Impact of inhaled nitric oxide on white matter damage in growth-restricted neonatal rats

Background: Stroke induced white matter damage is associated with neurological functional deficits, but the underlying mechanisms are not well understood. Endothelial nitric oxide synthase knockout (eNOS-/-) mice exhibited a higher mortality, more severe neurological functional deficit, and decreased neurogenesis, angiogenesis and arteriogenesis after stroke than wild type mice. There are no reports as to whether eNOS is related to the white matter change post-stroke. Methods: Adult male C57BL/6 WT and eNOS -/- mice were subjected to permanent middle cerebral artery occlusion (MCAo) by a filament and sacrificed 7 days after MCAo. Functional evaluation, infarct volume measurement, and immunostaining for analysis of white matter changes were performed. Results: There is no significant difference in the infarction volume between wild type and eNOS -/- (wild type : 23.09%±3.32%; eNOS-/-: 27.83%±4.92%, p=0.436, n=9/group). However, eNOS -/- mice showed significantly decreased functional outcome tested by the singal pellet reaching test (wild type: 38.46%%±1.43%, eNOS-/-: 27.45%±2.41%, p=0.0017). eNOS -/- mice also exhibited increased white matter damage compared to wild type mice, including decrease: 1. Axonal density stained by Bielshowsky Silver in the ipsilateral striatal bundles (wild type: 22.06%±3.0%, eNOS-/-: 13.32%±2.18%,, p=0.031), and in the contralateral striatal bundles (wild type: 65.35%±3.97%, eNOS-/-: 29.38%±5.84%, p=0.02); 2. Density of phasphorylated neurofilament by SMI31-immunoflureoscent staining (wild type: 24.11%±2.06%, eNOS-/-: 7.90%±1.70%, p=0.009); 3. The number of CNPase-positive oligodendrocytes in the ischemic border (wild type: 52.23±5.10, eNOS-/-: 35.59±5.33, p=0.041); 4. The number of NG2-positive oligodendrocyte progenitors in the ischemic border (wild type: 26.22±2.31, eNOS-/-: 18.38±1.95, p=0.0187). There is no significant difference in the density of Luxol fast blue stained myelin in the ipsilateral striatal bundles between wild type and eNOS -/- mice (wild type: 25.21%±3.64%; eNOS-/-: 21.39%±6.29%, p=0.260). Conclusions: We are the first to report that eNOS not only regulates vascular changes and neurogenesis, but also plays an important role in white matter changes after stroke.

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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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Gestational Hypoxia Induces White Matter Damage in Neonatal Rats: A New Model of Periventricular Leukomalacia

Brain Pathology ◽

10.1111/j.1750-3639.2004.tb00492.x ◽

2004 ◽

Vol 14 (1) ◽

pp. 1-10 ◽

Cited By ~ 85

Author(s):

Olivier Baud ◽

Jean-Luc Daire ◽

Yvette Dalmaz ◽

Romain H Fontaine ◽

Richard C. Krueger ◽

...

Keyword(s):

White Matter ◽

Periventricular Leukomalacia ◽

Neonatal Rats ◽

White Matter Damage ◽

New Model

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4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) Ameliorates Ischemia-Hypoxia-Induced White Matter Damage in Neonatal Rats through Inhibition of the Voltage-Gated Chloride Channel ClC-2

International Journal of Molecular Sciences ◽

10.3390/ijms160510457 ◽

2015 ◽

Vol 16 (12) ◽

pp. 10457-10469 ◽

Cited By ~ 7

Author(s):

Baixiong Zhao ◽

Hongyu Quan ◽

Teng Ma ◽

Yanping Tian ◽

Qiyan Cai ◽

...

Keyword(s):

White Matter ◽

Chloride Channel ◽

Disulfonic Acid ◽

Neonatal Rats ◽

White Matter Damage ◽

Voltage Gated

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Inhaled NO prevents hyperoxia-induced white matter damage in neonatal rats

Experimental Neurology ◽

10.1016/j.expneurol.2013.11.025 ◽

2014 ◽

Vol 252 ◽

pp. 114-123 ◽

Cited By ~ 22

Author(s):

Hoa Pham ◽

Gaelle Vottier ◽

Julien Pansiot ◽

Sy Duong-Quy ◽

Bieke Bollen ◽

...

Keyword(s):

White Matter ◽

Neonatal Rats ◽

White Matter Damage ◽

Inhaled No

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Protective effects of melatonin on the white matter damage of neonatal rats by regulating NLRP3 inflammasome activity

Neuroreport ◽

10.1097/wnr.0000000000001642 ◽

2021 ◽

Vol 32 (9) ◽

pp. 739-747

Author(s):

Miao Qin ◽

Yan Liu ◽

Mengya Sun ◽

Xianghong Li ◽

Jiaxin Xu ◽

...

Keyword(s):

White Matter ◽

Nlrp3 Inflammasome ◽

Protective Effects ◽

Neonatal Rats ◽

White Matter Damage ◽

Inflammasome Activity

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The neuroprotective effects of xenon on neonatal rats with white matter damage by regulating expression of microRNA-210 and HIF-1α

10.21203/rs.2.10732/v2 ◽

2019 ◽

Author(s):

xiangyun yin ◽

Jixiu Zhao ◽

Jian Jiang ◽

Hongmin Xi ◽

Xianghong Li ◽

...

Keyword(s):

White Matter ◽

Expression Level ◽

Neonatal Rats ◽

White Matter Damage ◽

Neuroprotective Effects ◽

Group A ◽

Group B ◽

Group D ◽

Time Point ◽

Brain Tissues

Abstract Background: White matter damage is a leading cause of acute mortality and chronic morbidity in preterm birth. Xenon is a general anesthetic with neuroprotective effects. We aimed to reveal the molecular basis and neuroprotective mechanism of Xe intervention in treating white matter damage by detecting the expression level of miR-210 and HIF-1α in brain tissues of 3-day-old neonatal rats. Methods: Three-day-old SD rats were randomly divided into sham group (Group A, n=24), LPS +HI group (Group B, n=24) and LPS+HI+Xe group (n=72). LPS+HI+Xe group was given Xenon gas inhalation for three hours after treatment of HI at 0h,2h,and 5h,and divided into three subgroups C,D,and E randomly. We investigated the WMD 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: Our study shows that the brain tissues of neonatal rat which stained by HE were pale, structure loosen, and psychosis along with apoptosis in group B, Xe treatment improved histological alterations and decreased the number of apoptotic cells in group C . The expression level of miR-210 increased significantly at all time points in group B compared to group A (p<0.05),While that was significantly lower at 0h and 48h than that of group C(p<0.05).Compared with group C,the expression of miR-210 in group D and group E decreased significantly at 0h, 24h and 48h (p<0.05).The level of HIF-1α protein in group B was significantly higher than that of group A at each time point, while significantly lower than that of group C at each time point and that of group D and E at 0h, 24h and 72h (p<0.05).Compared with group C and group D,the expression level of HIF-1α protein decreased significantly at 24h in group E (p<0.05). 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. Keywords: premature birth, Xenon, microRNA-210, HIF-1α, white matter damage

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