Cyclosporin A Increases Resting Mitochondrial Membrane Potential in SY5Y Cells and Reverses the Depressed Mitochondrial Membrane Potential of Alzheimer's Disease Cybrids

1998 ◽  
Vol 248 (1) ◽  
pp. 168-173 ◽  
Author(s):  
David S. Cassarino ◽  
Russell H. Swerdlow ◽  
Janice K. Parks ◽  
W.Davis Parker ◽  
James P. Bennett
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Membrane Potential ◽  
Cyclosporin A ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane

scholarly journals Selective Targeting of Non-nuclear Estrogen Receptors with PaPE-1 as a New Treatment Strategy for Alzheimer’s Disease

2020 ◽  
Vol 38 (4) ◽  
pp. 957-966
Author(s):  
Agnieszka Wnuk ◽  
Karolina Przepiórska ◽  
Joanna Rzemieniec ◽  
Bernadeta Pietrzak ◽  
Małgorzata Kajta
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Membrane Potential ◽  
Estrogen Receptors ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Neurodegenerative Disorder ◽  
Apoptotic Pathway ◽  
Selective Targeting ◽  
Nuclear Estrogen Receptors

Abstract Alzheimer’s disease (AD) is a multifactorial and severe neurodegenerative disorder characterized by progressive memory decline, the presence of Aβ plaques and tau tangles, brain atrophy, and neuronal loss. Available therapies provide moderate symptomatic relief but do not alter disease progression. This study demonstrated that PaPE-1, which has been designed to selectively activate non-nuclear estrogen receptors (ERs), has anti-AD capacity, as evidenced in a cellular model of the disease. In this model, the treatment of mouse neocortical neurons with Aβ (5 and 10 μM) induced apoptosis (loss of mitochondrial membrane potential, activation of caspase-3, induction of apoptosis-related genes and proteins) accompanied by increases in levels of reactive oxygen species (ROS) and lactate dehydrogenase (LDH) as well as reduced cell viability. Following 24 h of exposure, PaPE-1 inhibited Aβ-evoked effects, as shown by reduced parameters of neurotoxicity, oxidative stress, and apoptosis. Because PaPE-1 downregulated Aβ-induced Fas/FAS expression but upregulated that of Aβ-induced FasL, the role of PaPE-1 in controlling the external apoptotic pathway is controversial. However, PaPE-1 normalized Aβ-induced loss of mitochondrial membrane potential and restored the BAX/BCL2 ratio, suggesting that the anti-AD capacity of PaPE-1 particularly relies on inhibition of the mitochondrial apoptotic pathway. These data provide new evidence for an anti-AD strategy that utilizes the selective targeting of non-nuclear ERs with PaPE-1.

scholarly journals Selenomethionine Improves Mitochondrial Function by Upregulating Mitochondrial Selenoprotein in a Model of Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Chen Chen ◽  
Yao Chen ◽  
Zhong-Hao Zhang ◽  
Shi-Zheng Jia ◽  
Yu-Bin Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Membrane Potential ◽  
Energy Metabolism ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane Potential ◽  
Neurofibrillary Tangles ◽  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Amyloid Plaques

Alzheimer’s disease (AD), the most common neurodegenerative disease in elderly humans, is pathologically characterized by amyloid plaques and neurofibrillary tangles. Mitochondrial dysfunction that occurs in the early stages of AD, which includes dysfunction in mitochondrial generation and energy metabolism, is considered to be closely associated with AD pathology. Selenomethionine (Se-Met) has been reported to improve cognitive impairment and reduce amyloid plaques and neurofibrillary tangles in 3xTg-AD mice. Whether Se-Met can regulate mitochondrial dysfunction in an AD model during this process remains unknown.In this study, the N2a-APP695-Swedish (N2aSW) cell and 8-month-old 3xTg-AD mice were treated with Se-Met in vitro and in vivo. Our study showed that the numbers of mitochondria were increased after treatment with Se-Met. Se-Met treatment also significantly increased the levels of NRF1 and Mfn2, and decreased those of OPA1 and Drp1. In addition, the mitochondrial membrane potential was significantly increased, while the ROS levels and apoptosis rate were significantly decreased, in cells after treatment with Se-Met. The levels of ATP, complex IV, and Cyt c and the activity of complex V were all significantly increased. Furthermore, the expression level of SELENO O was increased after Se-Met treatment. Thus, Se-Met can maintain mitochondrial dynamic balance, promote mitochondrial fusion or division, restore mitochondrial membrane potential, promote mitochondrial energy metabolism, inhibit intracellular ROS generation, and reduce apoptosis. These effects are most likely mediated via upregulation of SELENO O. In summary, Se-Met improves mitochondrial function by upregulating mitochondrial selenoprotein in these AD models.

