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Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.

ABSTRACT: 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.

SUBMITTER: Stockstill K

PROVIDER: S-EPMC5940258 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.

Stockstill Katherine K Doyle Timothy M TM Yan Xisheng X Chen Zhoumou Z Janes Kali K Little Joshua W JW Braden Kathryn K Lauro Filomena F Giancotti Luigino Antonio LA Giancotti Luigino Antonio LA Harada Caron Mitsue CM Yadav Ruchi R Xiao Wen Hua WH Lionberger Jack M JM Neumann William L WL Bennett Gary J GJ Weng Han-Rong HR Spiegel Sarah S Salvemini Daniela D

The Journal of experimental medicine 20180427 5

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 multipl ...[more]

PMID: 29703731

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Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.

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Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.

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