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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Esposito, Emanuela Cuzzocrea, Salvatore Bryant, Leesa Obeid, Lina Snider, Ashley Petrache, Irina Doyle, Timothy Nicol, Grant Neumann, William L. Kamocki, Krzysztof Little, Joshua W. Chen, Collin Janes, Kali Li, Chao Salvemini, Daniela Chen, Zhoumou Bieberich, Erhard |
| Abstract | The ceramide-sphingosine 1-phosphate (S1P) rheostat is important in regulating cell fate. Several chemotherapeutic agents, including paclitaxel (Taxol), involve pro-apoptotic ceramide in their anticancer effects. The ceramide-to-S1P pathway is also implicated in the development of pain, raising the intriguing possibility that these sphingolipids may contribute to chemotherapy- induced painful peripheral neuropathy, which can be a critical dose-limiting side effect of many widely used chemotherapeutic agents.We demonstrate that the development of paclitaxel-induced neuropathic pain was associated with ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of S1P receptor subtype 1 (S1PR(1))- dependent neuroinflammatory processes as follows: activation of redox-sensitive transcription factors (NFκB) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF- and IL-1ß). Intrathecal delivery of the S1PR1 antagonist W146 reduced these neuroinflammatory processes but increased IL-10 and IL-4, potent anti-inflammatory/ neuroprotective cytokines. Additionally, spinal W146 reversed established neuropathic pain. Noteworthy, systemic administration of the S1PR1 modulator FTY720 (Food and Drug Administration- approved for multiple sclerosis) attenuated the activation of these neuroinflammatory processes and abrogated neuropathic pain without altering anticancer properties of paclitaxel and with beneficial effects extended to oxaliplatin. Similar effects were observed with other structurally and chemically unrelated S1PR1 modulators (ponesimod and CYM-5442) and S1PR1 antagonists (NIBR-14/15) but not S1PR1 agonists (SEW2871). Our findings identify for the first time the S1P/S1PR1 axis as a promising molecular and therapeutic target in chemotherapy-induced painful peripheral neuropathy, establish a mechanistic insight into the biomolecular signaling pathways, and provide the rationale for the clinical evaluation of FTY720 in chronic pain patients. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 30 |
| Volume Number | 289 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2014-07-25 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antineoplastic Agents, Phytogenic Adverse Effects Neuralgia Chemically Induced Enzymology Paclitaxel Receptors, Lysosphingolipid Metabolism Signal Transduction Drug Effects Anilides Pharmacology Animals Cytokines Enzyme Activation Fingolimod Hydrochloride Immunosuppressive Agents Indans Lysophospholipids Drug Therapy Organophosphonates Oxadiazoles Propylene Glycols Rats, Sprague-Dawley Antagonists & Inhibitors Sphingosine Analogs & Derivatives Thiazoles Thiophenes Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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