scholarly journals Ligands of the Mitochondrial 18 kDa Translocator Protein Attenuate Apoptosis of Human Glioblastoma Cells Exposed to Erucylphosphohomocholine

2008 ◽  
Vol 30 (5) ◽  
pp. 435-450
Author(s):  
Wilfried Kugler ◽  
Leo Veenman ◽  
Yulia Shandalov ◽  
Svetlana Leschiner ◽  
Ilana Spanier ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Cytochrome C ◽  
Cyclosporin A ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Translocator Protein ◽  
Glioblastoma Cells ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Induced Apoptosis

Background: We have previously shown that the anti-neoplastic agent erucylphosphohomocholine (ErPC3) requires the mitochondrial 18 kDa Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor (PBR), to induce cell death via the mitochondrial apoptosis pathway.Methods: With the aid of the dye JC-1 and cyclosporin A, applied to glioblastoma cells, we now investigated the significance of opening of the mitochondrial permeability transition pore (MPTP) for ErPC3-induced apoptosis in interaction with the TSPO ligands, PK 11195 and Ro5 4864. Furthermore, we measured cytochrome c release, and caspase-9 and -3 activation in this paradigm.Results: The human glioblastoma cell lines, U87MG, A172 and U118MG express the MPTP-associated TSPO, voltage-dependent anion channel and adenine nucleotide transporter. Indeed, ErPC3-induced apoptosis was inhibited by the MPTP blocker cyclosporin A and by PK 11195 and Ro5 4864 in a concentration-dependent manner. Furthermore, PK 11195 and Ro5 4864 inhibited collapse of the mitochondrial membrane potential, cytochrome c release, and caspase-9 and -3 activation caused by ErPC3 treatment.Conclusions: This study shows that PK 11195 and Ro5 4864 inhibit the pro-apoptotic function of ErPC3 by blocking its capacity to cause a collapse of the mitochondrial membrane potential. Thus, the TSPO may serve to open the MPTP in response to anti-cancer drugs such as ErPC3.

Cyclosporin A-induced oxidative stress is not the consequence of an increase in mitochondrial membrane potential

FEBS Journal ◽  
2007 ◽  
Vol 274 (12) ◽  
pp. 3003-3012 ◽  
Author(s):  
Marco van der Toorn ◽  
Henk F. Kauffman ◽  
Margaretha van der Deen ◽  
Dirk-Jan Slebos ◽  
Gerard H. Koëter ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Membrane Potential ◽  
Cyclosporin A ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane

scholarly journals Honokiol Attenuates Oligomeric Amyloid β1-42-Induced Alzheimer’s Disease in Mice Through Attenuating Mitochondrial Apoptosis and Inhibiting the Nuclear Factor Kappa-B Signaling Pathway

2017 ◽  
Vol 43 (1) ◽  
pp. 69-81 ◽  
Author(s):  
Mo Wang ◽  
Yu Li ◽  
Changwei Ni ◽  
Guijun Song
Keyword(s):  
Alzheimer’S Disease ◽  
Membrane Potential ◽  
Learning And Memory ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Memory Dysfunction ◽  
Nuclear Factor Kappa

