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. 2022 Jun 17;14(6):1296.
doi: 10.3390/pharmaceutics14061296.

Formulated Curcumin Prevents Paclitaxel-Induced Peripheral Neuropathy through Reduction in Neuroinflammation by Modulation of α7 Nicotinic Acetylcholine Receptors

Martial Caillaud  1   2 , Danielle Thompson  1 , Wisam Toma  1 , Alyssa White  1 , Jared Mann  1 , Jane L Roberts  1 , John W Bigbee  3 , David A Gewirtz  4 , M Imad Damaj  1
Affiliations

Formulated Curcumin Prevents Paclitaxel-Induced Peripheral Neuropathy through Reduction in Neuroinflammation by Modulation of α7 Nicotinic Acetylcholine Receptors

Martial Caillaud et al. Pharmaceutics. .

Abstract

Paclitaxel is widely used in the treatment of various types of solid malignancies. Paclitaxel-induced peripheral neuropathy (PIPN) is often characterized by burning pain, cold, and mechanical allodynia in patients. Currently, specific pharmacological treatments against PIPN are lacking. Curcumin, a polyphenol of Curcuma longa, shows antioxidant, anti-inflammatory, and neuroprotective effects and has recently shown efficacy in the mitigation of various peripheral neuropathies. Here, we tested, for the first time, the therapeutic effect of 1.5% dietary curcumin and Meriva (a lecithin formulation of curcumin) in preventing the development of PIPN in C57BL/6J mice. Curcumin or Meriva treatment was initiated one week before injection of paclitaxel and continued throughout the study (21 days). Mechanical and cold sensitivity as well as locomotion/motivation were tested by the von Frey, acetone, and wheel-running tests, respectively. Additionally, sensory-nerve-action-potential (SNAP) amplitude by caudal-nerve electrical stimulation, electronic microscopy of the sciatic nerve, and inflammatory-protein quantification in DRG and the spinal cord were measured. Interestingly, a higher concentration of curcumin was observed in the spinal cord with the Meriva diet than the curcumin diet. Our results showed that paclitaxel-induced mechanical hypersensitivity was partially prevented by the curcumin diet but completely prevented by Meriva. Both the urcumin diet and the Meriva diet completely prevented cold hypersensitivity, the reduction in SNAP amplitude and reduced mitochondrial pathology in sciatic nerves observed in paclitaxel-treated mice. Paclitaxel-induced inflammation in the spinal cord was also prevented by the Meriva diet. In addition, an increase in α7 nAChRs mRNA, known for its anti-inflammatory effects, was also observed in the spinal cord with the Meriva diet in paclitaxel-treated mice. The use of the α7 nAChR antagonist and α7 nAChR KO mice showed, for the first time in vivo, that the anti-inflammatory effects of curcumin in peripheral neuropathy were mediated by these receptors. The results presented in this study represent an important advance in the understanding of the mechanism of action of curcumin in vivo. Taken together, our results show the therapeutic potential of curcumin in preventing the development of PIPN and further confirms the role of α7 nAChRs in the anti-inflammatory effects of curcumin.

