scholarly journals Arc silence aggravates traumatic neuronal injury via mGluR1-mediated ER stress and necroptosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tao Chen ◽  
Jie Zhu ◽  
Yu-Hai Wang ◽  
Chun-Hua Hang
Keyword(s):  
Western Blot ◽  
Er Stress ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Associated Factors ◽  
Metabotropic Glutamate Receptor ◽  
Neuronal Injury ◽  
Early Gene ◽  
Neurological Deficits

AbstractDelayed neuronal death is associated with neurological deficits and mortality after traumatic brain injury (TBI), where post-synaptic density (PSD) proteins are thought to play key roles. The immediate-early gene (IEG) coded protein Arc is a brain-specific PSD protein that controls synaptic plasticity and learning behaviors. In this study, we investigated the expression and biological function of Arc in neuronal death after TBI in an in vitro model mimicked by traumatic neuronal injury (TNI) in cortical neurons. TNI caused a temporal increase of Arc expression at 3 and 6 h. Knockdown of Arc expression using small interfering RNA (Si-Arc-3) promoted TNI-induced cytotoxicity and apoptosis. The results of western blot showed that Si-Arc-3 transfection further enhanced the activation of endoplasmic reticulum (ER) stress-associated factors, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and caspase-12 after TNI. In addition, knockdown of Arc significantly increased expression of (receptor-interacting protein kinase 1) RIP1 and the number of necroptotic cells, which were apparently prevented by necrostatin-1 (Nec-1). The results of immunostaining and western blot showed that knockdown of Arc activated the metabotropic glutamate receptor 1 (mGluR1) and intracellular Ca2+ release in neurons. Mechanistically, the Si-Arc-3-induced activation of ER stress-associated factors, RIP1 expression, apoptosis, and necroptosis were partially reversed by the mGluR1 antagonist AIDA. In summary, our data suggest that silence of Arc expression aggravates neuronal death after TNI by promoting apoptosis and necroptosis. These data support for the first time that Arc may represent a novel candidate for therapies against TBI.

scholarly journals TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yan Zhou ◽  
Tao Tao ◽  
Guangjie Liu ◽  
Xuan Gao ◽  
Yongyue Gao ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Therapeutic Target ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Early Brain Injury ◽  
Neurological Deficits ◽  
Human Brain Tissue

AbstractNeuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

scholarly journals The Carbamate, Physostigmine does not Impair Axonal Transport in Rat Cortical Neurons

2021 ◽  
Vol 16 ◽  
pp. 263310552110202
Author(s):  
Sean X Naughton ◽  
Wayne D Beck ◽  
Zhe Wei ◽  
Guangyu Wu ◽  
Peter W Baas ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Cortical Neurons ◽  
Acetylcholinesterase Inhibitors ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Rat Cortical Neurons ◽  
Toxicological Mechanism

Among the various chemicals that are commonly used as pesticides, organophosphates (OPs), and to a lesser extent, carbamates, are most frequently associated with adverse long-term neurological consequences. OPs and the carbamate, pyridostigmine, used as a prophylactic drug against potential nerve agent attacks, have also been implicated in Gulf War Illness (GWI), which is often characterized by chronic neurological symptoms. While most OP- and carbamate-based pesticides, and pyridostigmine are relatively potent acetylcholinesterase inhibitors (AChEIs), this toxicological mechanism is inadequate to explain their long-term health effects, especially when no signs of acute cholinergic toxicity are exhibited. Our previous work suggests that a potential mechanism of the long-term neurological deficits associated with OPs is impairment of axonal transport (AXT); however, we had not previously evaluated carbamates for this effect. Here we thus evaluated the carbamate, physostigmine (PHY), a highly potent AChEI, on AXT using an in vitro neuronal live imaging assay that we have previously found to be very sensitive to OP-related deficits in AXT. We first evaluated the OP, diisopropylfluorophosphate (DFP) (concentration range 0.001-10.0 µM) as a reference compound that we found previously to impair AXT and subsequently evaluated PHY (concentration range 0.01-100 nM). As expected, DFP impaired AXT in a concentration-dependent manner, replicating our previously published results. In contrast, none of the concentrations of PHY (including concentrations well above the threshold for impairing AChE) impaired AXT. These data suggest that the long-term neurological deficits associated with some carbamates are not likely due to acute impairments of AXT.