Background: Increasing evidence indicates that amyloid β oligomer (AβO) is toxic to neurons in Alzheimer’s disease (AD) brain. The aim of the present study is to evaluate the effects of honokiol on AβO-induced learning and memory dysfunction in mice. Methods: AD mice model was established by AβO intrahippocampal injection. The cognitive function was evaluated using Morris water maze (MWM). Nissl staining was used to examine the hippocampal neuron damage. Primary hippocampal neurons were exposed to AβO. The apoptosis in the hippocampal tissues and primary neurons was assessed using terminal dexynucleotidyl transferase-mediated dUTP nick end labeling-neuronal nuclei (NeuN) and Hoechst staining, respectively. The mitochondrial membrane potential and radical oxygen species were detected using standard methods. Western blotting assay was used to check the expression levels of apoptotic and nuclear factor kappa-B (NF-κB) signaling-associated proteins and electrophoretic mobility shift assay was used to detect NF-κB-DNA binding. Results: Honokiol increased the time spend in the target zone of the AD mice in the MWM. In addition, honokiol dose-dependently attenuated AβO-induced hippocampal neuronal apoptosis, reactive oxygen species production and loss of mitochondrial membrane potential. Furthermore, AβO-induced NF-κB activation was inhibited by honokiol, as well as the upregulated amyloid precursor protein and β-secretase. Conclusion: Honokiol attenuates AβO-induced learning and memory dysfunction in mice and it may be a potential candidate in AD therapy.

scholarly journals Elevation of resting mitochondrial membrane potential of neural cells by cyclosporin A, BAPTA-AM, and Bcl-2

2000 ◽  
Vol 279 (3) ◽  
pp. C852-C859 ◽  
Author(s):  
Alicia J. Kowaltowski ◽  
Soraya S. Smaili ◽  
James T. Russell ◽  
Gary Fiskum
Keyword(s):  
Membrane Potential ◽  
Cyclosporin A ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Neuroblastoma Cells ◽  
Permeability Transition ◽  
Neural Cells ◽  
Acetoxymethyl Ester ◽  
Human Neuroblastoma

This study tested the hypothesis that the activity of the mitochondrial membrane permeability transition pore (PTP) affects the resting mitochondrial membrane potential (ΔΨ) of normal, healthy cells and that the anti-apoptotic gene product Bcl-2 inhibits the basal activity of the PTP. ΔΨ was measured by both fluorometric and nonfluorometric methods with SY5Y human neuroblastoma cells and with GT1–7 hypothalamic cells and PC12 pheochromocytoma cells in the absence and presence of Bcl-2 gene overexpression. The resting ΔΨ of Bcl-2 nonexpressing PC12 and wild-type SY5Y cells was increased significantly by the presence of the PTP inhibitor cyclosporin A (CsA) or by intracellular Ca2+ chelation through exposure to the acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid (BAPTA-AM). The ΔΨ of Bcl-2-overexpressing PC12 cells was larger than that of Bcl-2-negative cells and not significantly increased by CsA or by Ca2+ chelation. CsA did not present a significant effect on the ΔΨ monitored in unstressed GT1–7 cells but did inhibit the decrease in ΔΨ elicited by the addition of t-butyl hydroperoxide, an oxidative inducer of the mitochondrial permeability transition. These results support the hypothesis that an endogenous PTP activity can contribute to lowering the basal ΔΨ of some cells and that Bcl-2 can regulate the endogenous activity of the mitochondrial PTP.

