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Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain.

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Date
2016-11-01
Authors
Sisignano, Marco
Angioni, Carlo
Park, Chul-Kyu
Meyer Dos Santos, Sascha
Jordan, Holger
Kuzikov, Maria
Liu, Di
Zinn, Sebastian
Hohman, Stephan W
Schreiber, Yannick
Zimmer, Béla
Schmidt, Mike
Lu, Ruirui
Suo, Jing
Zhang, Dong-Dong
Schäfer, Stephan MG
Hofmann, Martine
Yekkirala, Ajay S
de Bruin, Natasja
Parnham, Michael J
Woolf, Clifford J
Ji, Ru-Rong
Scholich, Klaus
Geisslinger, Gerd
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(24 total)
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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.
Type
Journal article
Subject
TRPV1
chemotherapy-induced neuropathy
neuropathic pain
oxidized lipids
telmisartan
Permalink
https://hdl.handle.net/10161/13681
Published Version (Please cite this version)
10.1073/pnas.1613246113
Publication Info
Sisignano, Marco; Angioni, Carlo; Park, Chul-Kyu; Meyer Dos Santos, Sascha; Jordan, Holger; Kuzikov, Maria; ... Geisslinger, Gerd (2016). Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain. Proc Natl Acad Sci U S A, 113(44). pp. 12544-12549. 10.1073/pnas.1613246113. Retrieved from https://hdl.handle.net/10161/13681.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Ji

Ru-Rong Ji

Distinguished Professor of Anesthesiology, in the School of Medicine
I have been doing neuroscience and pain research for over 25 years in multiple academic institutes, including Duke University (2012-current), Harvard Medical School (1998-2012), Johns Hopkins Medical School, Karolinska Institute, and Peking University. The long-term goal of my lab is to identify molecular and cellular mechanisms that underlie the induction and resolution of pathological pain and develop novel pain therapeutics that can target these mechanisms, with specific focus on
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