Hypoxia-inducible factor-1α regulates microglial functions affecting neuronal survival in the acute phase of ischemic stroke in mice

Bok, Seoyeon; Kim, Young Eun; Woo, Youngsik; Kim, Soeun; Kang, Suk‐Jo; Lee, Yoontae; Ahn, G‐One

doi:10.18632/oncotarget.22851

Cited by 49 publications

(36 citation statements)

References 32 publications

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“…In line with this negative role for HIF-1, its myeloid-specific knock-out in mice has been shown to reduce neuronal and microglial death following hypoxia, lowering inflammation, and improving behavioral recovery [72]. Likewise, the knockdown of HIF-1 was sufficient to elicit an anti-inflammatory effect in BV2 cells exposed to CoCl 2 [72].…”

Section: Discussionmentioning

confidence: 92%

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

et al. 2020

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Melatonin exerts direct neuroprotection against cerebral hypoxic damage, but the mechanisms of its action on microglia have been less characterized. Using both in vitro and in vivo models of hypoxia, we here focused on the role played by silent mating type information regulation 2 homolog 1 (SIRT1) in melatonin’s effects on microglia. Viability of rat primary microglia or microglial BV2 cells and SH-SY5Y neurons was significantly reduced after chemical hypoxia with CoCl2 (250 μM for 24 h). Melatonin (1 μM) significantly attenuated CoCl2 toxicity on microglia, an effect prevented by selective SIRT1 inhibitor EX527 (5 μM) and AMP-activated protein kinase (AMPK) inhibitor BML-275 (2 μM). CoCl2 did not modify SIRT1 expression, but prevented nuclear localization, while melatonin appeared to restore it. CoCl2 induced nuclear localization of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-kB), an effect contrasted by melatonin in an EX527-dependent fashion. Treatment of microglia with melatonin attenuated potentiation of neurotoxicity. Common carotid occlusion was performed in p7 rats, followed by intraperitoneal injection of melatonin (10 mg/kg). After 24 h, the number of Iba1+ microglia in the hippocampus of hypoxic rats was significantly increased, an effect not prevented by melatonin. At this time, SIRT1 was only detectable in the amoeboid, Iba1+ microglial population selectively localized in the corpus callosum. In these cells, nuclear localization of SIRT1 was significantly lower in hypoxic animals, an effect prevented by melatonin. NF-kB showed an opposite expression pattern, where nuclear localization in Iba1+ cells was significantly higher in hypoxic, but not in melatonin-treated animals. Our findings provide new evidence for a direct effect of melatonin on hypoxic microglia through SIRT1, which appears as a potential pharmacological target against hypoxic-derived neuronal damage.

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Section: Discussionmentioning

confidence: 92%

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

et al. 2020

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“…Furthermore, other cell types, such as amacrine, horizontal, bipolar and microglial cells, contribute to the NO production during ischaemic proliferative retinopathy . Microglia are an essential mediator of neuroinflammation in many neurological disorders and are susceptible to HIF‐1α . Likewise, there are reports that describe that besides oligodendrocytes, the microglia are the glial cell types most susceptible to hypoxia and are extremely sensitive to their microenvironment .…”

