Evaluation of Cholesterol Reduction Activity of Methyl-β-cyclodextrin Using Differentiated Human Neurons and Astrocytes
Open accessAbstract
Recent advances in stem cell technology have enabled large-scale production of human cells such as cardiomyocytes, hepatocytes, and neurons for evaluation of pharmacologic effect and toxicity of drug candidates. The assessment of compound efficacy and toxicity using human cells should lower the high clinical attrition rates of drug candidates by reducing the impact of species differences on drug efficacy and toxicity from animal studies. Methyl-β-cyclodextrin (MBCD) has been shown to reduce lysosomal cholesterol accumulation in skin fibroblasts derived from patients with Niemann Pick type C disease and in the NPC1-/- mouse model. However, the compound has never been tested in human differentiated neurons. We have determined the cholesterol reduction effect of MBCD in neurons differentiated from human neural stem cells (NSCs) and commercially available astrocytes. The use of NSCs for producing differentiated neurons in large quantities can significantly reduce the production time and enhance the reproducibility of screening results. The EC(50) values of MBCD on cholesterol reduction in human neurons and astrocytes were 66.9 and 110.7 µM, respectively. The results indicate that human neurons differentiated from the NSCs and human astrocytes are useful tools for evaluating pharmacologic activity and toxicity of drug candidates to predict their clinical efficacy.
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A 4-day treatment with 100 μM methyl-β-cyclodextrin (MβCD) mitigates lysosomal cholesterol accumulation in ApoE4 hiPSC-derived astrocytes.
“We were able to mitigate lysosomal cholesterol accumulation in ApoE4 hiPSC-derived astrocytes with a 4-day treatment of 100 μM methyl-β-cyclodextrin (MβCD)”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [19]
The Results report that MβCD reduced cellular cholesterol in human astrocytes, but the Methods identify those cells as derived from normal human brain tissue, not ApoE4 hiPSCs. The Methods describe cholesterol measurements after 1 or 3 days of treatment, not a 4-day, 100 μM regimen; the paper does not establish a reduction specifically in lysosomal cholesterol in ApoE4 astrocytes. (LLM, conf=0.90)
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Cites
Arrowsmith, J. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3439 · Cited by 622 · see citing works
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- [1]Inglese J Johnson RL Simeonov A Xia M Zheng W Austin CP Auld DS High-throughput screening assays for the identification of chemical probes Nat Chem Biol 2007 3 466 479 17637779
- [2]Michelini E Cevenini L Mezzanotte L Coppa A Roda A Cell-based assays: fuelling drug discovery Anal Bioanal Chem 2010 398 227 238 20623273
- [3]Ebert AD Svendsen CN Stem cell model of spinal muscular atrophy Arch Neurol 2010 67 665 669 20558385 PMC3140872
- [4]Grskovic M Javaherian A Strulovici B Daley GQ Induced pluripotent stem cells--opportunities for disease modelling and drug discovery Nat Rev Drug Discov 2011 10 915 929 22076509
- [5]Sinnecker D Dirschinger RJ Goedel A Moretti A Lipp P Laugwitz KL Induced Pluripotent Stem Cells in Cardiovascular Research Rev Physiol Biochem Pharmacol 2012 22447279
- [6]Rosenbaum AI Maxfield FR Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches J Neurochem 2011 116 789 795 20807315 PMC3008286
- [7]Vanier MT Niemann-Pick disease type C Orphanet J Rare Dis 2010 5 16 20525256 PMC2902432
- [8]Rosenbaum AI Rujoi M Huang AY Du H Grabowski GA Maxfield FR Chemical screen to reduce sterol accumulation in Niemann-Pick C disease cells identifies novel lysosomal acid lipase inhibitors Biochim Biophys Acta 2009 1791 1155 1165 19699313 PMC2783675
- [9]Norman AW Demel RA de Kruyff B van Deenen LL Studies on the biological properties of polyene antibiotics. Evidence for the direct interaction of filipin with cholesterol J Biol Chem 1972 247 1918 1929 5012767
