Pharmacologic stabilization of hypoxia-inducible transcription factors protects developing mouse brain from hypoxia-induced apoptotic cell death

Trollmann, Regina; Richter, Mandy; Jung, Susan; Walkinshaw, Gail; Brackmann, Florian

doi:10.1016/j.neuroscience.2014.08.019

Cited by 28 publications

(19 citation statements)

References 71 publications

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“…The role of HIF in cell survival from I/R injury has been widely reported 14,15,21,41 . MB significantly increases HIF-1α protein content compared to both normoxic and OGD control groups (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

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Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress

Ryou¹,

Choudhury²,

Li³

et al. 2015

Neuroscience

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Brain ischemia and reperfusion (I/R) injury occurs in various pathological conditions, but there is no effective treatment currently available in clinical practice. Methylene blue (MB) is a century old drug with a newly discovered protective function in the ischemic stroke model. In the current investigation we studied the MB-induced neuroprotective mechanism focusing on stabilization and activation of hypoxia inducible factor-1α (HIF-1α) in an in vitro oxygen and glucose deprivation (OGD)-reoxygenation model. Methods HT22 cells were exposed to OGD (0.1% O2, 6h) and reoxygenation (21% O2, 24h). Cell viability was determined with the calcein AM assay. The dynamic change of intracellular O2 concentration was monitored by fluorescence lifetime imaging microscopy (FLTIM). Glucose uptake was quantified using the 2-[N-(7-Nitrobenz-2-Oxa- 1,3-Diazol-4-yl)Amino]- 2-Deoxy-D-Glucose (2-NBDG) assay. ATP concentration and glycolytic enzyme activity were examined by spectrophotometry. Protein content changes were measured by immunoblot: HIF-1α, prolyl hydroxylase 2(PHD2), erythropoietin (EPO), Akt, mTOR, and PIP5K. The contribution of HIF-1α activation in the MB-induced neuroprotective mechanism was confirmed by blocking HIF-1α activation with 2-methoxyestradiol-2 (2-MeOE2) and by transiently transfecting constitutively active HIF-1α. Results MB increases cell viability by about 50% vs. OGD control. Compared to the corresponding control, MB increases intracellular O2 concentration and glucose uptake as well as the activities of hexokinase and G-6-PDH, and ATP concentration. MB activates the EPO signaling pathway with a corresponding increase in HIF-1α. Phosphorylation of Akt was significantly increased with MB treatment followed by activation of the mTOR pathway. Importantly, we observed, MB increased nuclear translocation of HIF-1α vs. control (about 3 folds), which was shown by a ratio of nuclear:cytoplasmic HIF-1α protein content. Conclusion We conclude that MB protects the hippocampus derived neuronal cells against OGD-reoxygenation injury by enhancing energy metabolism and increasing HIF-1α protein content accompanied by an activation of the EPO signaling pathway.

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Section: Resultsmentioning

confidence: 99%

“…Stabilization of HIF protects O 2 -sensitive organs, such as brain and heart, by mitigating inflammatory 20 and apoptotic 21 responses, but a HIF-1-induced neuronal protective mechanism is not clear. Empirically, outcomes of HIF-1α stabilization and HIF-1 activation seem varied depending on the way HIF-1α is stabilized or activated.…”

Section: Introductionmentioning

confidence: 99%

Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress

Ryou¹,

Choudhury²,

Li³

et al. 2015

Neuroscience

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“…According to our results, DHA may protect the BBB integrity by preserving tight junction protein in response to ischemic injury. Cerebral ischemia induces the neurotoxic environment in brain and it could result in the severe neuronal cell damage, so we investigated the cell death marker such as Bax [62,63], caspase-3[64,65], and iNOS [66,67] in order to examine the protective effect of DHA against the neurotoxicity following ischemic stroke. In present study, DHA treatment reduced the expression of Bax and caspase-3 which is the marker of the mitochondrial cell death and iNOS in ischemic injured brain.…”

