| Background Paclitaxel is a widely used chemotherapeutic agent for ovarian cancer,breast cancer and pancreatic cancer.Unfortunately,it induces neuropathic pain after multiple doses and persists even after its termination.Moreover,commonly used analgesic drugs such as non-steroidal anti-inflammatory agents,anticonvulsants and antidepressant show little analgesic effect in paclitaxel-induced neuropathic pain(PINP).The occurrence of PINP significantly decreases the overall quality of life and prognosis in cancer patients.Currently,there is no effective therapeutic strategy for PINP due to its unknown mechanisms.Therefore,it is urgent for us to uncover novel therapeutic targets for the management of PINP.Peroxisome proliferator-activated receptor ?(PPAR?)is a nuclear transcription factor.It is a regulator of the expression of various genes,including G-protein coupled receptors,growth factors and antioxidant enzymes.PPAR? significantly affect the metabolism of lipid and glucose.Mounting evidence suggests that activation of PPAR? shows neuroprotective effect in ischemia/reperfusion injury,central nervous system injury and neurodegenerative diseases.Additionally,emerging evidence indicates that PPAR? might be a promising therapeutic target in chronic pain.Part et al.provide the first evidence that PPAR? agonist pioglitazone prevents the onset of thermal hyperalgesia in a rat model of spinal cord injury.Moreover,PPAR? agonists could attenuate inflammatory pain and periphery injury induced neuropathic pain.However,whether activation of PPAR? could ameliorate PINP and its mechanisms remain unknown.Nuclear factor erythroid 2-related factor 2(Nrf2)is a transcription factor regulating endogenous antioxidant defense.Under physiological conditions,Nrf2 is bound to Kelch-like ECH-associated protein 1(Keap1)in the cytoplasm,which leads to ubiquitination and constitutive degradation.In response to oxidative stress,Nrf2 is released from Keap1 and builds up in the cytoplasm followed with translocation into the nucleus.Then,it recognizes the appropriate antioxidant response elements sequence and initiates the transcription of anti-oxidative genes,including heme oxygenase-1(HO-1),NAD(P)H:quinone oxidoreductase-1 and superoxide dismutase.It is reported that reactive oxygen species(ROS)scavengers attenuate PINP,indicating a pivotal role of ROS in the development of PINP.Moreover,a growing body of evidence suggests that Nrf2 is a promising therapeutic target for defensing against oxidative stress.However,whether activation of Nrf2/HO-1 signaling pathway could attenuate PINP and its mechanisms remain unknown.It is well established that activation of PPAR? exerts its neuroprotective effects via its antioxidant property.Therefore,we hypothesize that activation of PPAR? may attenuate PINP through induction of Nrf2/HO-1 signaling pathway.In this study,intraperitoneal injection of paclitaxel was used for the establishment of PINP model.Different treatment strategies were used to evaluate the effect of PPAR? agonist and Nrf2 agonist on the development of PINP.Moreover,immunohistochemistry and western blot were used to observe the expression and localization of PPAR?,Nrf2 and HO-1 in the spinal cord.Methods and Results 1.Activation of PPAR? attenuated paclitaxel-induced neuropathic painMethods: Male Sprague-Dawley rats were used in the present study.Paclitaxel(2mg/kg)was injected intraperitoneally on 0 day(0 d),2 d,4 d,and 6 d as previously described to induce neuropathic pain.Mechanical paw withdrawal threshold(MPWT)was evaluated by Von Frey filament at 0 d,3 d,7 d,14 d and 21 d.To determine whether PPAR? agonist could alleviate established PINP,a single dose of rosiglitazone was injected intraperitoneally at 14 d.To determine whether repetitive treatment with rosiglitazone had a cumulative analgesic effect on PINP,rosiglitazone was injected intraperitoneally once daily from 14 d to 18 d.To determine whether PPAR? antagonist could reverse the analgesic effect of rosiglitazone,GW9662 was injected intraperitoneally 30 min before the injection of rosiglitazone.To determine whether early treatment with rosiglitazone could suppress the development of PINP,rosiglitazone was injected intraperitoneally once daily from 0 d to 6 d.Immunohistochemistry and western blot were used to observe the expression and localization of PPAR? in the spinal cord.Results: MPWT was significantly decreased from 7 d to 21 d in PINP rats.In contrast,vehicle rats showed no significant change in MPWT during the 21-day observation period.Intraperitoneal injection of rosiglitazone at the dose of 5 mg/kg had no significant effect on the MPWT compared with that of the vehicle group.However,intraperitoneal injection of rosiglitazone at the dose of 25 mg/kg and 50 mg/kg marked increased the MPWT in PINP rats,beginning at 1 