PPARγ activation mitigates mechanical allodynia in paclitaxel-induced neuropathic pain via induction of Nrf2/HO-1 signaling pathway

• Published in: Biomedicine & pharmacotherapy Vol. 129; p. 110356
• Main Authors: Zhou, Ya-Qun, Liu, Dai-Qiang, Chen, Shu-Ping, Chen, Nan, Sun, Jia, Wang, Xiao-Mei, Li, Dan-Yang, Tian, Yu-Ke, Ye, Da-Wei
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2020; Elsevier
• Subjects: Analgesics - pharmacology; Animals; Disease Models, Animal; Heme Oxygenase (Decyclizing) - metabolism; Hyperalgesia - chemically induced; Hyperalgesia - enzymology; Hyperalgesia - physiopathology; Hyperalgesia - prevention & control; Male; Neuralgia - chemically induced; Neuralgia - drug therapy; Neuralgia - enzymology; Neuralgia - physiopathology; Neuropathic pain; NF-E2-Related Factor 2 - metabolism; Oxidative stress; Paclitaxel; Pain Perception - drug effects; Pain Threshold - drug effects; PPAR gamma - agonists; PPAR gamma - metabolism; PPARγ; Rats, Sprague-Dawley; Rosiglitazone - pharmacology; Signal Transduction; Spinal Cord - drug effects; Spinal Cord - enzymology; Spinal Cord - physiopathology; Up-Regulation; Oxidative stress; ANOVA; Nrf2; ROS; Paclitaxel; Keap1; HO-1; PWT; PVDF; PINP; PPARγ; Neuropathic pain
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110356

[Display omitted] •Rosiglitazone attenuated established PINP via activation of PPARγ.•The analgesic effect of rosiglitazone could be reversed by PPARγ antagonist.•PPARγ activation mitigate PINP through activating Nrf2/HO-1 signaling pathway. Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect and is refractory to widely used analgesic drugs. Previous studies have demonstrated a protective role of peroxisome proliferator-activated receptor gama (PPARγ) in neuropathic pain. However, whether PPARγ activation could alleviate PINP remains to be elucidated. Our previous study has validated the analgesic effect of oltipraz, an nuclear factor erythroid-2 related factor 2 (Nrf2) activator, in a rat model of PINP. In this study, we tested the hypothesis that rosiglitazone, a selective agonist of PPARγ, could attenuate PINP through induction of Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Paclitaxel was injected intraperitoneally on four alternate days to induce neuropathic pain. Paw withdrawal threshold was used to evaluate mechanical allodynia. Western blot and immunofluorescence were used to examine the expression and distribution of PPARγ, Nrf2 and HO-1 in the spinal cord. Our results showed that rosiglitazone attenuated established PINP and delayed the onset of PINP via activation of PPARγ, which were reversed by PPARγ antagonist GW9662. Moreover, rosiglitazone inhibited downregulation of PPARγ in the spinal cord of PINP rats. Furthermore, the analgesic effect of rosiglitazone against PINP was abolished by trigonelline, an Nrf2 inhibitor. Finally, rosiglitazone significantly increased expression of Nrf2 and HO-1 in the spinal cord of PINP rats. Collectively, these results indicated that PPARγ activation might mitigate PINP through activating spinal Nrf2/HO-1 signaling pathway. Our results may provide an alternative option for PINP patients.