonist attenuates systemic lipopolysaccharide-induced brain white matter injury in neonatal rats

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. The present study was conducted to examine whether pioglitazone can reduce impairment of behavioral deficits mediated by inflammatory-induced brain white matter injury in neonatal rats. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 2 mg/kg) was administered to Sprague–Dawley rat pups on postnatal day 5 (P5), and i.p. administration of pioglitazone (20 mg/kg) or vehicle was performed 5 min after LPS injection. Sensorimotor behavioral tests were performed 24 h after LPS exposure, and changes in biochemistry of the brain was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, reduction of oligodendrocytes and mitochondrial activity, and increases in lipid peroxidation and brain inflammation, as indicated by the increment of interleukin-1β (IL-1β) levels and number of activated microglia in the neonatal rat brain. Pioglitazone treatment significantly improved LPS-induced neurobehavioral and physiological disturbances including the loss of body weight, hypothermia, righting reflex, wire-hanging maneuver, negative geotaxis, and hind-limb suspension in neonatal rats. The neuroprotective effect of pioglitazone against the loss of oligodendrocytes and mitochondrial activity was associated with attenuation of LPS-induced increment of thiobarbituric acid reactive substances (TBARS) content, IL-1β levels and number of activated microglia in neonatal rats. Our results show that pioglitazone prevents neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on microglial activation, IL-1β induction, lipid peroxidation, oligodendrocyte production and mitochondrial activity.

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Prospective Study of White Matter Health for an Altitude Chamber Research Program

Aerospace Medicine and Human Performance ◽

10.3357/amhp.5730.2021 ◽

2021 ◽

Vol 92 (4) ◽

pp. 215-222

Author(s):

Desmond M. Connolly ◽

Henry T. Lupa

Keyword(s):

White Matter ◽

Prospective Study ◽

Research Program ◽

Past History ◽

Brain Magnetic Resonance Imaging ◽

White Matter Injury ◽

Study Entry ◽

Exposure Limits ◽

Brain White Matter ◽

The University

INTRODUCTION: Hypobaric decompression has been associated with brain white matter injury. Relevant exposure limits are unknown, raising ethical concerns over safety of volunteers for altitude chamber research. To inform this, a prospective study of white matter status using brain Magnetic Resonance Imaging (MRI) was conducted before and after a 9-mo program of hypobaric research.METHODS: Volunteers underwent 3-D, volumetric, fluid attenuated inversion recovery (FLAIR) MRI at the University of Nottingham, UK, on study entry and again after their final exposure. MRI data were analyzed and reported independently at the University of Maryland, Baltimore, MD, USA. Entry criteria were 5 subcortical white matter hyperintensities (WMH) of total volume 0.08 mL.RESULTS: One volunteer failed screening with 63 WMH (total volume 2.38 mL). Eleven individuals completed 160 short-duration (< 1h) exposures (range 3 to 26) to 18,000 ft pressure altitude (maximum 40,000 ft), no more often than twice weekly. The cohort exhibited eight total WMH on study entry (total volume 0.166 mL) and five (mostly different) total WMH on exit (0.184 mL). Just one WMH (frontal lobe) was present on both entry and exit scans. Excess background WMH on MRI screening were associated with past mild traumatic brain injury (MTBI).CONCLUSIONS: One hypoxia familiarization plus multiple, brief, infrequent, nonhypoxic hypobaric exposures (with denitrogenation) have not promoted WMH in this small cohort. Less intensive programs of decompression stress do not warrant MRI screening. A negative past history of MTBI has strong negative predictive value for excess WMH in young healthy subjects (N 33).Connolly DM, Lupa HT. Prospective study of white matter health for an altitude chamber research program. Aerosp Med Hum Perform. 2021; 92(4):215222.

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The Neuroprotective Effects of Xenon on Neonatal Rats with White Matter Damage by Regulating Expression of microRNA-210 and HIF-1αThe Neuroprotective Effects of Xenon on Neonatal Rats with White Matter Damage by Regulating Expression of microRNA-210 and HIF-1α

10.21203/rs.3.rs-60259/v1 ◽

2020 ◽

Author(s):

Xiangyun Yin ◽

Jixiu Zhao ◽

Jian Jiang ◽

Hongmin Xi ◽

Xianghong Li ◽

...

