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. 2023 Jan-Dec:19:17448069231185694.
doi: 10.1177/17448069231185694.

Duloxetine prevents bortezomib and paclitaxel large-fiber chemotherapy-induced peripheral neuropathy (LF-CIPN) in sprague dawley rats

Niloufar Mansooralavi  1 , Eugen V Khomula  1 , Jon D Levine  1
Affiliations

Duloxetine prevents bortezomib and paclitaxel large-fiber chemotherapy-induced peripheral neuropathy (LF-CIPN) in sprague dawley rats

Niloufar Mansooralavi et al. Mol Pain. 2023 Jan-Dec.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, treatment-limiting, side-effect of several classes of chemotherapy drugs. While negatively impacting oncology patients' quality of life, chemotherapy-induced large-fiber (LF) neuropathy is amongst the least well understood components of CIPN, and one for which there is currently no established therapy. Preliminary clinical observations have led to the suggestion that Duloxetine, which is used for the treatment of pain associated with small-fiber CIPN (SF-CIPN), may be effective against LF-CIPN. In the present experiments we developed a model of LF-CIPN and studied the effect of Duloxetine on LF-CIPN induced by two neurotoxic chemotherapy agents: the proteasome inhibitor, Bortezomib, a first-line treatment of multiple myeloma; and, the anti-microtubule taxane, Paclitaxel, used in the treatment of solid tumors. Since there are currently no models for selective the study of LF-CIPN, our first aim was to establish a pre-clinical model in the rat. LF-CIPN was evaluated with the Current Perception Threshold (CPT) assay, which uses a high frequency (1000 Hz) electrical stimulus protocol that selectively activates large-fiber myelinated afferents. Our second aim was to use this model to test the hypothesis that Duloxetine can prevent LF-CIPN. We report that Bortezomib and Paclitaxel induce elevation of CPT, compatible with loss of large-fiber function, which are prevented by Duloxetine. Our findings support the clinical observation that Duloxetine may be an effective treatment for the large-fiber CIPN. We also suggest that CPT could be used as a biomarker for LF-CIPN in patients receiving neurotoxic chemotherapy.

Keywords: Chemotherapy-induced peripheral neuropathy (CIPN); bortezomib; current perception threshold (CPT); duloxetine; large-fiber cipn; paclitaxel; prevention protocol.

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Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
(a) Timeline for treatment with Bortezomib and Paclitaxel chemotherapy (CTX) and CPT measurements. Baseline CPT was recorded for 2 days before Bortezomib or Paclitaxel treatment was initiated. Bortezomib (0.2 mg/kg, i.v.) or Paclitaxel (1 mg/kg i.p.) was then administered intravenously (or intraperitoneally) every other day for 4 treatments. CPT was measured 24 h after the last administration of each chemotherapy drug, for 2 consecutive days, and then weekly for 3 weeks. (b) Timeline for the Prevention Protocol for the study of the effect of Duloxetine on Bortezomib- and Paclitaxel-induced large-fiber (LF) peripheral neuropathy. Two days of Baseline CPT were recorded, before the start of Duloxetine treatment. Duloxetine (10 mg/kg, i.p.) was then administered intraperitoneally every day for 10 consecutive days. Chemotherapy treatments (CTX) began 4 days after the start of Duloxetine treatments. Bortezomib (0.2 mg/kg, i.v.) or Paclitaxel (1 mg/kg, i.v.) was administered intravenously (or intraperitoneally) every other day for 4 treatments. CPT was measured 24 h after the last administration of both Duloxetine and chemotherapy drug, for 2 consecutive days, and then weekly for 3 weeks.
Figure 2.
Figure 2.
One group of rats was treated with Bortezomib, every other day for 4 treatments (BTZ); a second group was treated with Duloxetine (10 mg/kg, i.p.) daily for 10 doses, starting 3 days prior to the administration of the first dose of Bortezomib (0.2 mg/kg, i.v.) (DUL + BTZ). Compared to the BTZ baseline, CPT for the BTZ group was significantly increased after treatment (one-way RM ANOVA, F(3, 21) = 4.7, *p = 0.012). CPT for the DUL + BTZ group was significantly different from that for the BTZ group (two-way RM ANOVA, Treatment Factor, F(1, 15) = 16.2, **p = 0.0011; Interaction Factor F(3, 45) = 4.8, **p = 0.005). Significant “time x treatment” interaction, in addition to significant effect of treatment, indicates that the difference between BTZ and DUL + BTZ groups was time-dependent and therefore cannot be just a result of vertical shift between groups (e.g., due to the difference in baselines). Pretreatment with Duloxetine significantly attenuated BTZ-induced elevation of CPT at weeks 1–3 (Holm-Šídák’s multiple comparisons test, BTZ vs DUL + BTZ: Baseline, t(60) = 0.13, p = 0.9; Week 1, t(60) = 2.5, *p = 0.03; Week 2, t(60) = 4.2, ***p = 0.0004; ssWeek 3, t(60) = 3.8, **p = 0.0011). Data are mean ± SEM; n = 8 for BTZ group and n = 9 for DUL + BTZ group.
Figure 3.
Figure 3.
One group of rats was treated with Paclitaxel (1 mg/kg i.p.), every other day for 4 treatments (PTX); a second group was treated with Duloxetine (10 mg/kg, i.p.) daily for 10 doses starting 3 days prior to the administration of the first dose of Paclitaxel (DUL + PTX). Compared to the PTX baseline, CPT for the PTX group was significantly increased after PTX treatment (one-way RM ANOVA, F(3, 12) = 5.8, *p = 0.011). CPT for the DUL + PTX group was significantly different from that for the PTX group (two-way RM ANOVA, Interaction Factor F(3, 27) = 6.8, **p = 0.0015). Significant “time x treatment” interaction indicates that the difference between PTX and DUL + PTX groups was time-dependent and therefore cannot be just a result of vertical shift between groups (e.g., due to the difference in baselines). Pretreatment with Duloxetine significantly attenuated PTX-induced elevation of CPT at week 2 (Holm-Šídák’s multiple comparisons test, PTX vs DUL + PTX: Baseline, t(36) = 1.3, p = 0.3; Week 1, t(36) = 1.5, p = 0.3; Week 2, t(36) = 3.4, **p = 0.007; Week 3, t(36) = 2.3, p = 0.07). Data are mean ± SEM; n = 5 for PTX group and n = 6 for DUL + PTX group.
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