scholarly journals Pyridoxal Isonicotinoyl Hydrazone Improves Neurological Recovery by Attenuating Ferroptosis and Inflammation in Cerebral Hemorrhagic Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Hengli Zhang ◽  
Min Wen ◽  
Jiayu Chen ◽  
Chaojie Yao ◽  
Xiao Lin ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Interleukin 1 ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Chelating Agent ◽  
Underlying Mechanism ◽  
Necrosis Factor Alpha ◽  
Excess Iron

Ferroptosis and inflammation induced by cerebral hemorrhage result in an excessive inflammatory response and irreversible neuronal injury. Alleviating ferroptosis might be an effective way to prevent neuroinflammatory injury and promote neural functional recovery. Pyridoxal isonicotinoyl hydrazine (PIH), a lipophilic iron-chelating agent, has been reported to reduce excess iron-induced cytotoxicity. However, whether PIH could ameliorate the effects of hemorrhagic stroke is not completely understood. In the present study, the preventive effects of PIH in an intracerebral hemorrhage (ICH) mouse model were investigated. Neurological score, rotarod test, and immunofluorescence around the hematoma were assessed to evaluate the effects of PIH on hemorrhagic injury. The involvement of ferroptosis and inflammation was also examined in vitro to explore the underlying mechanism. Results showed that administration of PIH prevented neuronal cell death and reduced lipid peroxidation in Erastin-treated PC-12 cells. In vivo, mice treated with PIH after ICH attenuated neurological deficit scores. Additionally, we found PIH reduced ROS production, iron accumulation, and lipid peroxidation around the hematoma peripheral tissue. Meanwhile, ICH mice treated with PIH showed an upregulation of the key ferroptosis enzyme, glutathione peroxidase 4, and downregulation of cyclooxygenase-2. Moreover, PIH administration inhibited proinflammatory polarization and reduced interleukin-1 beta and tumor necrosis factor alpha in ICH mice. Collectively, these results demonstrated that PIH protects mice against hemorrhage stroke, which was associated with mitigation of inflammation and ferroptosis.

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

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.

scholarly journals The Potential Neuroprotective Role of Free and Encapsulated Quercetin Mediated by miRNA against Neurological Diseases

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1318
Author(s):  
Tarek Benameur ◽  
Raffaella Soleti ◽  
Chiara Porro
Keyword(s):  
Inflammatory Responses ◽  
Pathological Condition ◽  
Neurological Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
In Vivo Studies ◽  
Innovative Drug ◽  
Chronic Neuroinflammation

Chronic neuroinflammation is a pathological condition of numerous central nervous system (CNS) diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis and many others. Neuroinflammation is characterized by the microglia activation and concomitant production of pro-inflammatory cytokines leading to an increasing neuronal cell death. The decreased neuroinflammation could be obtained by using natural compounds, including flavonoids known to modulate the inflammatory responses. Among flavonoids, quercetin possess multiple pharmacological applications including anti-inflammatory, antitumoral, antiapoptotic and anti-thrombotic activities, widely demonstrated in both in vitro and in vivo studies. In this review, we describe the recent findings about the neuroprotective action of quercetin by acting with different mechanisms on the microglial cells of CNS. The ability of quercetin to influence microRNA expression represents an interesting skill in the regulation of inflammation, differentiation, proliferation, apoptosis and immune responses. Moreover, in order to enhance quercetin bioavailability and capacity to target the brain, we discuss an innovative drug delivery system. In summary, this review highlighted an important application of quercetin in the modulation of neuroinflammation and prevention of neurological disorders.

Selective Release of Calpain Produced αII-Spectrin (α-Fodrin) Breakdown Products by Acute Neuronal Cell Death

2002 ◽  
Vol 383 (5) ◽  
pp. 785-791 ◽  
Author(s):  
Satavisha Dutta ◽  
Yuk Chun Chiu ◽  
Albert W. Probert ◽  
Kevin K.W. Wang
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Injury ◽  
Nmda Receptor Antagonist ◽  
Breakdown Product ◽  
Calpain Inhibitor ◽  
Neural Cells

