Hypoxia-Ischemia Brain Damage Disrupts Brain Cholesterol Homeostasis in Neonatal Rats

Z, Yu; S, Li; Sh, Lv; Piao, Hong‐Guang; Yh, Zhang; Ym, Zhang; Ma, Hui; Zhang, J; Ck, Sun; Ap, Li

doi:10.1055/s-0029-1243175

Cited by 11 publications

(10 citation statements)

References 33 publications

(36 reference statements)

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“…As the most vulnerable oligodendroglial lineage cells, preOLs injury is a hallmark feature of white matter damage induced by hypoxia-ischemia (McTigue et al 2006;Yu et al 2009;Li et al 2010). Consistently, we demonstrated in this study that exposure of OPCs to OGD resulted in cell death as evidenced by increased membrane leakage of LDH, and neonatal pups exposed to hypoxia/ischemia resulted more preOLs damage and decreased in myelin production.…”

Section: Discussionsupporting

confidence: 88%

BNIP3 mediates pre‐myelinating oligodendrocyte cell death in hypoxia and ischemia

Guan

Chen

et al. 2013

Journal of Neurochemistry

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Developing oligodendrocytes, collectively termed 'pre-myelinating oligodendrocytes ' (preOLs), are vulnerable to hypoxic or ischemic insults. The underlying mechanism of this vulnerability remains unclear. Previously, we showed that Bcl-2⁄E1B-19K-interacting protein 3 (BNIP3), a proapoptotic member of the Bcl-2 family proteins, induced neuronal death in a caspase-independent manner in stroke. In this study, we investigated the role of BNIP3 in preOL cell death induced by hypoxia or ischemia. In primary oligodendrocyte progenitor cell (OPC) cultures exposed to oxygen-glucose deprivation, we found that BNIP3 was upregulated and levels of BNIP3 expression correlated with the death of OPCs. Upregulation of BNIP3 was observed in preOLs in the white matter in a neonatal rat model of stroke. Knockout of BNIP3 significantly reduced death of preOLs in the middle cerebral artery occlusion model in mice. Our results demonstrate a role of BNIP3 in mediating preOLs cell death induced by hypoxia or ischemia, and suggest that BNIP3 may be a new target for protecting oligodendrocytes from death after stroke.

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Section: Discussionsupporting

confidence: 88%

BNIP3 mediates pre‐myelinating oligodendrocyte cell death in hypoxia and ischemia

Guan

Chen

et al. 2013

Journal of Neurochemistry

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“…The level of HMGCR was unchanged at 6hr, but increased at 24hr after HI, which might prevent further reduction of cholesterol in the injured hemisphere. The other two studies of neonatal HI in P7 SD rats also reported the diminished cholesterol contents, which lasted longer for 3 days or 3 months following the initial insult ( 13 , 14 ). Disturbance of cholesterol homeostasis after neonatal HI may have adverse consequences on cell survival and brain development.…”

Section: Discussionmentioning

confidence: 81%

“…Therefore, cholesterol synthesis is sensitive to reduced O 2 availability and is limited in the conditions of hypoxia-ischemia (HI). This is evidenced by two studies in neonatal HI rats showing chronic loss of brain cholesterol lasting at least 3 days or 3 months following the insults ( 13 , 14 ). Unfortunately, there are no additional investigations on the changes of cholesterol metabolism in response to HI in the immature brain and the underlying mechanisms.…”

Section: Introductionmentioning

confidence: 95%

Upregulation of cholesterol 24-hydroxylase following hypoxia–ischemia in neonatal mouse brain