scholarly journals Biochanin A Alleviates Cerebral Ischemia/Reperfusion Injury by Suppressing Endoplasmic Reticulum Stress-Induced Apoptosis and p38MAPK Signaling Pathway In Vivo and In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Min-min Guo ◽  
Sheng-biao Qu ◽  
Hui-ling Lu ◽  
Wen-bo Wang ◽  
Mu-Liang He ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Biochanin A ◽  
Neurological Deficits ◽  
Mapk Phosphorylation ◽  
Cerebral Ischemia Reperfusion

We have previously shown that biochanin A exhibits neuroprotective properties in the context of cerebral ischemia/reperfusion (I/R) injury. The mechanistic basis for such properties, however, remains poorly understood. This study was therefore designed to explore the manner whereby biochanin A controls endoplasmic reticulum (ER) stress, apoptosis, and inflammation within fetal rat primary cortical neurons in response to oxygen-glucose deprivation/reoxygenation (OGD/R) injury, and in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury. For the OGD/R in vitro model system, cells were evaluated after a 2 h OGD following a 24 h reoxygenation period, whereas in vivo neurological deficits were evaluated following 2 h of ischemia and 24 h of reperfusion. The expression of proteins associated with apoptosis, ER stress (ERS), and p38 MAPK phosphorylation was evaluated in these samples. Rats treated with biochanin A exhibited reduced neurological deficits relative to control rats following MCAO/R injury. Additionally, GRP78 and CHOP levels rose following I/R modeling both in vitro and in vivo, whereas biochanin A treatment was associated with reductions in CHOP levels but further increases in GRP78 levels. In addition, OGD/R or MCAO/R were associated with markedly enhanced p38 MAPK phosphorylation that was alleviated by biochanin A treatment. Similarly, OGD/R or MCAO/R injury resulted in increases in caspase-3, caspase-12, and Bax levels as well as decreases in Bcl-2 levels, whereas biochanin A treatment was sufficient to reverse these phenotypes. Together, these findings thus demonstrate that biochanin A can alleviate cerebral I/R-induced damage at least in part via suppressing apoptosis, ER stress, and p38 MAPK signaling, thereby serving as a potent neuroprotective agent.

scholarly journals Glucose Deprivation Neuronal Injury in vitro is Modified by Withdrawal of Extracellular Glutamine

1990 ◽  
Vol 10 (3) ◽  
pp. 337-342 ◽  
Author(s):  
Hannelore Monyer ◽  
Dennis W. Choi
Keyword(s):  
Cortical Neurons ◽  
Excitatory Amino Acids ◽  
Neuronal Loss ◽  
Nmda Antagonist ◽  
Neuronal Injury ◽  
Glucose Deprivation ◽  
Glutamine Concentration ◽  
Energy Substrate ◽  
Cultured Cortical Neurons

Cultured cortical neurons deprived of glucose in a defined solution containing 2 m M glutamine became acutely swollen and went on to degenerate over the next day; this neuronal loss could be substantially attenuated by an N-methyl-D-aspartate (NMDA) antagonist. Removal of extracellular glutamine produced two effects: an increase in overall neuronal injury and a decrease in the protective effect of an NMDA antagonist. Both effects of glutamine removal were glutamine concentration dependent (EC50 for both ∼300 μ M) and not reversed by substitution of equimolar concentrations of alanine or arginine. These observations suggest that glucose deprivation neuronal injury may be tonically regulated by the presence of extracellular glutamine. We speculate that glutamine may reduce overall injury by serving as an energy substrate in the absence of glucose, but may increase NMDA receptor-mediated injury by serving as a precursor for transmitter excitatory amino acids.

