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Losartan, an Angiotensin II Type 1 Receptor Antagonist, Alleviates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain by Inhibiting Inflammatory Cytokines in the Dorsal Root Ganglia

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) adversely impacts quality of life and a challenge to treat with existing drugs used for neuropathic pain. Losartan, an angiotensin II type 1 receptor (AT1R) antagonist widely used to treat hypertension, has been reported to have analgesic effects in several pain models. In this study, we assessed losartan’s analgesic effect on paclitaxel-induced neuropathic pain (PINP) in rats and its mechanism of action in dorsal root ganglion (DRG). Rats received intraperitoneal injections of 2 mg/kg paclitaxel on days 0, 2, 4, and 6 and received single or multiple intraperitoneal injections of losartan potassium dissolved in phosphate-buffered saline at various times. The mechanical thresholds, protein levels of inflammatory cytokines, and cellular location of AT1R and interleukin 1β (IL-1β) in the DRG were assessed with behavioral testing, Western blotting, and immunohistochemistry, respectively. Data were analyzed by two-way repeated-measures analysis of variance for the behavioral test or the Mann-Whitney U test for the Western blot analysis and immunohistochemistry. Single and multiple injections of losartan ameliorated PINP, and losartan delayed the development of PINP. Paclitaxel significantly increased, and losartan subsequently decreased, the expression levels of inflammatory cytokines, including IL-1β and tumor necrosis factor α (TNF-α), in the lumbar DRG. AT1R and IL-1β were expressed in both neurons and satellite cells and losartan decreased the intensity of IL-1β in the DRG. Losartan ameliorates PINP by decreasing inflammatory cytokines including IL-1β and TNF-α in the DRG. Our findings provide a new or add-on therapy for CIPN patients.

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Abbreviations

CINP:

chemotherapy-induced peripheral neuropathy

AT1R:

angiotensin II type 1 receptor

PINP:

paclitaxel-induced neuropathic pain

DRG:

dorsal root ganglion

IL-1β:

interleukin 1β

TNF-α:

tumor necrosis factor α

DMSO:

dimethyl sulfoxide

PBS:

phosphate-buffered saline

MCP-1:

monocyte chemoattractant protein 1

GAPDH:

glyceraldehydes-3-phosphate dehydrogenase

GFAP:

glial fibrillary acidic protein

DAPI:

4′,6-diamidino-2-phenylindole

p-NFκB:

phosphorylated nuclear factor kappa B

NFκB:

nuclear factor kappa B

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Acknowledgements

This work was supported by grants to S.A. from the Peggy and Avinash Ahuja Foundation and the Helen Buchanan and Stanley Joseph Seeger Endowment at The University of Texas MD Anderson Cancer Center. The authors thank Joe Munch (Department of Scientific Publications, The University of Texas MD Anderson Cancer Center) for the editorial assistance.

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Authors and Affiliations

  1. Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Eunsoo Kim, Seon-Hee Hwang, Salahadin Abdi & Hee Kee Kim

  2. Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Busan, Republic of Korea

    Eunsoo Kim & Hae-Kyu Kim

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Contributions

EK: conception, design, data acquisition, analysis, interpretation, and writing of the manuscript. S-HH: design, data acquisition, analysis, and interpretation and preparation of the manuscript. H-KK: conception and interpretation, and preparation of the manuscript. SA: conception, design, interpretation, and writing of the manuscript. HKK: conception, design, data acquisition, analysis, interpretation, and writing of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hee Kee Kim.

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The animals used in the experiment were approved by the Institutional Animal Care and Use Committee (IACUC) of The University of Texas MD Anderson Cancer Center. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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The authors declare that they have no competing interests.

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Kim, E., Hwang, SH., Kim, HK. et al. Losartan, an Angiotensin II Type 1 Receptor Antagonist, Alleviates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain by Inhibiting Inflammatory Cytokines in the Dorsal Root Ganglia. Mol Neurobiol 56, 7408–7419 (2019). https://doi.org/10.1007/s12035-019-1616-0

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