Abstract Activation of calpain results in the breakdown of α II spectrin (αfodrin), a neuronal cytoskeleton protein, which has previously been detected in various in vitro and in vivo neuronal injury models. In this study, a 150 kDa spectrin breakdown product (SBDP150) was found to be released into the cellconditioned media from SHSY5Y cells treated with the calcium channel opener maitotoxin (MTX). SBDP150 release can be readily quantified on immunoblot using an SBDP150- specific polyclonal antibody. Increase of SBDP150 also correlated with cell death in a timedependent manner. MDL28170, a selective calpain inhibitor, was the only protease inhibitor tested that significantly reduced MTXinduced SBDP150 release. The cellconditioned media of cerebellar granule neurons challenged with excitotoxins (NMDA and kainate) also exhibited a significant increase of SBDP150 that was attenuated by pretreatment with an NMDA receptor antagonist, R()-3-(2-carbopiperazine-4-yl)propyl-1- phosphonic acid (CPP), and MDL28170. In addition, hypoxic/hypoglycemic challenge of cerebrocortical cultures also resulted in SBDP150 liberation into the media. These results support the theory that an antibody based detection of SBDP150 in the cellconditioned media can be utilized to quantify injury to neural cells. Furthermore, SBDP150 may potentially be used as a surrogate biomarker for acute neuronal injury in clinical settings.

scholarly journals Evaluation of Antioxidant and Anti-Inflammatory Activity of Anthocyanin-Rich Water-Soluble Aronia Dry Extracts

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4055 ◽  
Author(s):  
Mariusz Banach ◽  
Magdalena Wiloch ◽  
Katarzyna Zawada ◽  
Wojciech Cyplik ◽  
Wojciech Kujawski
Keyword(s):  
Lipid Peroxidation ◽  
Interleukin 1 ◽  
Radical Scavenging ◽  
Water Soluble ◽  
Anthocyanin Content ◽  
Necrosis Factor Alpha ◽  
Paramagnetic Resonance ◽  
Markers Of Inflammation ◽  
Radical Scavenging Properties

Aronia fruits contain many valuable components that are beneficial to human health. However, fruits are characterized by significant variations in chemical composition dependent on the growing conditions and harvesting period. Therefore, there is a need to formulate the extracts with a precisely defined content of health-promoting substances. Aronia dry extracts (ADE) were prepared from frozen pomace applying water extraction, followed by purification and spray-drying. Subsequently, the content of anthocyanins, phenolic acids, and polyphenols was determined. The high-quality chokeberry pomace enabled obtaining extracts with anthocyanin content much higher than the typical market standards. Moreover, it was found that the antioxidant capacity of aronia extracts exceeded those found in other fruit preparations. Antioxidant and free-radical scavenging properties were evaluated using a 2,2′-diphenyl-1-picrylhydrazyl using Electron Paramagnetic Resonance (EPR) spectroscopy (DPPH-EPR) test and Oxygen Radical Absorbance Capacity (ORAC) assay. The inhibition of lipid peroxidation and the level of inflammatory markers have been also investigated using lipopolysaccharide (LPS)-stimulated RAW 264 cells. It was revealed that ADE standardized to 25% of anthocyanins depresses the level of markers of inflammation and lipid peroxidation (Interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and malondialdehyde (MDA)) in in vitro conditions. Additionally, it was confirmed that ADE at all analyzed concentrations did not show any cytotoxic effect as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.

scholarly journals Cylindromatosis mediates neuronal cell death in vitro and in vivo

2018 ◽  
Vol 25 (8) ◽  
pp. 1394-1407 ◽  
Author(s):  
Goutham K. Ganjam ◽  
Nicole Angela Terpolilli ◽  
Sebastian Diemert ◽  
Ina Eisenbach ◽  
Lena Hoffmann ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell

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 Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Youngmun Lee ◽  
Sunyoung Kim ◽  
Yeonsoo Oh ◽  
Young-Mi Kim ◽  
Young-Won Chin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Memory Impairment ◽  
Neuronal Damage ◽  
Biological Activities ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ros Generation ◽  
Garcinia Mangostana

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer’s disease.

Degradation of mutant huntingtin via the ubiquitin/proteasome system is modulated by FE65

2012 ◽  
Vol 443 (3) ◽  
pp. 681-689 ◽  
Author(s):  
Wan Ning Vanessa Chow ◽  
Hon Wing Luk ◽  
Ho Yin Edwin Chan ◽  
Kwok-Fai Lau
Keyword(s):  
Cell Death ◽  
Degradation Mechanism ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Adaptor Protein ◽  
Ubiquitin Proteasome System ◽  
Exon 1 ◽  
Ubiquitin Proteasome

