Marine Compound Xyloketal B as a Potential Drug Development Target for Neuroprotection

Xyloketal B is a natural compound isolated from the mangrove fungus, Xylaria sp. in the South China Sea. In the past decade, studies have shown that xyloketal B exhibits anti-oxidative, anti-inflammatory, and anti-apoptotic abilities and may serve as a treatment for ischemic stroke. Xyloketal B has been shown to interact with both neurons and residential microglial cells and regulate a number of proteins involved in the apoptotic events during ischemia. Such mechanisms include inhibition of specific NADPH oxidase subunits, upregulation of HO-1, increase of Bcl-1/Bax ratio, and downregulation of TLR4 receptor. Both in vitro and in vivo stroke models have validated its potential in preventing ischemia-induced neuronal cell death. This review summarizes our current understanding of the effects of xyloketal B in ischemic conditions. As stroke ranks second in the causes of mortality worldwide and still lacks effective treatment, it is necessary to seek novel therapeutic options. Understanding the role of xyloketal B in ischemic stroke could reveal a new aspect of stroke treatment.

Download Full-text

miR-214 Alleviates Ischemic Stroke-Induced Neuronal Death by Targeting DAPK1 in Mice

Frontiers in Neuroscience ◽

10.3389/fnins.2021.649982 ◽

2021 ◽

Vol 15 ◽

Author(s):

Yan Shi ◽

Tian Tian ◽

Er-Li Cai ◽

Can Yang ◽

Xin Yang

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Neuronal Death ◽

Therapeutic Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Neurological Deficits ◽

Tunel Staining

BackgroundIschemic stroke induces neuronal cell death and causes brain dysfunction. Preventing neuronal cell death after stroke is key to protecting the brain from stroke damage. Nevertheless, preventative measures and treatment strategies for stroke damage are scarce. Emerging evidence suggests that microRNAs (miRNAs) play critical roles in the pathogenesis of central nervous system (CNS) disorders and may serve as potential therapeutic targets.MethodsA photochemically induced thrombosis (PIT) mouse model was used as an ischemic stroke model. qRT-PCR was employed to assess changes in miRNAs in ischemic lesions of PIT-stroke mice and primary cultured neurons subjected to oxygen-glucose deprivation (OGD). 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed to evaluate brain infarction tissues in vivo. TUNEL staining was employed to assess neuronal death in vitro. Neurological scores and motor coordination were investigated to evaluate stroke damage, including neurological deficits and motor function.ResultsIn vivo and in vitro results demonstrated that levels of miR-124 were significantly decreased following stroke, whereas changes in death-associated protein kinase 1 (DAPK1) levels exhibited the converse pattern. DAPK1 was identified as a direct target of miR-124. N-methyl-D-aspartate (NMDA) and OGD-induced neuronal death was rescued by miR-124 overexpression. Upregulation of miR-124 levels significantly improved PIT-stroke damage, including the overall neurological function in mice.ConclusionWe demonstrate the involvement of the miR-124/DAPK1 pathway in ischemic neuronal death. Our results highlight the therapeutic potential of targeting this pathway for ischemic stroke.

Download Full-text

Metabolome Changes in Cerebral Ischemia

Cells ◽

10.3390/cells9071630 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1630 ◽

Cited By ~ 4

Author(s):

Tae Hwan Shin ◽

Da Yeon Lee ◽

Shaherin Basith ◽

Balachandran Manavalan ◽

Man Jeong Paik ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

In Vitro Models ◽

Experimental Models ◽

Metabolic Changes ◽

Metabolic Disturbances

Cerebral ischemia is caused by perturbations in blood flow to the brain that trigger sequential and complex metabolic and cellular pathologies. This leads to brain tissue damage, including neuronal cell death and cerebral infarction, manifesting clinically as ischemic stroke, which is the cause of considerable morbidity and mortality worldwide. To analyze the underlying biological mechanisms and identify potential biomarkers of ischemic stroke, various in vitro and in vivo experimental models have been established investigating different molecular aspects, such as genes, microRNAs, and proteins. Yet, the metabolic and cellular pathologies of ischemic brain injury remain not fully elucidated, and the relationships among various pathological mechanisms are difficult to establish due to the heterogeneity and complexity of the disease. Metabolome-based techniques can provide clues about the cellular pathologic status of a condition as metabolic disturbances can represent an endpoint in biological phenomena. A number of investigations have analyzed metabolic changes in samples from cerebral ischemia patients and from various in vivo and in vitro models. We previously analyzed levels of amino acids and organic acids, as well as polyamine distribution in an in vivo rat model, and identified relationships between metabolic changes and cellular functions through bioinformatics tools. This review focuses on the metabolic and cellular changes in cerebral ischemia that offer a deeper understanding of the pathology underlying ischemic strokes and contribute to the development of new diagnostic and therapeutic approaches.

