Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain
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- Katherine Stockstill
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Timothy M. Doyle
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Xisheng Yan
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 2
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- Zhoumou Chen
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Kali Janes
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Joshua W. Little
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Kathryn Braden
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Filomena Lauro
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Luigino Antonio Giancotti
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Caron Mitsue Harada
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
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- Ruchi Yadav
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 2
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- Wen Hua Xiao
- Department of Anesthesiology, University of California, San Diego, La Jolla, CA 4
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- Jack M. Lionberger
- Department of Internal Medicine, Division of Hematology, Oncology, and Cellular Therapeutics, Saint Louis University School of Medicine, St. Louis, MO 5
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- William L. Neumann
- Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 6
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- Gary J. Bennett
- Department of Anesthesiology, University of California, San Diego, La Jolla, CA 4
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- Han-Rong Weng
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 2
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- Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, VA 7
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- Daniela Salvemini
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 1
書誌事項
- 公開日
- 2018-04-27
- 権利情報
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- http://www.rupress.org/terms/
- https://creativecommons.org/licenses/by-nc-sa/4.0/
- DOI
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- 10.1084/jem.20170584
- 公開者
- Rockefeller University Press
この論文をさがす
説明
<jats:p>The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.</jats:p>
収録刊行物
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- Journal of Experimental Medicine
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Journal of Experimental Medicine 215 (5), 1301-1313, 2018-04-27
Rockefeller University Press