Keyword(s):

White Matter ◽

Expression Level ◽

Neonatal Rats ◽

Rt Pcr ◽

White Matter Damage ◽

Neuroprotective Effects ◽

Brain White Matter ◽

Group A ◽

Group B ◽

Brain Tissues

Abstract Background:Premature infant is a significant health care burden. White matter damage (WMD) is a leading cause of acute mortality and chronic morbidity in preterm. Xenon (Xe) intervention was given to the 3-day-old neonatal rats with brain white matter injury. By detecting the changes in the expression level of microRNA210 and hypoxia inducible factor 1α (HIF-1α) in brain tissue before and after xenon intervention, we can research the molecular basis and the mechanism of neuroprotective on effect of xenon on brain white matter damage in neonatal rats.Methods:Three-day-old SD rats were randomly divided into sham group(Group A, n=24), lipopolysaccharide(LPS)+hypoxia-ischemia(HI) group (Group B, n=24) and LPS+HI+Xe group ( n=72). The onset of Xe inhalation started at 0,2 and 5 hours in subgroups C,D,and E respectively.We investigated the neurobehavioral deficits by performing TUNEL and hematoxylin and eosin (HE) staining and examining the expression of miR-210and HIF-1α in brain tissues via RT-PCR and western blot. Results: Xe treatment improved the histological alterations and decreased the number of apoptotic cells in group C pups.Compared to group A,Detection of miR-210 level by RT-PCR. the expression level of miR-210 in neonatal rats' periventricular tissue increased significantly at all time points in group B (p<0.05).While the expression level of miR-210 in brain tissues of group B was significantly lower at 48h and 72h than that of group C(p<0.05).Similarly,Detection of HIF-1α protein by Western blot. The level of HIF-1α protein in group B brain tissues was significantly higher than that of group A at each time point (p<0.05), Xe treatment resulted in a marked increase in HIF-1α in C,D, and E subgroups (P < 0.05, compared to group B).Conclusions: These results demonstrate that the expression of HIF-1α and miR-210 increased in periventricular tissues and Xe could relieve the white matter damage by up-regulating the expression of HIF-1α and its target gene miR-210.The Xe therapeutic time window was within 5 hours after intervention, the sooner the better.

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Use of High Resolution 3D Diffusion Tensor Imaging to Study Brain White Matter Development in Live Neonatal Rats

Frontiers in Psychiatry ◽

10.3389/fpsyt.2011.00054 ◽

2011 ◽

Vol 2 ◽

Cited By ~ 8

Author(s):

Yu Cai ◽

Matthew S. McMurray ◽

Ipek Oguz ◽

Hong Yuan ◽

Martin A. Styner ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

High Resolution ◽

Diffusion Tensor ◽

Neonatal Rats ◽

Brain White Matter ◽

White Matter Development

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Melatonin Ameliorates Axonal Hypomyelination of Periventricular White Matter by Transforming A1 to A2 Astrocyte via JAK2/STAT3 Pathway in Neonatal Rats Induced by Lipopolysaccharide Injection

10.21203/rs.3.rs-841144/v1 ◽

2021 ◽

Author(s):

Shuqi Jiang ◽

Huifang Wang ◽

Qiuping Zhou ◽

Qian Li ◽

Nan Liu ◽

...

Keyword(s):