Download Full-text

Down-Regulation of Lncrna MALAT1 Attenuates Neuronal Cell Death Through Suppressing Beclin1-Dependent Autophagy by Regulating Mir-30a in Cerebral Ischemic Stroke

Cellular Physiology and Biochemistry ◽

10.1159/000480337 ◽

2017 ◽

Vol 43 (1) ◽

pp. 182-194 ◽

Cited By ~ 71

Author(s):

Dong Guo ◽

Ji Ma ◽

Lei Yan ◽

Tengfei Li ◽

Zhiguo Li ◽

...

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Ischemic Injury ◽

Down Regulation ◽

Cerebral Ischemic Stroke ◽

Cerebral Ischemic

Background/Aims: LncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was reported to be highly expressed in an in vitro mimic of ischemic stroke conditions. However, the exact biological role of MALAT1 and its underlying mechanism in ischemic stroke remain to be elucidated. Methods: The roles of MALAT1 and miR-30a on cell death and infarct volume and autophagy were evaluated in experimental ischemic stroke. The relationships between miR-30a and MALAT1, Beclin1 were confirmed by luciferase reporter assay. The autophagy inhibitor 3-methyadenine (3-MA) was used to examine the impact of autophagy on ischemic injury. Results: We found that MALAT1, along with the levels of conversion from autophagy-related protein microtubule-associated protein light chain 3-I (LC3-I) to LC3-phosphatidylethanolamine conjugate (LC3-II), as well as Beclin1 were up-regulated and miR-30a was down-regulated in cerebral cortex neurons after oxygen-glucose deprivation (OGD) and mouse brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Down-regulation of MALAT1 suppressed ischemic injury and autophagy in vitro and in vivo. Furthermore, MALAT1 may serve as a molecular sponge for miR-30a and negatively regulate its expression. In addition, MALAT1 overturned the inhibitory effect of miR-30a on ischemic injury and autophagy in vitro and in vivo, which might be involved in the derepression of Beclin1, a direct target of miR-30a. Mechanistic analyses further revealed that autophagy inhibitor 3-methyadenine (3-MA) markedly suppressed OGD-induced neuronal cell death and MCAO-induced ischemic brain infarction. Conclusion: Taken together, our study first revealed that down-regulation of MALAT1 attenuated neuronal cell death through suppressing Beclin1-dependent autophagy by regulating miR-30a expression in cerebral ischemic stroke. Besides, our study demonstrated a novel lncRNA-miRNA-mRNA regulatory network that is MALAT1-miR-30a-Beclin1 in ischemic stroke, contributing to a better understanding the pathogenesis and progression of ischemic stroke.

Download Full-text

Role of NAD(P)H:quinone oxidoreductase in the progression of neuronal cell death in vitro and following cerebral ischaemia in vivo

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2003.01601.x ◽

2003 ◽

Vol 84 (5) ◽

pp. 1028-1039 ◽

Cited By ~ 23

Author(s):

Krisztian J. Kapinya ◽

Ulrike Harms ◽

Christoph Harms ◽

Katharina Blei ◽

Juri Katchanov ◽

...

Keyword(s):

Cell Death ◽

Cerebral Ischaemia ◽

Neuronal Cell Death ◽

Neuronal Cell

Download Full-text

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

Nutrients ◽

10.3390/nu13041318 ◽

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.

Download Full-text

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

Biological Chemistry ◽

10.1515/bc.2002.082 ◽

2002 ◽

Vol 383 (5) ◽

pp. 785-791 ◽

Cited By ~ 38

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.

Download Full-text

Cylindromatosis mediates neuronal cell death in vitro and in vivo

Cell Death and Differentiation ◽

10.1038/s41418-017-0046-7 ◽

2018 ◽

Vol 25 (8) ◽

pp. 1394-1407 ◽

Cited By ~ 6

Author(s):

Goutham K. Ganjam ◽

Nicole Angela Terpolilli ◽

Sebastian Diemert ◽

Ina Eisenbach ◽

Lena Hoffmann ◽

...

Keyword(s):

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell

Download Full-text

Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/1681254 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 7

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.

Download Full-text

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/3640753 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

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.

Download Full-text

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

Biochemical Journal ◽

10.1042/bj20112175 ◽

2012 ◽

Vol 443 (3) ◽

pp. 681-689 ◽

Cited By ~ 15

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.

Download Full-text