Alzheimer’s Disease Presenilin-1 Mutation Sensitizes Neurons to Impaired Autophagy Flux and Propofol Neurotoxicity: Role of Calcium Dysregulation

Yang, Meirong; Wang, Yan; Ge, Liang; Xu, Zhendong; Chu, Charleen T.; Wei, Huafeng

doi:10.3233/jad-180858

Cited by 23 publications

(15 citation statements)

References 48 publications

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“…This dual effect of cytoprotection versus cytotoxicity depends on exposure levels. Similar to the results of neuronal studies [21,23,24], the inhalational anesthetic sevoflurane was a more potent modifier of breast cancer cell survival in vitro than propofol. These results suggest general anesthetics have similar effects on cell survival in different cell types.…”

Section: Discussionsupporting

confidence: 70%

“…In various kinds of neurons, general anesthetics at low concentrations for short durations promote cell survival, proliferation and neurogenesis by adequate or physiological increase of cytosolic Ca 2+ concentrations via activation of InsP 3 receptor (InsP 3 R) Ca 2+ channel and subsequent Ca 2+ release from the endoplasmic reticulum (ER) [ 20 – 23 ] or Ca 2+ influx from extracellular space [ 24 ], thus resulting in preconditioning cytoprotection [ 25 ] or promoting autophagy [ 18 ]. However, general anesthetics at high concentrations for prolonged duration cause cell death directly by pathological Ca 2+ release from the ER via excessive activation of InsP 3 R [ 17 , 20 ] or abnormal Ca 2+ influx from extracellular space.…”

Section: Discussionmentioning

confidence: 99%

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Sevoflurane modulates breast cancer cell survival via modulation of intracellular calcium homeostasis

Deng

Vipani

et al. 2020

BMC Anesthesiol

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Background Some retrospective and in vitro studies suggest that general anesthetics influence breast cancer recurrence and metastasis. We compared the effects of general anesthetics sevoflurane versus propofol on breast cancer cell survival, proliferation and invasion in vitro. The investigation focused on effects in intracellular Ca2+ homeostasis as a mechanism for general anesthetic-mediated effects on breast cancer cell survival and metastasis. Methods Estrogen receptor-positive (MCF7) and estrogen receptor-negative (MDA-MB-436) human breast cancer cell lines along with normal breast tissue (MCF10A) were used. Cells were exposed to sevoflurane or propofol at clinically relevant and extreme doses and durations for dose- and time-dependence studies. Cell survival, proliferation and migration following anesthetic exposure were assessed. Intracellular and extracellular Ca2+ concentrations were modulated using Ca2+ chelation and a TRPV1 Ca2+ channel antagonist to examine the role of Ca2+ in mediating anesthetic effects. Results Sevoflurane affected breast cancer cell survival in dose-, time- and cell type-dependent manners. Sevoflurane, but not propofol, at equipotent and clinically relevant doses (2% vs. 2 μM) for 6 h significantly promoted breast cell survival in all three types of cells. Paradoxically, extreme exposure to sevoflurane (4%, 24 h) decreased survival in all three cell lines. Chelation of cytosolic Ca2+ dramatically decreased cell survival in both breast cancer lines but not control cells. Inhibition of TRPV1 receptors significantly reduced cell survival in all cell types, an effect that was partially reversed by equipotent sevoflurane but not propofol. Six-hour exposure to sevoflurane or propofol did not affect cell proliferation, metastasis or TRPV1 protein expression in any type of cell. Conclusion Sevoflurane, but not propofol, at clinically relevant concentrations and durations, increased survival of breast cancer cells in vitro but had no effect on cell proliferation, migration or TRPV1 expression. Breast cancer cells require higher cytoplasmic Ca2+ levels for survival than normal breast tissue. Sevoflurane affects breast cancer cell survival via modulation of intracellular Ca2+ homeostasis.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Sevoflurane modulates breast cancer cell survival via modulation of intracellular calcium homeostasis

Deng

Vipani

et al. 2020

BMC Anesthesiol

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“…Considering dantrolene's dose-dependent effects on neuroprotection in other neurodegenerative diseases [29], intranasal dantrolene is also expected to provide better therapeutic effects with few side effects in these diseases. It should be noted the therapeutic dose of dantrolene would need to be worked out for each disease [33].…”

Section: Discussionmentioning

confidence: 99%

Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice

Shi

Zhang

Gao

et al. 2020

JAD

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Background/Objective: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice. Methods: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration. Results: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and-independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice. Conclusions: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.

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“…After inhibiting the activity of InsP3R and RyR, the cytotoxicity and increased Ca 2+ levels are attenuated. More interestingly, the combined inhibition of both receptors paradoxically increases the amount of cytosolic Ca 2+ entering PC12 cells from the extracellular space, increasing cytotoxicity (Yang et al, 2019 ). In addition to InsP3R, RyR alone might be critical for modulating neurotoxicity in human microglia and THP-1 cells (Klegeris et al, 2007 ; Holland and Pessah, 2021 ).…”

Section: The Effects Of Ca 2+ On Neurotoxicitymentioning

confidence: 99%

Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits

Guan

Cao

Yang

et al. 2021

Front. Mol. Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by the production and deposition of β-amyloid protein (Aβ) and hyperphosphorylated tau, leading to the formation of β-amyloid plaques (APs) and neurofibrillary tangles (NFTs). Although calcium ions (Ca2+) promote the formation of APs and NFTs, no systematic review of the mechanisms by which Ca2+ affects the development and progression of AD has been published. Therefore, the current review aimed to fill the gaps between elevated Ca2+ levels and the pathogenesis of AD. Specifically, we mainly focus on the molecular mechanisms by which Ca2+ affects the neuronal networks of neuroinflammation, neuronal injury, neurogenesis, neurotoxicity, neuroprotection, and autophagy. Furthermore, the roles of Ca2+ transporters located in the cell membrane, endoplasmic reticulum (ER), mitochondria and lysosome in mediating the effects of Ca2+ on activating neuronal networks that ultimately contribute to the development and progression of AD are discussed. Finally, the drug candidates derived from herbs used as food or seasoning in Chinese daily life are summarized to provide a theoretical basis for improving the clinical treatment of AD.

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Alzheimer’s Disease Presenilin-1 Mutation Sensitizes Neurons to Impaired Autophagy Flux and Propofol Neurotoxicity: Role of Calcium Dysregulation

Cited by 23 publications

References 48 publications

Sevoflurane modulates breast cancer cell survival via modulation of intracellular calcium homeostasis

Sevoflurane modulates breast cancer cell survival via modulation of intracellular calcium homeostasis

Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice

Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits

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