An unstable expansion of the polyglutamine repeat within exon 1 of the protein Htt (huntingtin) causes HD (Huntington's disease). Mounting evidence shows that accumulation of N-terminal mutant Htt fragments is the source of disruption of normal cellular processes which ultimately leads to neuronal cell death. Understanding the degradation mechanism of mutant Htt and improving its clearance has emerged as a new direction in developing therapeutic approaches to treat HD. In the present study we show that the brain-enriched adaptor protein FE65 is a novel interacting partner of Htt. The binding is mediated through WW–polyproline interaction and is dependent on the length of the polyglutamine tract. Interestingly, a reduction in mutant Htt protein level was observed in FE65-knockdown cells, and the process requires the UPS (ubiquitin/proteasome system). Moreover, the ubiquitination level of mutant Htt was found to be enhanced when FE65 is knocked down. Immunofluroescence staining revealed that FE65 associates with mutant Htt aggregates. Additionally, we demonstrated that overexpression of FE65 increases mutant Htt-induced cell death both in vitro and in vivo. These results suggest that FE65 facilitates the accumulation of mutant Htt in cells by preventing its degradation via the UPS, and thereby enhances the toxicity of mutant Htt.

scholarly journals Absence of cytotoxicity towards microglia of iron oxide (α-Fe2O3) nanorhombohedra

2016 ◽  
Vol 5 (3) ◽  
pp. 836-847 ◽  
Author(s):  
Crystal S. Lewis ◽  
Luisa Torres ◽  
Jeremy T. Miyauchi ◽  
Cyrus Rastegar ◽  
Jonathan M. Patete ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Necrosis Factor Alpha ◽  
Cytotoxic Effects ◽  
Nanoparticle Exposure ◽  
Cellular Iron ◽  
Therapeutic Setting ◽  
The Central Nervous System ◽  
Factor Alpha

Abstract Understanding the nature of interactions between nanomaterials, such as commercially ubiquitous hematite (α-Fe2O3) nanorhombohedra (N-Rhomb) and biological systems is of critical importance for gaining insight into the practical applicability of nanomaterials. Microglia represent the first line of defense in the central nervous system (CNS) during severe injury or disease such as Parkinson's and Alzheimer's disease as illustrative examples. Hence, to analyze the potential cytotoxic effect of N-Rhomb exposure in the presence of microglia, we have synthesized Rhodamine B (RhB)-labeled α-Fe2O3 N-Rhomb, with lengths of 47 ± 10 nm and widths of 35 ± 8 nm. Internalization of RhB-labeled α-Fe2O3 N-Rhomb by microglia in the mouse brain was observed, and a dose-dependent increase in the cellular iron content as probed by cellular fluorescence was detected in cultured microglia after nanoparticle exposure. The cells maintained clear functional viability, exhibiting little to no cytotoxic effects after 24 and 48 hours at acceptable, physiological concentrations. Importantly, the nanoparticle exposure did not induce microglial cells to produce either tumor necrosis factor alpha (TNFα) or interleukin 1-beta (IL1β), two pro-inflammatory cytokines, nor did exposure stimulate the production of nitrites and reactive oxygen species (ROS), which are common indicators for the onset of inflammation. Finally, we propose that under the conditions of our experiments, i.e. in the presence of RhB labeled-α-Fe2O3 N-Rhomb maintaining concentrations of up to 100 μg mL−1 after 48 hours of incubation, the in vitro and in vivo internalization of RhB-labeled α-Fe2O3 N-Rhomb are likely to be clathrin-dependent, which represents a conventional mechanistic uptake route for most cells. Given the crucial role that microglia play in many neurological disorders, understanding the potential cytotoxic effects of these nanostructures is of fundamental importance if they are to be used in a therapeutic setting.

scholarly journals The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Solomon Habtemariam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Rosmarinus Officinalis ◽  
Brain Inflammation ◽  
Important Species

Rosemary (Rosmarinus officinalisL.) is one of the most economically important species of the family Lamiaceae. Native to the Mediterranean region, the plant is now widely distributed all over the world mainly due to its culinary, medicinal, and commercial uses including in the fragrance and food industries. Among the most important group of compounds isolated from the plant are the abietane-type phenolic diterpenes that account for most of the antioxidant and many pharmacological activities of the plant. Rosemary diterpenes have also been shown in recent years to inhibit neuronal cell death induced by a variety of agents bothin vitroandin vivo. The therapeutic potential of these compounds for Alzheimer’s disease (AD) is reviewed in this communication by giving special attention to the chemistry of the compounds along with the various pharmacological targets of the disease. The multifunctional nature of the compounds from the general antioxidant-mediated neuronal protection to other specific mechanisms including brain inflammation and amyloid beta (Aβ) formation, polymerisation, and pathologies is discussed.

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