Electron Microscopy ◽

White Matter ◽

Neurological Dysfunction ◽

Periventricular White Matter ◽

Neonatal Rats ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Tnf Α ◽

Phenotype Transformation

Abstract Background: Astrocyte A1/A2 phenotypes may play differential role in the pathogenesis of periventricular white matter (PWM) damage in septic postnatal rats. In this study, we sought to determine whether melatonin(MEL) would improve the axonal hypomyelination and neurological dysfunction, and, if so, to ascertain whether this may be related to transformation of astrocyte A1 to A2 phenotype.Methods: One-day-old Sprague–Dawley rats were divided into control, LPS, and LPS+MEL groups. Immunofluorescence was performed to detect IBA1, GFAP, MAG, C3 and S100A10 in the PWM of neonatal rats. C1q, IL-1α and TNF-α expression were assessed by immunofluorescence and ELISA. Electron microscopy was conducted to observe alterations of axonal myelin sheath in the PWM, and the number of PLP and MBP positive oligdendrocytes was caculated using in situ hybridization. The effects of MEL on locomotor ability, spatial learning and memory were evaluated by behavioral testing. In vitro, A1 astrocyte was induced by IL-1α, C1q and TNF-α, the effect of MEL on C3 and S100A10 expression was determined by Western blot and immunofluorescence. JAK2/STAT3 signaling pathway was investigated to determine whether it was involved in modulation of A1/A2 phenotype transformation.Results: At 1 and 3 days after LPS injection, IBA1+ microglia in the PWM were significantly increased in cell numbers which generated excess amounts of IL-1α, TNF-α, and C1q. The number of A1 astrocytes was significantly increased at 7-28d after LPS injection. In rats given MEL treatment, the number of A1 astrocytes was significantly decreaed, but that of A2 astrocytes, PLP+, MBP+ and MAG+ cells was increased. By electron microscopy, ultrastructural features of axonal hypomyelination were attenuated by MEL. Furthermore, MEL improved neurological dysfunction as evaluated by different neurological tests. In vitro, MEL decreased the C3 significantly, and upregulated expression of S100A10 in primary astrocytes subjected to IL-1α, TNF-α and C1q treatment. Additionally, JAK2/STAT3 signaling pathway was found to be involved in modulation of A1/A2 phenotype transformation. Conclusions: MEL effectively alleviates PWMD of septic neonatal rats, and that it is most likely through modulating astrocyte phenotypic transformation from A1 to A2 via the MT1/JAK2/STAT3 pathway.

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Synaptic Injury in the Thalamus Accompanies White Matter Injury in Hypoxia/Ischemia-Mediated Brain Injury in Neonatal Rats

BioMed Research International ◽

10.1155/2019/5249675 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Na Liu ◽

Xin Tong ◽

Wanjie Huang ◽

Jianhua Fu ◽

Xindong Xue

Keyword(s):

White Matter ◽

White Matter Injury ◽

Neonatal Rat ◽

Morris Water Maze Test ◽

Neonatal Rats ◽

Sprague Dawley ◽

Artery Ligation ◽

Compensatory Response ◽

Significant Difference ◽

Hypoxia Ischemia

The broad spectrum of disabilities caused by white matter injury (WMI) cannot be explained simply by hypomyelination. Synaptic injury in the thalamus may be related to disabilities in WMI survivors. Neuronal injury in the thalamus has been found most commonly in autopsy cases of preterm WMI. We hypothesized that hypoxia/ischemia (HI) in neonatal rats results in synaptic abnormalities in the thalamus that contribute to disabilities in WMI survivors. We examined changes in synapses in a neonatal rat model of HI-induced WMI. Right common carotid artery ligation and hypoxia (8% oxygen for 2.5 hours (h)) were performed in three-day-old Sprague-Dawley rats. We found HI rats performed worse in the Morris water maze test than sham rats, suggesting long-term cognition impairment after HI injury. A loss of synapses in the thalamus accompanied by hypomyelination and oligodendrocytes (OLs) reduction was observed. At the ultrastructural level, reductions in active zone (AZ) length and postsynaptic density (PSD) thickness were detected at 2 weeks after HI exposure. Furthermore, increased expression of synaptophysin and PSD-95 in both groups was observed from 3 days (d) to 21 d after hypoxic/ischemic (HI) injury. PSD-95 expression was significantly lower in HI rats than in sham rats from 14 d to 21 d after HI injury, and synaptophysin expression was significantly lower in HI rats from 7 d to 14 d after HI injury. However, no significant difference in synaptophysin expression was observed between HI rats and sham rats at 21 d after HI injury. The results demonstrated synaptic abnormalities in the thalamus accompanied by hypomyelination in WMI in response to HI exposure, which may contribute to the diverse neurological defects observed in WMI patients. Although synaptic reorganization occurred as a compensatory response to HI injury, the impairments in synaptic transmission were not reversed.

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