Mesenchymal Stem Cells (MSCs) Coculture Protects [Ca2+]i Orchestrated Oxidant Mediated Damage in Differentiated Neurons In Vitro

Cell-therapy modalities using mesenchymal stem (MSCs) in experimental strokes are being investigated due to the role of MSCs in neuroprotection and regeneration. It is necessary to know the sequence of events that occur during stress and how MSCs complement the rescue of neuronal cell death mediated by [Ca2+]i and reactive oxygen species (ROS). In the current study, SH-SY5Y-differentiated neuronal cells were subjected to in vitro cerebral ischemia-like stress and were experimentally rescued from cell death using an MSCs/neuronal cell coculture model. Neuronal cell death was characterized by the induction of proinflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β and -12, up to 35-fold with corresponding downregulation of anti-inflammatory cytokine transforming growth factor (TGF)-β, IL-6 and -10 by approximately 1 to 7 fold. Increased intracellular calcium [Ca2+]i and ROS clearly reaffirmed oxidative stress-mediated apoptosis, while upregulation of nuclear factor NF-B and cyclo-oxygenase (COX)-2 expressions, along with ~41% accumulation of early and late phase apoptotic cells, confirmed ischemic stress-mediated cell death. Stressed neuronal cells were rescued from death when cocultured with MSCs via increased expression of anti-inflammatory cytokines (TGF-β, 17%; IL-6, 4%; and IL-10, 13%), significantly downregulated NF-B and proinflammatory COX-2 expression. Further accumulation of early and late apoptotic cells was diminished to 23%, while corresponding cell death decreased from 40% to 17%. Low superoxide dismutase 1 (SOD1) expression at the mRNA level was rescued by MSCs coculture, while no significant changes were observed with catalase (CAT) and glutathione peroxidase (GPx). Interestingly, increased serotonin release into the culture supernatant was proportionate to the elevated [Ca2+]i and corresponding ROS, which were later rescued by the MSCs coculture to near normalcy. Taken together, all of these results primarily support MSCs-mediated modulation of stressed neuronal cell survival in vitro.

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Cytokinin Plant Hormones Have Neuroprotective Activity in In Vitro Models of Parkinson’s Disease

Molecules ◽

10.3390/molecules26020361 ◽

2021 ◽

Vol 26 (2) ◽

pp. 361

Author(s):

Gabriel Gonzalez ◽

Jiří Grúz ◽

Cosimo Walter D’Acunto ◽

Petr Kaňovský ◽

Miroslav Strnad

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Neuronal Cell Death ◽

Disease Model ◽

Neuronal Cell ◽

Zeatin Riboside ◽

Neuroprotective Activity ◽

Protective Activity

Cytokinins are adenine-based phytohormones that regulate key processes in plants, such as cell division and differentiation, root and shoot growth, apical dominance, branching, and seed germination. In preliminary studies, they have also shown protective activities against human neurodegenerative diseases. To extend knowledge of the protection (protective activity) they offer, we investigated activities of natural cytokinins against salsolinol (SAL)-induced toxicity (a Parkinson’s disease model) and glutamate (Glu)-induced death of neuron-like dopaminergic SH-SY5Y cells. We found that kinetin-3-glucoside, cis-zeatin riboside, and N6-isopentenyladenosine were active in the SAL-induced PD model. In addition, trans-, cis-zeatin, and kinetin along with the iron chelator deferoxamine (DFO) and the necroptosis inhibitor necrostatin 1 (NEC-1) significantly reduced cell death rates in the Glu-induced model. Lactate dehydrogenase assays revealed that the cytokinins provided lower neuroprotective activity than DFO and NEC-1. Moreover, they reduced apoptotic caspase-3/7 activities less strongly than DFO. However, the cytokinins had very similar effects to DFO and NEC-1 on superoxide radical production. Overall, they showed protective activity in the SAL-induced model of parkinsonian neuronal cell death and Glu-induced model of oxidative damage mainly by reduction of oxidative stress.

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Effects of S-2474, a novel nonsteroidal anti-inflammatory drug, on amyloid β protein-induced neuronal cell death

British Journal of Pharmacology ◽

10.1038/sj.bjp.0704261 ◽

2001 ◽

Vol 134 (3) ◽

pp. 673-681 ◽

Cited By ~ 39

Author(s):

Tatsurou Yagami ◽

Keiichi Ueda ◽

Kenji Asakura ◽

Toshiyuki Sakaeda ◽

Takayuki Kuroda ◽

...