scholarly journals Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Veronica Granatiero ◽  
Marco Pacifici ◽  
Anna Raffaello ◽  
Diego De Stefani ◽  
Rosario Rizzuto
Keyword(s):  
Cell Fate ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Calcium Uniporter ◽  
Organelle Morphology

Neurodegenerative diseases are a large and heterogeneous group of disorders characterized by selective and progressive death of specific neuronal subtypes. In most of the cases, the pathophysiology is still poorly understood, although a number of hypotheses have been proposed. Among these, dysregulation of Ca2+ homeostasis and mitochondrial dysfunction represent two broadly recognized early events associated with neurodegeneration. However, a direct link between these two hypotheses can be drawn. Mitochondria actively participate to global Ca2+ signaling, and increases of [Ca2+] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca2+ waves. Most importantly, while mitochondrial Ca2+ overload has been proposed as the no-return signal, triggering apoptotic or necrotic neuronal death, until now direct evidences supporting this hypothesis, especially in vivo, are limited. Here, we took advantage of the identification of the mitochondrial Ca2+ uniporter (MCU) and tested whether mitochondrial Ca2+ signaling controls neuronal cell fate. We overexpressed MCU both in vitro, in mouse primary cortical neurons, and in vivo, through stereotaxic injection of MCU-coding adenoviral particles in the brain cortex. We first measured mitochondrial Ca2+ uptake using quantitative genetically encoded Ca2+ probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca2+ uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca2+ overload causes alteration of organelle morphology and dysregulation of global Ca2+ homeostasis. Most importantly, MCU overexpression in vivo is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca2+ overload is per se sufficient to cause neuronal cell death both in vitro and in vivo, thus highlighting a potential key step in neurodegeneration.

scholarly journals Lapatinib protects against epileptic seizures via halting glutathione peroxidase 4-dependent ferroptosis

2020 ◽  
Author(s):  
Jining Jia ◽  
Qin Li ◽  
Qianyi Sun ◽  
Nan Yang ◽  
Kangni Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Glutathione Peroxidase ◽  
Western Blot ◽  
Neuronal Death ◽  
Epileptic Seizures ◽  
List Type ◽  
Dominant Form ◽  
Neuroprotective Strategy

ABSTRACTBackground and PurposeRepetitive epileptic seizures trigger massive neuronal death. Therefore, neuroprotection plays a role in preventing neuronal death and inversely suppresses seizure generation. Additionally, some studies have shown ferroptosis, featured by lipid peroxidation (a dominant form of oxidative stress in the brain), is of paramount importance in epileptic seizures. Lapatinib can play a first-line anti-tumor role by targeting oxidative stress and a recent work illustrates the improvement of encephalomyelitis in rodent models after lapatinib treatment. We hypothesize whether lapatinib can protect against ferroptosis in epileptic seizures via regulating lipid peroxidation.Experimental ApproachThe epileptic behavior of the mice was recorded after intracranial injection of KA. Western blot and RT-qPCR were used to detect the protein expression of 4-hydroxynonenal (4-HNE) and glutathione peroxidase 4 (GPX4) and the mRNA expression of prostaglandin endoperoxide synthase 2 (PTGS2) in vivo and in vitro. The level of lipid reactive oxygen species (lipid ROS) in cells pretreated with lapatinib was analyzed by flow cytometry.Key ResultsLapatinib remarkably prevented KA-induced epileptic seizures in mice and ferroptosis was involved in the neuroprotection of lapatinib. Compared with the model group, western blot showed that lapatinib significantly upregulated the levels of GPX4. In the ferroptotic cell death model, lapatinib exerted neuroprotection via up-regulating GPX4. Treatment with Ras-selective lethal small molecule 3 (RSL3), a selective GPX4 inhibitor abrogated its anti-ferroptotic potential.Conclusions and ImplicationsThese results illustrated that lapatinib has neuroprotective potential against KA-triggered epileptic seizures via suppressing GPX4-dependent ferroptosis.What is already knownActivation of ferroptosis occurs in epileptic seizures.What this study addsLapatinib protects brain against epileptic seizures via blocking ferroptosis.GPX4-dependent ferroptosis is involved in the neuroprotection of lapatinib.What is the clinical significanceInhibition of ferroptosis by lapatinib represents a potential neuroprotective strategy for epileptic patients.

