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Neonatal hypoxia-ischemia in rat elicits a region-specific neurotrophic response in SVZ microglia.

ABSTRACT: BACKGROUND:Recent findings describe microglia as modulators of neurogenesis in the subventricular zone (SVZ). SVZ microglia in the adult rat are thought to adopt a neurotrophic phenotype after ischemic stroke. Early postnatal microglia are endogenously activated and may therefore exhibit an increased sensitivity to neonatal hypoxia-ischemia (HI). The goal of this study was to investigate the impact of cortico-striatal HI on the microglial phenotype, function, and gene expression in the early postnatal SVZ. METHODS:Postnatal day (P)7 rats underwent sham or right-hemispheric HI surgery. Microglia in the SVZ, the uninjured cortex, and corpus callosum were immunohistochemically analyzed at P10, P20, and P40. The transcriptome of microdissected SVZ and cortical microglia was analyzed at P10 and P20, and the effect of P10 SVZ microglia on neurosphere generation in vitro was studied. RESULTS:The microglial response to HI was region-specific. In the SVZ, a microglial accumulation, prolonged activation and phagocytosis was noted that was not observed in the cortex and corpus callosum. The transcriptome of SVZ microglia and cortical microglia were distinct, and after HI, SVZ microglia concurrently upregulated pro- and anti-inflammatory as well as neurotrophic genes. In vitro, microglia isolated from the SVZ supported neurosphere generation in a concentration-dependent manner. CONCLUSIONS:Microglia are an inherent cellular component of the early postnatal SVZ and undergo developmental changes that are affected on many aspects by neonatal HI injury. Our results demonstrate that early postnatal SVZ microglia are sensitive to HI injury and display a long-lasting region-specific response including neurotrophic features.

SUBMITTER: Fisch U

PROVIDER: S-EPMC6969423 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Neonatal hypoxia-ischemia in rat elicits a region-specific neurotrophic response in SVZ microglia.

Fisch Urs U Brégère Catherine C Geier Florian F Chicha Laurie L Guzman Raphael R

Journal of neuroinflammation 20200118 1

<h4>Background</h4>Recent findings describe microglia as modulators of neurogenesis in the subventricular zone (SVZ). SVZ microglia in the adult rat are thought to adopt a neurotrophic phenotype after ischemic stroke. Early postnatal microglia are endogenously activated and may therefore exhibit an increased sensitivity to neonatal hypoxia-ischemia (HI). The goal of this study was to investigate the impact of cortico-striatal HI on the microglial phenotype, function, and gene expression in the e ...[more]

PMID: 31954397

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Project description:Neonatal hypoxia-ischemia (nHI) is a major cause of death or subsequent disabilities in infants. Hypoxia-ischemia causes brain lesions, which are induced by a strong reduction in oxygen and nutrient supply. Hypothermia is the only validated beneficial intervention, but not all newborns respond to it and today no pharmacological treatment exists. Among possible therapeutic agents to test, trans-resveratrol is an interesting candidate as it has been reported to exhibit neuroprotective effects in some neurodegenerative diseases. This experimental study aimed to investigate a possible neuroprotection by resveratrol in rat nHI, when administered to the pregnant rat female, at a nutritional dose. Several groups of pregnant female rats were studied in which resveratrol was added to drinking water either during the last week of pregnancy, the first week of lactation, or both. Then, 7-day old pups underwent a hypoxic-ischemic event. Pups were followed longitudinally, using both MRI and behavioral testing. Finally, a last group was studied in which breastfeeding females were supplemented 1 week with resveratrol just after the hypoxic-ischemic event of the pups (to test the curative rather than the preventive effect). To decipher the molecular mechanisms of this neuroprotection, RT-qPCR and Western blots were also performed on pup brain samples. Data clearly indicated that when pregnant and/or breastfeeding females were supplemented with resveratrol, hypoxic-ischemic offspring brain lesions were significantly reduced. Moreover, maternal resveratrol supplementation allowed to reverse sensorimotor and cognitive deficits caused by the insult. The best recoveries were observed when resveratrol was administered during both gestation and lactation (2 weeks before the hypoxic-ischemic event in pups). Furthermore, neuroprotection was also observed in the curative group, but only at the latest stages examined. Our hypothesis is that resveratrol, in addition to the well-known neuroprotective benefits via the sirtuin's pathway (antioxidant properties, inhibition of apoptosis), has an impact on brain metabolism, and more specifically on the astrocyte-neuron lactate shuttle (ANLS) as suggested by RT-qPCR and Western blot data, that contributes to the neuroprotective effects.

Dataset Information

Neonatal hypoxia-ischemia in rat elicits a region-specific neurotrophic response in SVZ microglia.

Publications

Neonatal hypoxia-ischemia in rat elicits a region-specific neurotrophic response in SVZ microglia.

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