Keywords: chemotherapy; curcumin; neuroinflammation; peripheral neuropathy; α7 nACh receptors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Prevention of PIPN signs with the curcumin and Meriva diets. (A) Mice were treated with cur-diet or Meriva-diet for 4 weeks (before, during, and after paclitaxel). (B) Motivation and locomotion were evaluated by the wheel-running test at D7. (C) Mechanical (von Frey test) and (D) cold (acetone test) hypersensitivity were tested at BL, D7, D14, and D21. (E) Sensory-nerve-conduction velocity and (F) sensory-nerve-compound-action-potential amplitude were measured at D22. Values are expressed as mean ± SEM. n = 12/group. Results were compared using two-way ANOVA (C,D), one-way ANOVA (B,E,F), and post-hoc Tukey’s test (*: p < 0.05, **: p < 0.01 and ***: p < 0.001 vs. reg-diet/Veh; (#: p < 0.05, ##: p < 0.01 and ###: p < 0.001 vs. reg-diet/PAC). BL = baseline; D = day; Cur = curcumin; Reg = regular; PAC = paclitaxel; Veh = vehicle.
Figure 3
Figure 3
Morphological features of sciatic nerves: transmission-electron-microscopy pictures of sciatic-nerve longitudinal sections. Pictures showing mitochondrial ultrastructure in the control group (VEH), the paclitaxel-treated group (PAC), the paclitaxel + curcumin 1.5%-treated group (PAC + Cur) and the paclitaxel + Meriva 1.5%-treated group (PAC + Meriva), in myelinated (A) and non-myelinated fibers (B). The red arrows show mitochondria with a pathological aspect. Bar scales: 2.5 μm.
Figure 4
Figure 4
Ur-diet mitigates the reduction in intraepidermal-nerve-fiber (IENF) density at 22 days post-paclitaxel injection. (A) Quantification of IENF density in hind-paw skin at day 22 post-treatment. (B) Immunostained sections of control (VEH), paclitaxel-treated group (PAC), the paclitaxel + curcumin 1.5%-treated group (PAC + Cur), and the paclitaxel + Meriva 1.5% -treated group (PAC + Meriva), with the hind-paw skin showing the IENFs. Values are expressed as mean ± SEM. n = 8/group. Results were compared using two-way ANOVA with post-hoc Tukey’s test and t-test (*: p < 0.05 vs. vehicle; #: p < 0.05 vs. Reg-diet/PAC). Reg = regular; Veh = vehicle; PAC = paclitaxel; Cur = curcumin. Bar scales: 20 μm.
Figure 5
Figure 5
Multiplex-array measurement of inflammation markers in DRG (A) and spinal cord (B) at 22 days after injection of paclitaxel with or without Meriva-diet. Values are expressed as mean ± SEM. n = 6/group. Results were compared using one-way ANOVA and post-hoc Tukey’s test (*: p < 0.05 and ***: p < 0.001 vs. vehicle group; #: p < 0.05 vs. paclitaxel group). WT = wild type; VEH = vehicle; Reg = regular; PAC = paclitaxel.
Figure 6
Figure 6
α-7 nicotinic acetylcholine receptor (α7 nAChR) mRNA expression in dorsal-root ganglia (DRG) and spinal cord: α7 nAChR mRNA expression was measured at day 22 after paclitaxel injection in DRG (A) and spinal cord (B). Values are expressed as mean ± SEM. n = 8/group. Results were compared using one-way ANOVA and post-hoc Tukey’s test (***: p < 0.001). (C) Mechanical hypersensitivity was tested at D7 and D14 after the first injection of paclitaxel with the von Frey test for Meriva-diet and MLA, an α7 nAChR antagonist. Values are expressed as mean ± SEM. n = 8/group. Results were compared using one-way ANOVA and post-hoc Tukey’s test (***: p < 0.001 vs. vehicle; ##: p < 0.05 vs. paclitaxel) Reg = regular; Veh = vehicle; PAC = paclitaxel; Cur = curcumin; D = day; MLA = methyllycaconitine citrate.
Figure 7
Figure 7
Prevention of PIPN signs by Meriva diets depending on α7 nAChRs: WT and α7 nAChR KO mice were treated with Meriva-diet for 2 weeks (before, during and after paclitaxel). (A) Mechanical (von Frey test) and (B) cold (acetone test) hypersensitivity were tested at BL, D7, and D14. (C) Motivation and locomotion were evaluated by the wheel-running test at D7. (D) Sensory-nerve-compound-action-potential amplitude was measured at D21. Values are expressed as mean ± SEM. n = 8/group. Results were compared using two-way ANOVA (A,B) and one-way ANOVA (C,D) and post-hoc Tukey’s test (*: p < 0.05 and ***: p < 0.001 vs. WT reg-diet/Veh or KO reg-diet/Veh; (#: p < 0.05, ##: p < 0.01 and ###: p < 0.001 vs. WT reg-diet/PAC or KO reg-diet/PAC). WT = wild type; KO = knock out; Veh = vehicle; Reg = regular; PAC = paclitaxel; BL = baseline; D = day.
Figure 1
Figure 1
Body weight changes in mice and plasma/tissue levels of the curcumin diet and Meriva diet. (A) Experimental design of the curcumin and Meriva diets. (B) Body-weight measurement occurred every other day for 14 days. (C) Plasma concentration of curcumin after two weeks of the curcumin diet or Meriva diet, measured by mass spectrometry. (D) Central and peripheral nervous tissues, liver, kidney, and spleen concentration of curcumin after two weeks of the curcumin diet or Meriva diet, measured by mass spectrometry. Values are expressed as mean ± SEM. n = 8/group. Results were compared using two-way ANOVA (B) with post-hoc Tukey’s test and t-test (C,D) (*: p < 0.05 vs. cur-diet).
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References

    1. Katona I., Weis J. Diseases of the Peripheral Nerves. Handb. Clin. Neurol. 2017;145:453–474. doi: 10.1016/B978-0-12-802395-2.00031-6. - DOI - PubMed
    1. Pachman D.R., Qin R., Seisler D.K., Smith E.M.L., Beutler A.S., Ta L.E., Lafky J.M., Wagner-Johnston N.D., Ruddy K.J., Dakhil S., et al. Clinical Course of Oxaliplatin-Induced Neuropathy: Results from the Randomized Phase III Trial N08CB (Alliance) J. Clin. Oncol. 2015;33:3416–3422. doi: 10.1200/JCO.2014.58.8533. - DOI - PMC - PubMed
    1. Ewertz M., Qvortrup C., Eckhoff L. Chemotherapy-Induced Peripheral Neuropathy in Patients Treated with Taxanes and Platinum Derivatives. Acta Oncol. 2015;54:587–591. doi: 10.3109/0284186X.2014.995775. - DOI - PubMed
    1. Park S.B., Lin C.S.-Y., Krishnan A.V., Friedlander M.L., Lewis C.R., Kiernan M.C. Early, Progressive, and Sustained Dysfunction of Sensory Axons Underlies Paclitaxel-Induced Neuropathy. Muscle Nerve. 2011;43:367–374. doi: 10.1002/mus.21874. - DOI - PubMed
    1. Gornstein E.L., Schwarz T.L. Neurotoxic Mechanisms of Paclitaxel Are Local to the Distal Axon and Independent of Transport Defects. Exp. Neurol. 2017;288:153–166. doi: 10.1016/j.expneurol.2016.11.015. - DOI - PMC - PubMed