- [10]Carpenter MK Inokuma MS Denham J Mujtaba T Chiu CP Rao MS Enrichment of neurons and neural precursors from human embryonic stem cells Exp Neurol 2001 172 383 397 11716562
- [11]Swistowski A Peng J Han Y Swistowska AM Rao MS Zeng X Xeno-free defined conditions for culture of human embryonic stem cells, neural stem cells and dopaminergic neurons derived from them PLoS One 2009 4 e6233 19597550 PMC2705186
- [12]Davidson CD Ali NF Micsenyi MC Stephney G Renault S Dobrenis K Ory DS Vanier MT Walkley SU Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression PLoS One 2009 4 e6951 19750228 PMC2736622
- [13]Liu B Ramirez CM Miller AM Repa JJ Turley SD Dietschy JM Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid J Lipid Res 2010 51 933 944 19965601 PMC2853461
- [14]Liu B Turley SD Burns DK Miller AM Repa JJ Dietschy JM Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse Proc Natl Acad Sci U S A 2009 106 2377 2382 19171898 PMC2650164
- [15]Lloyd-Evans E Morgan AJ He X Smith DA Elliot-Smith E Sillence DJ Churchill GC Schuchman EH Galione A Platt FM Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium Nat Med 2008 14 1247 1255 18953351
- [16]Rosenbaum AI Zhang G Warren JD Maxfield FR Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells Proc Natl Acad Sci U S A 2010 107 5477 5482 20212119 PMC2851804
- [18]Arrowsmith J Trial watch: phase III and submission failures: 2007–2010 Nat Rev Drug Discov 2011 10 87 21283095
- [19]Rittirsch D Hoesel LM Ward PA The disconnect between animal models of sepsis and human sepsis J Leukoc Biol 2007 81 137 143 17020929
- [20]Desagher S Glowinski J Premont J Astrocytes protect neurons from hydrogen peroxide toxicity J Neurosci 1996 16 2553 2562 8786431 PMC6578753
- [21]Kim YM Chung HT Kim SS Han JA Yoo YM Kim KM Lee GH Yun HY Green A Li J Simmons RL Billiar TR Nitric oxide protects PC12 cells from serum deprivation-induced apoptosis by cGMP-dependent inhibition of caspase signaling J Neurosci 1999 19 6740 6747 10436031 PMC6782848
- [22]Zeng X Chen J Deng X Liu Y Rao MS Cadet JL Freed WJ An in vitro model of human dopaminergic neurons derived from embryonic stem cells: MPP+ toxicity and GDNF neuroprotection Neuropsychopharmacology 2006 31 2708 2715 17109014 PMC1852423
- [23]Chen FW Li C Ioannou YA Cyclodextrin induces calcium-dependent lysosomal exocytosis PLoS One 2010 5 e15054 21124786 PMC2993955
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Lee, H., Cho, S., Kim, M.-J., Park, Y. J., Cho, E., Jo, Y. S., Kim, Y.-S., Lee, J. Y., Thoudam, T., Woo, S.-H., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113183 · Cited by 93 · see citing works
- Authors
- Swaroop, M., Thorne, N., Rao, M. S., Austin, C. P., McKew, J. C., & Zheng, W.
- Affiliations
- National Institutes of Health (US)
- National Center for Advancing Translational Sciences (US)
- Corresponding author
- Zheng, Wei
- Venue
- SLAS Discovery
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 17
- Issue
- 9
- Pages
- 1243-1251
- ISSN
- 2472-5552 (ISSN-L)
- PMC
- PMC3530257
- OpenAlex
- W2152528933
- Cited by
- 22
- References
- 1
- Citations by year
- 2024: 1 · 2023: 3 · 2020: 2 · 2019: 2 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 1
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- SLAS DISCOVERY (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (ZIBHG200319)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Keywords
- methyl-β-cyclodextrin, cholesterol lowering, lysosomal cholesterol accumulation, Niemann-Pick disease type C, human neurons, astrocytes, neural stem cell differentiation, EC50
- MeSH terms
- Animals, Anticholesteremic Agents, Astrocytes, Cell Differentiation, Cells, Cultured, Cholesterol, Drug Evaluation, Preclinical, Fibroblasts, Fluorescent Antibody Technique, Humans, Lysosomes, Neurons, beta-Cyclodextrins, Mice, Induced Pluripotent Stem Cells, Neural Stem Cells
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