Zhu

Guo

et al. 2018

Pediatr Res

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Background Maintenance of cholesterol homeostasis is crucial for brain development. Brain cholesterol relies on de novo synthesis and is cleared primarily by conversion to 24S-hydroxycholesterol (24S-HC) with brain-specific cholesterol 24-hydroxylase (CYP46A1). We aimed to investigate the impact of hypoxia-ischemia (HI) on brain cholesterol metabolism in the neonatal mice. Methods Postnatal day 9 C57BL/6 pups were subjected to HI using the Vannucci model. CYP46A1 expression was assessed by western blotting and its cellular localization was determined by immunofluorescence staining. The amount of brain cholesterol, 24S-HC in the cortex and in the serum was measured with ELISA. Results There was a transient cholesterol loss at 6hr after HI. CYP46A1 was significantly up-regulated at 6hr and 24hr following HI with a concomitant increase of 24S-HC in the ipsilateral cortex and in the serum. The serum levels of 24S-HC correlated with those in the brain, as well as with necrotic and apoptotic cell death evaluated by the expression of spectrin breakdown products and cleaved caspase-3 at 6hr and 24hr after HI. Conclusions Enhanced cholesterol turnover by activation of CYP46A1 represents disrupted brain cholesterol homeostasis early after neonatal HI. 24S-HC might be a novel blood biomarker for severity of hypoxic-ischemic encephalopathy with potential clinical application.

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“…We focused on this region of the brain because the effects of HI are most striking in the hippocampus and overlying cortex in this neonatal HI rat model. This method is widely used to quantify brain damage in such models and has been validated since 1998 (39)(40)(41)(42)(43)(44).…”

Section: Histologymentioning

confidence: 99%

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

et al. 2012

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Background: Both hypothermia and erythropoietin (ePO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (hI). We investigated a possible additive effect of the use of a combination of hypothermia-ePO in a rat model of neonatal hI. Methods: at postnatal day 7, rats were subjected to hI and then randomized to 3 h of hypothermia, ePO, or both. sensorimotor function was assessed by the cylinder-rearing test (cRT) at 2 and 5 wk after hI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. results: Multivariable analysis using general linear modeling showed that hypothermia, ePO, and the interaction hypothermia × gender were determinants of sensorimotor function, both at 2 and 5 wk after hI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the cRT. Maximal improvement in males was 26% after combined treatment with hypothermia and ePO. histological outcome was improved by hypothermia only with no additional effect of ePO or gender. conclusion: hypothermia after hI improved sensorimotor function in females more than in males. There was a borderline additive effect of ePO when combined with hypothermia. histology of brain lesion volume and white matter damage was improved only by hypothermia.P erinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury and is associated with long-term neurological sequelae such as cognitive dysfunction, developmental delay, seizures, and sensory and/or motor impairment (1,2). Several studies in newborn rodents indicate that reduction of brain temperature by 2-5 °C even for 3 h, when started within 6 h after HI, provides neuroprotection and improved behavioral outcome (3-6).The neuroprotective effects of hypothermia of mildly asphyxiated newborns have been demonstrated, but in clinical practice, morbidity and mortality remain considerable (30-45%) (7,8). The combination of hypothermia and other pharmacologic strategies after birth asphyxia may improve long-term neurodevelopment (9). Erythropoietin (EPO) has been shown to reduce brain lesion volume in an experimental setting of neonatal HI (10-13). In addition, EPO treatment of perinatally asphyxiated human term neonates has also proven to be beneficial (14). In recent studies with a rodent model, females appear to benefit more from neuroprotective interventions after HI, such as hypothermia, EPO,.The aim of the present study was to test whether the addition of EPO to hypothermia has additive neuroprotective effects as compared with a single treatment and to examine possible gender effects. Results HypothermiaSham-treated rats did not show a paw preference in the cylinder-rearing test (CRT) (paw preference < ±5%, data not shown). A significant paw preference of the unimpaired forepaw in the normothermia groups was observed at both 2 and 5 wk after HI (Figure 1). Differences between males and females in the normothermia group were not statistically significant. In fema...

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Hypoxia-Ischemia Brain Damage Disrupts Brain Cholesterol Homeostasis in Neonatal Rats

Cited by 11 publications

References 33 publications

BNIP3 mediates pre‐myelinating oligodendrocyte cell death in hypoxia and ischemia

BNIP3 mediates pre‐myelinating oligodendrocyte cell death in hypoxia and ischemia

Upregulation of cholesterol 24-hydroxylase following hypoxia–ischemia in neonatal mouse brain

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

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