Keyword(s):

Cell Death ◽

Neuronal Cell Death ◽

Amyloid Β ◽

Neuronal Cell ◽

Amyloid Β Protein ◽

Inflammatory Drug ◽

Β Protein ◽

Anti Inflammatory

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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.

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The endogenous estrogen metabolite 2-methoxyestradiol induces apoptotic neuronal cell death in vitro

Life Sciences ◽

10.1016/0024-3205(96)00116-6 ◽

1996 ◽

Vol 58 (17) ◽

pp. 1461-1467 ◽

Cited By ~ 18

Author(s):

Yuzo Nakagawa-Yagi ◽

Nobuo Ogane ◽

Yutaka Inoki ◽

Naomi Kitoh

Keyword(s):

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Estrogen Metabolite ◽

Endogenous Estrogen

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A novel compound, RS-1178, specifically inhibits neuronal cell death mediated by β-amyloid-induced macrophage activation in vitro

Brain Research ◽

10.1016/s0006-8993(02)02898-6 ◽

2002 ◽

Vol 946 (2) ◽

pp. 298-306 ◽

Cited By ~ 16

Author(s):

Shigeko Uryu ◽

Shinya Tokuhiro ◽

Takako Murasugi ◽

Tomiichiro Oda

Keyword(s):

Cell Death ◽

Macrophage Activation ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Β Amyloid

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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

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From tau phosphorylation to tau aggregation: what about neuronal death?

Biochemical Society Transactions ◽

10.1042/bst0380967 ◽

2010 ◽

Vol 38 (4) ◽

pp. 967-972 ◽

Cited By ~ 50

Author(s):

Luc Buée ◽

Laëtitia Troquier ◽

Sylvie Burnouf ◽

Karim Belarbi ◽

Anneke Van der Jeugd ◽

...

Keyword(s):

Cell Death ◽

Cognitive Impairment ◽

Neurodegenerative Disorders ◽

Neuronal Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Tau Phosphorylation ◽

Tau Proteins ◽

Phosphorylated Tau ◽

Sequence Of Events

Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.

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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.

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Isoflavones Induce BEX2-Dependent Autophagy to Prevent ATR-Induced Neurotoxicity in SH-SY5Y Cells

Cellular Physiology and Biochemistry ◽

10.1159/000484075 ◽

2017 ◽

Vol 43 (5) ◽

pp. 1866-1879 ◽

Cited By ~ 10

Author(s):

Peng Li ◽

Kun Ma ◽

Hao-Yu Wu ◽

Yan-Ping Wu ◽

Bai-Xiang Li

Keyword(s):

Cell Death ◽

Neuronal Apoptosis ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Green Tea Polyphenols ◽

Key Factors ◽

Related Proteins ◽

Catabolic Process ◽

Plant Compounds

Background/Aims: Atrazine (ATR) is a broad-spectrum herbicide in wide use around the world. However, ATR is neurotoxic and can cause cell death in dopaminergic neurons, leading to neurodegenerative disorders. Autophagy is the basic cellular catabolic process involving the degradation of proteins and damaged organelles. Studies have shown that certain plant compounds can induce autophagy and prevent neuronal cell death. This prompted us to investigate plant compounds that might reduce the neurotoxic effects of ATR. Methods: By CCK-8 and flow cytometry, we tested the ability of five candidate compounds—isoflavones, resveratrol, quercetin, curcumin, and green tea polyphenols—to protect cells from ATR. Changes in the expression of tyrosine hydroxylase (TH) and brain-expressed X-linked 2 (BEX2), autophagy-related proteins and key factors in mTOR signaling, were detected by Western blotting. Results: Isoflavones had the strongest activity against ATR-induced neuronal apoptosis. ATR reduced the expression of TH and BEX2, whereas isoflavones increased TH and BEX2 expression. In addition, ATR inhibited autophagy, whereas isoflavones induced autophagy through the accumulation of LC3-II and decreased expression of p62; this effect was abolished by 3-methyladenine (3-MA). Furthermore, BEX2 siRNA abolished isoflavone-mediated autophagy and neuroprotection in vitro. Conclusion: Isoflavones activate BEX2-dependent autophagy, protecting against ATR-induced neuronal apoptosis.

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