The common antitussive agent dextromethorphan protects against hyperoxia-induced cell death in established in vivo and in vitro models of neonatal brain injury

Despite the introduction of therapeutic hypothermia, neonatal hypoxic ischemic (HI) brain injury remains a common cause of developmental disability. Development of rational adjuvant therapies to hypothermia requires understanding of the pathways of cell death and survival modulated by HI. The conceptualization of the apoptosis-necrosis “continuum” in neonatal brain injury predicts mechanistic interactions between cell death and hydrid forms of cell death such as programmed or regulated necrosis. Many of the components of the signaling pathway regulating programmed necrosis have been studied previously in models of neonatal HI. In some of these investigations, they participate as part of the apoptotic pathways demonstrating clear overlap of programmed death pathways. Receptor interacting protein (RIP)-1 is at the crossroads between types of cellular death and survival and RIP-1 kinase activity triggers formation of the necrosome (in complex with RIP-3) leading to programmed necrosis. Neuroprotection afforded by the blockade of RIP-1 kinase following neonatal HI suggests a role for programmed necrosis in the HI injury to the developing brain. Here, we briefly review the state of the knowledge about the mechanisms behind programmed necrosis in neonatal brain injury recognizing that a significant proportion of these data derive from experiments in cultured cell and some from in vivo adult animal models. There are still more questions than answers, yet the fascinating new perspectives provided by the understanding of programmed necrosis in the developing brain may lay the foundation for new therapies for neonatal HI.

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Early bedside broadband near-infrared spectroscopy (bNIRS) markers of neonatal brain injury: quantifying oxygenation and in-vivo mitochondrial function

Biophotonics and Biomedical Microscopy ◽

10.1117/12.2584758 ◽

2020 ◽

Author(s):

Ilias Tachtsidis

Keyword(s):

Infrared Spectroscopy ◽

Brain Injury ◽

Near Infrared Spectroscopy ◽

Mitochondrial Function ◽

Near Infrared ◽

Neonatal Brain ◽

Neonatal Brain Injury

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Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury

Nature Communications ◽

10.1038/s41467-021-24469-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhongyuan Bao ◽

Yinlong Liu ◽

Binglin Chen ◽

Zong Miao ◽

Yiming Tu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Lipid Peroxidation ◽

Cell Death ◽

Brain Injury ◽

Neuronal Degeneration ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Prokineticin 2

AbstractProkineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.

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BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury

International Journal of Molecular Sciences ◽

10.3390/ijms222111395 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11395

Author(s):

So Yoon Ahn ◽

Dong Kyung Sung ◽

Yun Sil Chang ◽

Se In Sung ◽

Young Eun Kim ◽

...

Keyword(s):

Stem Cells ◽

Cell Death ◽

Mesenchymal Stem Cells ◽

Brain Injury ◽

Therapeutic Efficacy ◽

Inflammatory Responses ◽

Apoptotic Cell ◽

Glucose Deprivation

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

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Hypoxic Preconditioning Suppresses Glial Activation and Neuroinflammation in Neonatal Brain Insults

Mediators of Inflammation ◽

10.1155/2015/632592 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Chien-Yi Chen ◽

Wei-Zen Sun ◽

Kai-Hsiang Kang ◽

Hung-Chieh Chou ◽

Po-Nien Tsao ◽

...

Keyword(s):

Brain Injury ◽

Inflammatory Responses ◽

Hypoxic Preconditioning ◽

Glial Activation ◽

Neonatal Brain ◽

Mixed Glial Culture ◽

Neonatal Brain Injury ◽

Promising Therapeutic Approach ◽

Hypoxia Ischemia

Perinatal insults and subsequent neuroinflammation are the major mechanisms of neonatal brain injury, but there have been only scarce reports on the associations between hypoxic preconditioning and glial activation. Here we use neonatal hypoxia-ischemia brain injury model in 7-day-old rats andin vitrohypoxia model with primary mixed glial culture and the BV-2 microglial cell line to assess the effects of hypoxia and hypoxic preconditioning on glial activation. Hypoxia-ischemia brain insult induced significant brain weight reduction, profound cell loss, and reactive gliosis in the damaged hemisphere. Hypoxic preconditioning significantly attenuated glial activation and resulted in robust neuroprotection. As early as 2 h after the hypoxia-ischemia insult, proinflammatory gene upregulation was suppressed in the hypoxic preconditioning group.In vitroexperiments showed that exposure to 0.5% oxygen for 4 h induced a glial inflammatory response. Exposure to brief hypoxia (0.5 h) 24 h before the hypoxic insult significantly ameliorated this response. In conclusion, hypoxic preconditioning confers strong neuroprotection, possibly through suppression of glial activation and subsequent inflammatory responses after hypoxia-ischemia insults in neonatal rats. This might therefore be a promising therapeutic approach for rescuing neonatal brain injury.