Platelets apoptosis in rats after global brain ischemia

2018 ◽  
pp. 27-35
Author(s):  
А.А. Соколовская ◽  
Э.Д. Вирюс ◽  
В.В. Александрин ◽  
А.С. Роткина ◽  
К.А. Никифорова ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Ischemic Stroke ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Brain Ischemia ◽  
Mitochondrial Membrane ◽  
Male Rats ◽  
Global Brain Ischemia ◽  
Platelet Apoptosis ◽  
Global Brain

Цель исследования. Ишемические повреждения головного мозга, являются одной из наиболее частой причин инвалидности и смертности во всем мире. Недавно была установлена роль апоптоза тромбоцитов в патофизиологии инсульта, однако его механизмы до сих пор остаются невыясненными. Несмотря на различные экспериментальные модели, направленные на мониторинг апоптоза тромбоцитов, результаты, относительно изучения и выявления апоптоза тромбоцитов при ишемии головного мозга у крыс, весьма немногочисленны. Цель исследования - анализ апоптоза тромбоцитов с помощью метода проточной цитофлуориметрии на модели глобальной ишемии мозга у крыс. Методика. В экспериментах использовано 6 крыс-самцов Вистар в возрасте от 5 до 6 мес., разделенных на 2 группы: интактный контроль (К) и глобальная ишемия головного мозга. Модель глобальной ишемии головного мозга у крыс воспроизводилась путём билатеральной окклюзии общих сонных артерий на фоне гипотензии. Уровень системного артериального давления снижали посредством кровопотери до 40-45 мм рт. ст. Суспензию тромбоцитов крыс получали методом гельфильтрации с использованием сефарозы 2B. Для анализа экстернализации фосфатидилсерина (ФС) тромбоциты крыс инкубировали с Аннексином V-PE в связывающем буфере. Для оценки митохондриального мембранного потенциала (ММП) тромбоциты инкубировали с катионным красителем JC-1. После инкубации образцы немедленно анализировали на проточном цитофлуориметре FACSCalibur (Becton Dickinson, США). Результаты. Согласно полученным данным, экстернализация ФС на тромбоцитах крыс, перенесших инсульт, была значительно выше (53,45 ± 4,21%), чем в контрольной группе крыс (5,27 ± 2,40%). Данный эффект подтверждается выраженной деполяризацией митохондриальных мембран (DYm). После экспериментальной ишемии мозга почти 40% тромбоцитов было деполяризовано. Заключение. Использованный в работе подбор методов и маркеров обеспечивает понимание механизмов апоптоза тромбоцитов как в экспериментальных, так и в клинических условиях. Полученные данные позволяют сделать заключение, что апоптоз тромбоцитов является одним из факторов развития глобальной ишемии головного мозга у крыс. Результаты могут быть использованы для понимания механизмов, участвующих в развитии ишемического повреждения, что, в свою очередь, может быть использовано при разработке новых терапевтических стратегий. Aim. Stroke is one of the most common causes of disability and mortality worldwide. Multiple experimental models of stroke have focused on monitoring of platelet apoptosis. However, studies on and detection of platelet apoptosis in rats with ischemic stroke are very scarce. We investigated platelet apoptosis in rats with global brain ischemia using flow cytometry. Methods. Experiments were carried out on healthy, adult Wistar male rats weighing 300-350 g. The rats were divided into the following 2 groups: intact rats and rats with global brain ischemia. Global brain ischemia was induced by two-vessel (2-VO) carotid occlusion in combination with hypotension. Systemic blood pressure was reduced by 40-45 mm Hg by inducing haemorrhage. Platelets were isolated by gel filtration on Sepharose 2B. For evaluation of phosphatidylserine (PS) externalization, platelets were incubated with Annexin V-PE and analyzed on FACSCalibur (BD Biosciences). Mitochondrial membrane potential (DY) was measured during platelets apoptosis using JC-1, a mitochondrial membrane potential indicator. Platelets were analyzed by flow cytometry immediately after the incubation. Results. PS externalization on platelets was significantly greater after global brain ischemia (53.45 ± 4.21%) than in the control group (5.27 ± 2.40%). Pronounced depolarization of mitochondrial membrane potential (DYm) confirmed this finding. In the rat group with experimental brain ischemia, almost 40% (35.24 ± 5.21%) of platelets were depolarized. Conclusion. Our results provide insight into mechanisms involved in platelet apoptosis during ischemic stroke and can be used in further development of new therapeutic strategies.

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