New treatment target for paclitaxel-induced pain [PreClinical]

1. In mouse models, the lipid metabolite 9,10 EpOME was identified as an important mediator of paclitaxel-induced peripheral neuropathic pain (PIPN).

2. Following the inhibition of the upstream lipid oxygenase CYP2J with drug, levels of 9,10 EpOME were reduced and PIPN was significantly reduced as well.

Evidence Rating Level: 2 (Good)

Study Rundown: Paclitaxel is currently the first line therapy for breast cancer; however, a main side effect of this therapy is peripheral neuropathy. This side effect involves pain in the extremities without a painful stimulus. The goal of this study was to determine the mechanism through which PIPN is induced, in order to identify a treatment that could lead to the alleviation of the pain experienced by patients.

Using dorsal root ganglia cells from mice, the levels of lipid metabolites were measured following paclitaxel administration. The levels of a linoleic acid metabolite, 9,10-EpOME, were elevated in the mice. This metabolite was found to increase the frequency of nerve firing and reduce the pain threshold of mice. Correspondingly, the expression of CYP2J, the lipid oxygenase that synthesizes 9,10 EpOME, was increased in these mice. When CYP2J was inhibited with the drugs telmisartan or terfenadine, the production of 9,10-EpOME was diminished and led to decreased sensitivity to both mechanical and thermal stimuli.

The researchers in this study were able to elucidate the mechanism through which paclitaxel induces peripheral neuropathy, allowing for the discovery of a novel treatment for this debilitating side effect. Although future studies will need to determine the efficacy of this treatment in humans as well as the benefit that it truly has on pain levels, it provides a promising option towards alleviating pain in patients taking paclitaxel.

Click to read the study in PNAS

Relevant Reading: Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis

In-Depth [animal study]: Varying doses of paclitaxel were administered to mice and nervous system components were extracted after 8 days. Liquid chromatography-mass spectroscopy was then used to look for altered levels of lipid metabolites. A lineoleic acid derivative, 9,10-EpOME, was found to be the only lipid elevated in the mice that received paclitaxel (p<0.05).

The effect of this metabolite on neuronal firing was then assessed. Patch clamp recorders were used to measure the spontaneous excitatory post synaptic potentials (sEPSCs) of spinal cord slices from mice following the administration of varying concentrations of 9,10-EpOME. Neuron firing was potentiated with the addition of capsaicin, a compound known to increase neuronal firing and induce pain. A concentration-dependent increase in firing was noted with 9,10-EpOME, supporting the hypothesis of its role in PIPN.

In an evaluation of lipid oxygenases, the levels of CYP2J expression were found to be elevated using qRT-PCR (p<0.01). CYP2J was determined to be most likely involved in 9,10-EpOME production. Because of the potential role of this enzyme in the development of neuropathy, inhibitors of this enzyme were used to target this pathway and the effects on sEPSC frequency and hypersensitivity to stimuli were assessed. In vivo, the administration of telmisartan and terfenadine significantly reduced 9,10-EpOME levels (p<0.05). These drugs also reduced mechanical and thermal hypersensitivity in mice (p<0.05).

Image: PD

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