h,peaking at 2 h,and lasting for 4 h.Moreover,repeated injection of rosiglitazone notably reversed the mechanical allodynia in PINP rats without signs of tolerance.The analgesic effect of rosiglitazone was suppressed by PPAR? antagonist GW9662.The MPWT of PINP rats early treated with rosiglitazone was significantly higher than that of vehicle rats at 7 d and 14 d,but not 21 d.In addition,the spinal expression of PPAR? in PINP rats was significantly decreased compared with vehicle rats.Multiple dose of rosiglitazone markedly upregulated the spinal expression of PPAR? in PINP rats,which was reversed by GW9662.Finally,PPAR? was colocalized primarily with neuron,and rarely with astrocyte and microglia.2.Induction of Nrf2/HO-1 signaling pathway attenuated paclitaxel-induced neuropathic painMethods: Male Sprague-Dawley rats were used in the present study.The establishment of PINP model was consistent with section one.To determine whether Nrf2 activator could alleviate established PINP,a single dose of oltipraz was injected intraperitoneally at 14 d.To determine whether repetitive treatment with oltipraz had a cumulative analgesic effect on PINP,oltipraz was injected intraperitoneally once daily from 14 d to 18 d.To determine whether Nrf2 inhibitor could reverse the analgesic effect of oltipraz,trigonelline was injected intraperitoneally 30 min before the injection of oltipraz.To determine whether early treatment with oltipraz could suppress the development of PINP,oltipraz was injected intraperitoneally once daily from 0 d to 6 d.Immunohistochemistry and western blot were used to observe the expression and localization of Nrf2 and HO-1 in the spinal cord.Results: Intraperitoneal injection of oltipraz at the dose of 10 mg/kg had no significant effect on the MPWT compared with that of the vehicle group.However,intraperitoneal injection of oltipraz at the dose of 50 mg/kg and 100 mg/kg marked increased the MPWT in PINP rats,beginning at 0.5 h,peaking at 1 h,and lasting for 2 h.Moreover,repeated injection of oltipraz notably reversed the mechanical allodynia in PINP rats without signs of tolerance.The analgesic effect of oltipraz was suppressed by Nrf2 inhibitor trigonelline.The MPWT of PINP rats early treated with oltipraz was significantly higher than that of vehicle rats at 7 d,but not 14 d and 21 d.In addition,the spinal expression of Nrf2 and HO-1 in PINP rats was significantly increased compared with vehicle rats.Multiple dose of oltipraz further upregulated the spinal expression of Nrf2 and HO-1 in PINP rats,which was abolished by trigonelline.Finally,Nrf2 and HO-1 were colocalized primarily with neuron,and rarely with astrocyte and microglia.3.Activation of PPAR? attenuated paclitaxel-induced neuropathic pain through induction of Nrf2/HO-1 signaling pathwayMethods: Male Sprague-Dawley rats were used in the present study.The establishment of PINP model was consistent with section one.To determine whether Nrf2 inhibitor could reverse the analgesic effect of rosiglitazone,trigonelline was injected intraperitoneally 30 min before the injection of rosiglitazone.Immunohistochemistry and western blot and were used to observe the expression and localization of Nrf2 and HO-1 in the spinal cord.Results: Intraperitoneal injection of rosiglitazone at the dose of 50 mg/kg marked increased the MPWT in PINP rats,which was blocked by Nrf2 inhibitor trigonelline.In addition,the spinal expression of Nrf2 and HO-1 in PINP rats was significantly increased compared with vehicle rats.Multiple dose of rosiglitazone further upregulated the spinal expression of Nrf2 and HO-1 in PINP rats,which was eliminated by trigonelline.4.Statistical analysis Data are expressed as mean ± SEM and analyzed using the Graph Pad Prism.One-way analysis of variance(ANOVA)followed by Bonferroni post hoc test was used for western blot data.Two-way ANOVA with repeated measures,followed by Bonferroni post hoc test was used for behavioral data.p < 0.05 was considered statistically significant.Conclusions 1.Activation of PPAR? attenuates established PINP,and delays the onset of mechanical allodynia in paclitaxel treated rats.2.Activation of Nrf2/HO-1 signaling pathway attenuates established PINP,and delays the onset of mechanical allodynia in paclitaxel treated rats.3.Activation of PPAR? attenuates PINP through induction of Nrf2/HO-1 signaling pathway.Significance The present study demonstrated that two commonly used drugs(rosiglitazone and oltipraz)in clinic could ameliorate mechanical allodynia in a rat model of PINP.Moreover,we demonstrated the detailed mechanisms underlying the analgesic of rosiglitazone against PINP.However,further clinical studies are warranted to determine whether rosiglitazone and oltipraz could improve the symptoms of PINP patients. |
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