Section: Discussionmentioning

confidence: 99%

Dehydroascorbic Acid Attenuates Ischemic Brain Edema and Neurotoxicity in Cerebral Ischemia: An in vivo Study

et al. 2015

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Ischemic stroke results in the diverse phathophysiologies including blood brain barrier (BBB) disruption, brain edema, neuronal cell death, and synaptic loss in brain. Vitamin C has known as the potent anti-oxidant having multiple functions in various organs, as well as in brain. Dehydroascorbic acid (DHA) as the oxidized form of ascorbic acid (AA) acts as a cellular protector against oxidative stress and easily enters into the brain compared to AA. To determine the role of DHA on edema formation, neuronal cell death, and synaptic dysfunction following cerebral ischemia, we investigated the infarct size of ischemic brain tissue and measured the expression of aquaporin 1 (AQP-1) as the water channel protein. We also examined the expression of claudin 5 for confirming the BBB breakdown, and the expression of bcl 2 associated X protein (Bax), caspase-3, inducible nitric oxide synthase (iNOS) for checking the effect of DHA on the neurotoxicity. Finally, we examined postsynaptic density protein-95 (PSD-95) expression to confirm the effect of DHA on synaptic dysfunction following ischemic stroke. Based on our findings, we propose that DHA might alleviate the pathogenesis of ischemic brain injury by attenuating edema, neuronal loss, and by improving synaptic connection.

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“…By contrast, the use of global hypoxia as a model of injury seeks to reduce many of the complex pathological changes caused by ischemia in order to clarify the molecular pathways involved in the arrest or attenuation of oligodendrocyte development in a less biased environment. Specifically, models of acute systemic hypoxia (Strasser et al, 2016; Trollmann et al, 2014) and chronic hypoxia have been able to elicit WMI similar to that observed in preterm infants, interestingly, changes in these models are characterized by differentiation abnormalities rather than decreased cell viability (Buser et al, 2012; Jablonska et al, 2012; Scafidi et al, 2014; Segovia et al, 2008).…”

Section: Introductionmentioning

confidence: 97%

Region specific oligodendrocyte transcription factor expression in a model of neonatal hypoxic injury

Affeldt

Obenaus

Chan

et al. 2017

Intl J of Devlp Neuroscience

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White matter injury (WMI) of prematurity is associated with a spectrum of neurological disorders ranging from mild cognitive and behavioral deficits to cerebral palsy. Translational studies have implicated impaired oligodendrocyte development after hypoxia as the primary cause of WMI, but the underlying mechanisms remain poorly understood. The goal of this study was to identify alterations in the expression of oligodendrocyte precursor cell transcription factors in a mouse model of transient mild global hypoxia. Postnatal day (P) 7 mouse pups were exposed to hypoxia (7.5% O) for 60minutes. We compared oligodendrocyte differentiation and subsequent myelin formation between hypoxia and sham animals at P9, P14 and P28 by examining the expression of key transcription factor regulators of oligodendrocyte differentiation (Ascl1, Olig1, Olig2, and Nkx2.2), as well as APC, a mature oligodendrocyte marker, in the major white matter regions including the corpus callosum, external capsule and anterior commissure. We also examined the effect on myelin formation by examining two myelin specific protein constituents, myelin associated glycoprotein (MAG) and myelin basic protein (MBP), in white matter tracts and whole brain lysate respectively. We found that transient hypoxia at P7 altered the expression of Ascl1, Olig1 and Nkx2.2, resulting in delayed myelination in the external capsule. In addition, our study showed that oligodendrocyte progenitor cells specified several days prior to a hypoxic event are more susceptible to maturation arrest than those specified shortly prior to hypoxia. Our results suggest that alterations of Ascl1, Olig1 and Nkx2.2 underlie impaired oligodendrocyte differentiation and deficient myelination in WMI. These transcription factors are potential therapeutic targets for the treatment of WMI in preterm infants.

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Pharmacologic stabilization of hypoxia-inducible transcription factors protects developing mouse brain from hypoxia-induced apoptotic cell death

Cited by 28 publications

References 71 publications

Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress

Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress

Dehydroascorbic Acid Attenuates Ischemic Brain Edema and Neurotoxicity in Cerebral Ischemia: An in vivo Study

Region specific oligodendrocyte transcription factor expression in a model of neonatal hypoxic injury

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