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Pioglitazone, a PPARγ agonist, reduces cisplatin-evoked neuropathic pain by protecting against oxidative stress

Khasabova, Iryna A.a; Khasabov, Sergey G.a; Olson, Julie K.a; Uhelski, Megan L.a; Kim, Amy H.a; Albino-Ramírez, Alejandra M.b; Wagner, Chad L.a; Seybold, Virginia S.a; Simone, Donald A.a,*

doi: 10.1097/j.pain.0000000000001448
Research Paper

Painful peripheral neuropathy is a dose-limiting side effect of cisplatin treatment. Using a murine model of cisplatin-induced hyperalgesia, we determined whether a PPARγ synthetic agonist, pioglitazone, attenuated the development of neuropathic pain and identified underlying mechanisms. Cisplatin produced mechanical and cold hyperalgesia and decreased electrical thresholds of Aδ and C fibers, which were attenuated by coadministration of pioglitazone (10 mg/kg, intraperitoneally [i.p.]) with cisplatin. Antihyperalgesic effects of pioglitazone were blocked by the PPARγ antagonist T0070907 (10 mg/kg, i.p.). We hypothesized that the ability of pioglitazone to reduce the accumulation of reactive oxygen species (ROS) in dorsal root ganglion (DRG) neurons contributed to its antihyperalgesic activity. Effects of cisplatin and pioglitazone on somatosensory neurons were studied on dissociated mouse DRG neurons after 24 hours in vitro. Incubation of DRG neurons with cisplatin (13 µM) for 24 hours increased the occurrence of depolarization-evoked calcium transients, and these were normalized by coincubation with pioglitazone (10 µM). Oxidative stress in DRG neurons was considered a significant contributor to cisplatin-evoked hyperalgesia because a ROS scavenger attenuated hyperalgesia and normalized the evoked calcium responses when cotreated with cisplatin. Pioglitazone increased the expression and activity of ROS-reducing enzymes in DRG and normalized cisplatin-evoked changes in oxidative stress and labeling of mitochondria with the dye MitoTracker Deep Red, indicating that the antihyperalgesic effects of pioglitazone were attributed to its antioxidant properties in DRG neurons. These data demonstrate clear benefits of broadening the use of the antidiabetic drug pioglitazone, or other PPARγ agonists, to minimize the development of cisplatin-induced painful neuropathy.

Pioglitazone, a PPARγ agonist used for glucose control in diabetes, reduced neuropathic pain from cisplatin by blocking oxidative stress.

aDepartment of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, United States

bInter American University of Puerto Rico, Bayamón, PR, United States.

Corresponding author. Address: Department of Diagnostic and Biological Sciences, University of Minnesota, 515 Delaware St SE, Minneapolis, MN 55455, Unites States. Tel.: 612-625-6464. E-mail address: (D.A. Simone).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received March 28, 2018

Received in revised form November 18, 2018

Accepted November 19, 2018

© 2019 International Association for the Study of Pain
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