Oxidative stress and endoplasmic reticulum (ER) stress in the development of neonatal hypoxic–ischaemic brain injury

Birth asphyxia in term neonates affects 1–2/1000 live births and results in the development of hypoxic–ischaemic encephalopathy with devastating life-long consequences. The majority of neuronal cell death occurs with a delay, providing the potential of a treatment window within which to act. Currently, treatment options are limited to therapeutic hypothermia which is not universally successful. To identify new interventions, we need to understand the molecular mechanisms underlying the injury. Here, we provide an overview of the contribution of both oxidative stress and endoplasmic reticulum stress in the development of neonatal brain injury and identify current preclinical therapeutic strategies.

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Oxidative Stress: Major Threat in Traumatic Brain Injury

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180627120501 ◽

2018 ◽

Vol 17 (9) ◽

pp. 689-695 ◽

Cited By ~ 37

Author(s):

Nidhi Khatri ◽

Manisha Thakur ◽

Vikas Pareek ◽

Sandeep Kumar ◽

Sunil Sharma ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Mitochondrial Dysfunction ◽

Calcium Influx ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Physical Assault ◽

Mortality And Morbidity ◽

Primary Injury

Background & Objective: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies. Conclusion: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.

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The LPA-CDK5-Tau Pathway Mediates Neuronal Injury in an In Vitro Model of Ischemia-Reperfusion Insult

10.21203/rs.3.rs-685165/v1 ◽

2021 ◽

Author(s):

Yaya Wang ◽

Jie Zhang ◽

Liqin Huang ◽

Yanhong Mo ◽

Changyu Wang ◽

...

Keyword(s):

Brain Injury ◽

Molecular Mechanisms ◽

Biological Effects ◽

Ischemia Reperfusion ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ischemic Brain ◽

Pathophysiological Process ◽

Vitro Model

Abstract Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

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Silica nanoparticles mediated neuronal cell death in corpus striatum of rat brain: implication of mitochondrial, endoplasmic reticulum and oxidative stress

Journal of Nanoparticle Research ◽

10.1007/s11051-014-2664-z ◽

2014 ◽

Vol 16 (11) ◽

Cited By ~ 16

Author(s):

Arshiya Parveen ◽

Syed Husain Mustafa Rizvi ◽

Farzana Mahdi ◽

Sandeep Tripathi ◽

Iqbal Ahmad ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Silica Nanoparticles ◽

Rat Brain ◽

Corpus Striatum ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

And Oxidative Stress

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Therapeutic Time Window for Edaravone Treatment of Traumatic Brain Injury in Mice

BioMed Research International ◽

10.1155/2013/379206 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 11

Author(s):

Kazuyuki Miyamoto ◽

Hirokazu Ohtaki ◽

Kenji Dohi ◽

Tomomi Tsumuraya ◽

Dandan Song ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Neuronal Death ◽

Time Window ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Therapeutic Time Window

Traumatic brain injury (TBI) is a major cause of death and disability in young people. No effective therapy is available to ameliorate its damaging effects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profile of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0 mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. The production of superoxide radicals (O2∙-) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours after CCI, with oxidative stress and neuronal cell death becoming apparent after 6 hours. Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease inO2∙-levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI.

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Damage to the Endoplasmic Reticulum and Activation of Apoptotic Machinery by Oxidative Stress in Ischemic Neurons

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600005 ◽

2005 ◽

Vol 25 (1) ◽

pp. 41-53 ◽

Cited By ~ 116

Author(s):

Takeshi Hayashi ◽

Atsushi Saito ◽

Shuzo Okuno ◽

Michel Ferrand-Drake ◽

Robert L Dodd ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Neuronal Degeneration ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Wild Type ◽

Transgenic Rats ◽

The Brain

The endoplasmic reticulum (ER), which plays a role in apoptosis, is susceptible to oxidative stress. Because superoxide is produced in the brain after ischemia/reperfusion, oxidative injury to this organelle may be implicated in ischemic neuronal cell death. Activating transcription factor-4 (ATF-4) and C/EBP-homologous protein (CHOP), both of which are involved in apoptosis, are induced by severe ER stress. Using wild-type and human copper/zinc superoxide dismutase transgenic rats, we observed induction of these molecules in the brain after global cerebral ischemia and compared them with neuronal degeneration. In ischemic, wild-type brains, expression of ATF-4 and CHOP was increased in the hippocampal CA1 neurons that would later undergo apoptosis. Transgenic rats had a mild increase in ATF-4 and CHOP and minimal neuronal degeneration, indicating that superoxide was involved in ER stress-induced cell death. We further confirmed attenuation on induction of these molecules in transgenic mouse brains after focal ischemia. When superoxide was visualized with ethidium, signals for ATF-4 and superoxide overlapped in the same cells. Moreover, lipids in the ER were robustly peroxidized by ischemia but were attenuated in transgenic animals. This indicates that superoxide attacked and damaged the ER, and that oxidative ER damage is implicated in ischemic neuronal cell death.

