title: Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain.
abstract: Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany; Marco.Sisignano@med.uni-frankfurt.de.
authors: Marco
authors: 0000-0002-7581-0951
authors: M
authors: Sisignano
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Carlo
authors: C
authors: Angioni
authors: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710.|Department of Neurobiology, Duke University Medical Center, Durham, NC 27710.
authors: Chul-Kyu
authors: CK
authors: Park
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), D-60596 Frankfurt, Germany.
authors: Sascha
authors: S
authors: Meyer Dos Santos
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), D-60596 Frankfurt, Germany.
authors: Holger
authors: H
authors: Jordan
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology-ScreeningPort, D-22525 Hamburg, Germany.
authors: Maria
authors: M
authors: Kuzikov
authors: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710.|Department of Neurobiology, Duke University Medical Center, Durham, NC 27710.
authors: Di
authors: D
authors: Liu
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Sebastian
authors: S
authors: Zinn
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Stephan W
authors: SW
authors: Hohman
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Yannick
authors: Y
authors: Schreiber
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Béla
authors: B
authors: Zimmer
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), D-60596 Frankfurt, Germany.
authors: Mike
authors: M
authors: Schmidt
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Ruirui
authors: R
authors: Lu
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Jing
authors: J
authors: Suo
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Dong-Dong
authors: DD
authors: Zhang
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Stephan M G
authors: SM
authors: Schäfer
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), D-60596 Frankfurt, Germany.
authors: Martine
authors: M
authors: Hofmann
authors: F. M. Kirby Neurobiology Center, Department of Neurobiology, Harvard Medical School, Children's Hospital Boston, Boston, MA 02115.
authors: Ajay S
authors: AS
authors: Yekkirala
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), D-60596 Frankfurt, Germany.
authors: Natasja
authors: N
authors: de Bruin
authors: Fraunhofer Institute for Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), D-60596 Frankfurt, Germany.
authors: Michael J
authors: MJ
authors: Parnham
authors: F. M. Kirby Neurobiology Center, Department of Neurobiology, Harvard Medical School, Children's Hospital Boston, Boston, MA 02115.
authors: Clifford J
authors: CJ
authors: Woolf
authors: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710.|Department of Neurobiology, Duke University Medical Center, Durham, NC 27710.|Pain Research Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Ru-Rong
authors: RR
authors: Ji
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.
authors: Klaus
authors: K
authors: Scholich
authors: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES (Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit), University Hospital, Goethe-University, D-60590 Frankfurt, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), D-60596 Frankfurt, Germany.
authors: Gerd
authors: G
authors: Geisslinger
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000633:toxicity; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008041:Linoleic Acids / Q000097:blood / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D009437:Neuralgia / Q000139:chemically induced / Q000517:prevention & control*; D017239:Paclitaxel / Q000494:pharmacology* / Q000633:toxicity; D017288:Pain Threshold / Q000187:drug effects; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D001565:Benzoates; C000717350:CYP2J2 protein, human; C000717353:Cyp2j6 protein, mouse; D008041:Linoleic Acids; C051208:9,10-epoxy-12-octadecenoic acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D017239:Paclitaxel; D000077333:Telmisartan
keywords: TRPV1; chemotherapy-induced neuropathy; neuropathic pain; oxidized lipids; telmisartan