Section: Discussionmentioning

confidence: 99%

iNOS‐inhibitor driven neuroprotection in a porcine retina organ culture model

Hurst

Mueller‐Buehl

Hofmann

et al. 2020

J Cellular Molecular Medi

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Since 1995, 11 million animals per year were used for research purposes in the EU, an average of 2.5 million in Germany alone, with an upward trend. 1 Ophthalmological research also frequently uses laboratory animals. An important field of research is the understanding of retinal degeneration, as its causes are not yet fully understood preventing successful treatment.In the last years, we developed retinal organ culture models, to test new therapies without euthanasia of laboratory animals. [2][3][4][5] These models are based on porcine retinae, which can be obtained as a waste product from the food industry. The morphology and AbstractNitrite oxide plays an important role in the pathogenesis of various retinal diseases, especially when hypoxic processes are involved. This degeneration can be simulated by incubating porcine retinal explants with CoCl 2 . Here, the therapeutic potential of iNOS-inhibitor 1400W was evaluated. Degeneration through CoCl 2 and treatment with the 1400W were applied simultaneously to porcine retinae explants.Three groups were compared: control, CoCl 2 , and CoCl 2 + iNOS-inhibitor (1400W).At days 4 and 8, retinal ganglion cells (RGCs), bipolar, and amacrine cells were analysed. Furthermore, the influence on the glia cells and different stress markers were evaluated. Treatment with CoCl 2 resulted in a significant loss of RGCs already after 4 days, which was counteracted by the iNOS-inhibitor. Expression of HIF-1α and its downstream targets confirmed the effective treatment with 1400W. After 8 days, the CoCl 2 group displayed a significant loss in amacrine cells and also a drastic reduction in bipolar cells was observed, which was prevented by 1400W. The decrease in microglia could not be prevented by the inhibitor. CoCl 2 induces strong degeneration in porcine retinae by mimicking hypoxia, damaging certain retinal cell types.Treatment with the iNOS-inhibitor counteracted these effects to some extent, by preventing loss of retinal ganglion and bipolar cells. Hence, this inhibitor seems to be a very promising treatment for retinal diseases. K E Y W O R D S hypoxia, iNOS-inhibitor 1400W, organ culture, retina, retinal ganglion cells | 4313 HURST eT al. How to cite this article: Hurst J, Mueller-Buehl AM, Hofmann L, et al. iNOS-inhibitor driven neuroprotection in a porcine retina organ culture model. J Cell Mol Med. 2020;24:4312-4323. https://doi.

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“…Upregulation of HO-1 attenuated pro-inflammatory cytokine production by microvascular endothelium. HIF1 activation upregulated phagocytic activities in microglia selectively under hypoxic conditions, regulating the functions of microglia such as chemotaxis and production of cytokines or ROS ( Bok et al, 2017 ).…”

Section: Hif and Phd Pharmacological Modulation In Ischaemic Strokementioning

confidence: 99%

Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors

Chen

Lai

Zhu³

et al. 2018

Front. Cell Dev. Biol.

189

137

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Hypoxia inducible factor (HIF) is the master oxygen sensor within cells and is central to the regulation of cell responses to varying oxygen levels. HIF activation during hypoxia ensures optimum ATP production and cell integrity, and is associated both directly and indirectly with reactive oxygen species (ROS) formation. HIF activation can either reduce ROS formation by suppressing the function of mitochondrial tricarboxylic acid cycle (TCA cycle), or increase ROS formation via NADPH oxidase (NOX), a target gene of HIF pathway. ROS is an unavoidable consequence of aerobic metabolism. In normal conditions (i.e., physioxia), ROS is produced at minimal levels and acts as a signaling molecule subject to the dedicated balance between ROS production and scavenging. Changes in oxygen concentrations affect ROS formation. When ROS levels exceed defense mechanisms, ROS causes oxidative stress. Increased ROS levels can also be a contributing factor to HIF stabilization during hypoxia and reoxygenation. In this review, we systemically review HIF activation and ROS formation in the brain during hypoxia and hypoxia/reoxygenation. We will then explore the literature describing how changes in HIF levels might provide pharmacological targets for effective ischaemic stroke treatment. HIF accumulation in the brain via HIF prolyl hydroxylase (PHD) inhibition is proposed as an effective therapy for ischaemia stroke due to its antioxidation and anti-inflammatory properties in addition to HIF pro-survival signaling. PHD is a key regulator of HIF levels in cells. Pharmacological inhibition of PHD increases HIF levels in normoxia (i.e., at 20.9% O2 level). Preconditioning with HIF PHD inhibitors show a neuroprotective effect in both in vitro and in vivo ischaemia stroke models, but post-stroke treatment with PHD inhibitors remains debatable. HIF PHD inhibition during reperfusion can reduce ROS formation and activate a number of cellular survival pathways. Given agents targeting individual molecules in the ischaemic cascade (e.g., antioxidants) fail to be translated in the clinic setting, thus far, HIF pathway targeting and thereby impacting entire physiological networks is a promising drug target for reducing the adverse effects of ischaemic stroke.

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Hypoxia-inducible factor-1α regulates microglial functions affecting neuronal survival in the acute phase of ischemic stroke in mice

Cited by 49 publications

References 32 publications

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

iNOS‐inhibitor driven neuroprotection in a porcine retina organ culture model

Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors

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