The AMPAR antagonist perampanel regulates neuronal necroptosis via Akt/GSK3β signaling after acute traumatic injury in cortical neurons

2020 ◽  
Vol 19 ◽  
Author(s):  
Tao Chen ◽  
Li-Kun Yang ◽  
Jie Zhu ◽  
Chun-Hua Hang ◽  
Yu-Hai Wang
Keyword(s):  
Traumatic Brain Injury ◽  
Protective Effect ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Therapeutic Potential ◽  
Traumatic Injury ◽  
Neuroprotective Effects ◽  
Stroke Models ◽  
Cultured Cortical Neurons

Background: Perampanel is a highly selective and non-competitive α-amino-3-hydroxy-5 -methyl-4-isoxazole propionate (AMPA) receptor (AMPAR) antagonist, which has been licensed as an orally administered antiepileptic drug in more than 55 countries. Recently, perampanel was found to exert neuroprotective effects in hemorrhagic and ischemic stroke models. Objective: In this study, the protective effect of perampanel was investigated. Method: The protective effect of perampanel was investigated in an in vitro traumatic neuronal injury (TNI) model in primary cultured cortical neurons. Conclusion: Our present data suggest that necroptosis plays a key role in the pathogenesis of neuronal death after TNI, and that perampanel might have therapeutic potential for patients with traumatic brain injury (TBI).

Butylparaben Induces the Neuronal Death Through the ER Stress-Mediated Apoptosis of Primary Cortical Neurons

2022 ◽  
Author(s):  
Moon Yi Ko ◽  
Sung-Ae Hyun ◽  
Sumi Jang ◽  
Joung-Wook Seo ◽  
Jaerang Rho ◽  
...  
Keyword(s):  
Er Stress ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Primary Cortical Neurons

scholarly journals A1 adenosine receptors mediate hypoglycemia-induced neuronal injury

2004 ◽  
Vol 32 (1) ◽  
pp. 129-144 ◽  
Author(s):  
CP Turner ◽  
MR Blackburn ◽  
SA Rivkees
Keyword(s):  
Adenosine Receptors ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Caspase 3 ◽  
Neuronal Injury ◽  
Glucose Deprivation ◽  
Cellular Mechanisms ◽  
Neuronal Viability ◽  
Rat Cortical Neurons ◽  
A1 Adenosine Receptors

The cellular mechanisms that lead to neuronal death following glucose deprivation are not known, although it is recognized that hypoglycemia can lead to perturbations in intracellular calcium ([Ca2+]i) levels. Recently, activation of A1 adenosine receptors (A1AR) has been shown to alter [Ca2+]i and promote neuronal death. Thus, we examined if A1AR activation contributes to hypoglycemia-induced neuronal injury using rat cortical neurons. First, we observed that hypoglycemia was associated with large increases in neuronal adenosine release. Next, decreased neuronal viability was seen with progressive reduction in glucose concentration (25, 6, 3, 0.75 and 0 mM). Using the calcium-sensitive dye, Fluo-3, we observed both acute and long-term changes in relative [Ca2+]i during hypoglycemic conditions. Demonstrating a role for adenosine in this process, both the loss in neuronal viability and the early changes in [Ca2+]i were reversed by treatment with A1AR antagonists (8-cyclopentyl, 1,3-dipropylxanthine; 9-chloro-2-(2-furyl)(1,2,4)-triazolo(1,5-c)quinazolin-5-amine; and N-cyclopentyl-9-methyladenine). We also found that hypoglycemia induced the expression of the pro-apoptotic enzyme, caspase-3, and that A1AR antagonism reversed hypoglycemia-induced caspase-3 activity. Collectively, these data show that hypoglycemia induces A1ARs activation leading to alterations in [Ca2+]i, which plays a prominent role in leading to hypoglycemia-induced neuronal death.

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