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RIPK1 or RIPK3 deletion prevents progressive neuronal cell death and improves memory function after traumatic brain injury

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01236-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Antonia Clarissa Wehn ◽

Igor Khalin ◽

Marco Duering ◽

Farida Hellal ◽

Carsten Culmsee ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Brain Damage ◽

Molecular Mechanisms ◽

Memory Function ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Interacting Protein ◽

Deficient Mice

AbstractTraumatic brain injury (TBI) causes acute and subacute tissue damage, but is also associated with chronic inflammation and progressive loss of brain tissue months and years after the initial event. The trigger and the subsequent molecular mechanisms causing chronic brain injury after TBI are not well understood. The aim of the current study was therefore to investigate the hypothesis that necroptosis, a form a programmed cell death mediated by the interaction of Receptor Interacting Protein Kinases (RIPK) 1 and 3, is involved in this process. Neuron-specific RIPK1- or RIPK3-deficient mice and their wild-type littermates were subjected to experimental TBI by controlled cortical impact. Posttraumatic brain damage and functional outcome were assessed longitudinally by repetitive magnetic resonance imaging (MRI) and behavioral tests (beam walk, Barnes maze, and tail suspension), respectively, for up to three months after injury. Thereafter, brains were investigated by immunohistochemistry for the necroptotic marker phosphorylated mixed lineage kinase like protein(pMLKL) and activation of astrocytes and microglia. WT mice showed progressive chronic brain damage in cortex and hippocampus and increased levels of pMLKL after TBI. Chronic brain damage occurred almost exclusively in areas with iron deposits and was significantly reduced in RIPK1- or RIPK3-deficient mice by up to 80%. Neuroprotection was accompanied by a reduction of astrocyte and microglia activation and improved memory function. The data of the current study suggest that progressive chronic brain damage and cognitive decline after TBI depend on the expression of RIPK1/3 in neurons. Hence, inhibition of necroptosis signaling may represent a novel therapeutic target for the prevention of chronic post-traumatic brain damage.

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STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury after Stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.169 ◽

2015 ◽

Vol 35 (12) ◽

pp. 2043-2051 ◽

Cited By ~ 21

Author(s):

Joo Eun Jung ◽

Hulya Karatas ◽

Yu Liu ◽

Ayfer Yalcin ◽

Joan Montaner ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Brain Injury ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Glucose Deprivation ◽

Injury Mechanism ◽

Ht22 Cells ◽

Signal Transducers ◽

Human Stroke

Oxidative stress is a major brain injury mechanism after ischemic stroke. 12/15-lipoxygenase (12/15-LOX) is a key mediator of oxidative stress, contributing to neuronal cell death and vascular leakage. Nonetheless, the mechanism leading to its upregulation is currently unknown. We show here that Signal Transducers and Activators of Transcription (STATs), specifically STAT6 and possibly STAT1, increase transcription of 12/15-LOX in neuronal cells. Both p-STAT6 and −1 bound to specific STAT binding sites in the mouse 12/15-LOX promoter. Small interfering RNA (siRNA) knockdown showed STAT6 to be the dominant regulator, reducing 12/15-LOX promoter activation and cell death in oxidatively stressed HT22 cells. STAT6 siRNA efficiently prevented the increase of 12/15-LOX in murine primary neurons, both after induction of oxidative stress and after oxygen-glucose deprivation. Early activation of STAT6 and STAT1 in mice was consistent with a role in regulating 12/15-LOX in focal ischemia. Brains of human stroke patients showed increased p-STAT6 and p-STAT1 in the peri-infarct region, along with 12/15-LOX and markers of apoptosis. These results link STAT6 and STAT1 to the 12/15-LOX damage pathway and suggest disregulation of STAT-dependent transcription as injury mechanism in stroke. Selectively targeting STATs may thus be a novel therapeutic approach to reducing brain injury after a stroke.

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γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/2961079 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Hui-qin Li ◽

Sheng-nan Xia ◽

Si-yi Xu ◽

Pin-yi Liu ◽

Yue Gu ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Ischemic Stroke ◽

Brain Injury ◽

Cerebral Ischemia ◽

Er Stress ◽

Neuronal Apoptosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Neuronal Cell

Ischemic stroke is a severe and acute neurological disorder with limited therapeutic strategies currently available. Oxidative stress is one of the critical pathological factors in ischemia/reperfusion injury, and high levels of reactive oxygen species (ROS) may drive neuronal apoptosis. Rescuing neurons in the penumbra is a potential way to recover from ischemic stroke. Endogenous levels of the potent ROS quencher glutathione (GSH) decrease significantly after cerebral ischemia. Here, we aimed to investigate the neuroprotective effects of γ-glutamylcysteine (γ-GC), an immediate precursor of GSH, on neuronal apoptosis and brain injury during ischemic stroke. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice, neuronal cell lines, and primary neurons. Our data indicated that exogenous γ-GC treatment mitigated oxidative stress, as indicated by upregulated GSH and decreased ROS levels. In addition, γ-GC attenuated ischemia/reperfusion-induced neuronal apoptosis and brain injury in vivo and in vitro. Furthermore, transcriptomics approaches and subsequent validation studies revealed that γ-GC attenuated penumbra neuronal apoptosis by inhibiting the activation of protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1α (IRE1α) in the endoplasmic reticulum (ER) stress signaling pathway in OGD/R-treated cells and ischemic brain tissues. To the best of our knowledge, this study is the first to report that γ-GC attenuates ischemia-induced neuronal apoptosis by suppressing ROS-mediated ER stress. γ-GC may be a promising therapeutic agent for ischemic stroke.

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Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

Current Pharmaceutical Design ◽

10.2174/1381612826666201112144006 ◽

2020 ◽

Vol 26 ◽

Author(s):

Nimra Javaid ◽

Muhammad Ajmal Shah ◽

Azhar Rasul ◽

Zunera Chauhdary ◽

Uzma Saleem ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ellagic Acid ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Acetylcholinesterase Activity ◽

Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

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