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Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15606462 ◽

2015 ◽

Vol 36 (6) ◽

pp. 1059-1074 ◽

Cited By ~ 47

Author(s):

Xiaoning Han ◽

Xi Lan ◽

Qiang Li ◽

Yufeng Gao ◽

Wei Zhu ◽

...

Keyword(s):

Cell Death ◽

Brain Injury ◽

Rho Kinase ◽

Receptor Activation ◽

Prostaglandin E ◽

Arterial Blood ◽

Receptor Inhibition ◽

Ep3 Receptor

Prostaglandin E2 EP3 receptor is the only prostaglandin E2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68+ microglia, but increased the number of Ym-1+ M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase–mediated cytotoxicity and proinflammatory responses.

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C-Type Natriuretic Peptide Ameliorates Vascular Injury and Improves Neurological Outcomes in Neonatal Hypoxic-Ischemic Brain Injury in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22168966 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8966

Author(s):

Guofang Shen ◽

Shirley Hu ◽

Zhen Zhao ◽

Lubo Zhang ◽

Qingyi Ma

Keyword(s):

Brain Injury ◽

Natriuretic Peptide ◽

Glucose Deprivation ◽

In Vitro Models ◽

Neurological Deficits ◽

Vascular Protection ◽

The Brain

C-type natriuretic peptide (CNP) is an important vascular regulator that is present in the brain. Our previous study demonstrated the innate neuroprotectant role of CNP in the neonatal brain after hypoxic-ischemic (HI) insults. In this study, we further explored the role of CNP in cerebrovascular pathology using both in vivo and in vitro models. In a neonatal mouse HI brain injury model, we found that intracerebroventricular administration of recombinant CNP dose-dependently reduces brain infarct size. CNP significantly decreases brain edema and immunoglobulin G (IgG) extravasation into the brain tissue, suggesting a vasculoprotective effect of CNP. Moreover, in primary brain microvascular endothelial cells (BMECs), CNP dose-dependently protects BMEC survival and monolayer integrity against oxygen-glucose deprivation (OGD). The vasculoprotective effect of CNP is mediated by its innate receptors NPR2 and NPR3, in that inhibition of either NPR2 or NPR3 counteracts the protective effect of CNP on IgG leakage after HI insult and BMEC survival under OGD. Of importance, CNP significantly ameliorates brain atrophy and improves neurological deficits after HI insults. Altogether, the present study indicates that recombinant CNP exerts vascular protection in neonatal HI brain injury via its innate receptors, suggesting a potential therapeutic target for the treatment of neonatal HI brain injury.

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Altered Cytochrome c Display Precedes Apoptotic Cell Death in Drosophila

The Journal of Cell Biology ◽

10.1083/jcb.144.4.701 ◽

1999 ◽

Vol 144 (4) ◽

pp. 701-710 ◽

Cited By ~ 92

Author(s):

Johnson Varkey ◽

Po Chen ◽

Ronald Jemmerson ◽

John M. Abrams

Keyword(s):

Cell Death ◽

Cytochrome C ◽

Apoptotic Cell ◽

In Vitro Models ◽

Caspase Activity ◽

Caspase Activation ◽

Conditional Expression ◽

Necessary And Sufficient

Drosophila affords a genetically well-defined system to study apoptosis in vivo. It offers a powerful extension to in vitro models that have implicated a requirement for cytochrome c in caspase activation and apoptosis. We found that an overt alteration in cytochrome c anticipates programmed cell death (PCD) in Drosophila tissues, occurring at a time that considerably precedes other known indicators of apoptosis. The altered configuration is manifested by display of an otherwise hidden epitope and occurs without release of the protein into the cytosol. Conditional expression of the Drosophila death activators, reaper or grim, provoked apoptogenic cytochrome c display and, surprisingly, caspase activity was necessary and sufficient to induce this alteration. In cell-free studies, cytosolic caspase activation was triggered by mitochondria from apoptotic cells but identical preparations from healthy cells were inactive. Our observations provide compelling validation of an early role for altered cytochrome c in PCD and suggest propagation of apoptotic physiology through reciprocal, feed-forward amplification involving cytochrome c and caspases.

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