Journal Article

Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain

Parnham, Michael J., Geisslinger, Gerd, Angioni, Carlo, Lu, Ruirui, Hofmann, Martine, Yekkirala, Ajay S., Woolf, Clifford J., Dos Santos, Sascha Meyer, de Bruin, Natasja, Jordan, Holger, Ji, Ru-Rong, Scholich, Klaus, Zimmer, Béla, Park, Chul-Kyu, Hohman, Stephan W., Schäfer, Stephan M. G., Suo, Jing, Zinn, Sebastian, Sisignano, Marco, Kuzikov, Maria, Liu, Di, Schreiber, Yannick, Schmidt, Mike, Zhang, Dong-Dong

2016

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Angiotensin II Type 1 Receptor Blockers - pharmacology / Animals / Antineoplastic Agents, Phytogenic - pharmacology / Antineoplastic Agents, Phytogenic - toxicity / Benzimidazoles - pharmacology / Benzoates - pharmacology / Biological Sciences / Chemotherapy / Cytochrome P-450 Enzyme System - genetics / Cytochrome P-450 Enzyme System - metabolism / Female / Ganglia, Spinal - drug effects / Ganglia, Spinal - metabolism / Gene Expression Regulation, Enzymologic - drug effects / HEK293 Cells / Humans / Hypersensitivity / Linoleic Acids - blood / Linoleic Acids - metabolism / Male / Medical Sciences / Metabolites / Mice, Inbred C57BL / Molecular Targeted Therapy - methods / Neuralgia - chemically induced / Neuralgia - prevention & control / Paclitaxel - pharmacology / Paclitaxel - toxicity / Pain / Pain Threshold - drug effects / Protein expression / Rodents / Side effects / Telmisartan