Peroxisome proliferator-activated receptor gamma agonist ELB00824 suppresses oxaliplatin-induced pain, neuronal hypersensitivity, and oxidative stress.
Peroxisome proliferator-activated receptor gamma agonist ELB00824 suppresses oxaliplatin-induced pain, neuronal hypersensitivity, and oxidative stress.
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DOI：
10.1016/j.neuropharm.2022.109233
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发表时间：
2022-11-01
影响因子：
4.7
通讯作者：
Ye, Yi
中科院分区：
文献类型：
--
作者：
Zhang, Morgan;Hu, Min;Alles, Sascha R. A.;Montera, Marena A.;Adams, Ian;Santi, Maria D.;Inoue, Kenji;Tu, Nguyen Huu;Westlund, Karin N.;Ye, Yi
化疗引起的神经病理性疼痛（CINP）是化疗药物的一种使人衰弱且难以治疗的副作用。CINP以氧化应激和神经元超敏反应为标志。过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）是一种转录因子，调节氧化应激和炎症相关基因。我们推测，PPARγ激动剂通过减少氧化应激和抑制神经元超敏反应来保护CIPN。为了检验我们的假设，在BALB/c小鼠中通过奥沙利铂的短期或长期治疗引入急性或慢性CIPN。CIPN小鼠用新型血脑屏障（BBB）可穿透的PPARγ激动剂ELB 00824或BBB不可穿透的PPARγ激动剂吡格列酮或溶剂处理。冷异常性疼痛，机械异常性疼痛，运动协调，镇静和成瘾分别用干冰，冯弗雷细丝，梁行走试验，和条件性位置偏爱。通过测量蛋白质氧化的副产物（羰基和3-硝基酪氨酸）和脂质过氧化[硫代巴比妥酸反应物质（TBARS）]威尔斯Cat、Sod 2、Ppargc 1a的基因表达来评估氧化应激。使用分离的背根神经节神经元的全细胞电生理学测量ELB 00824对伤害感受器兴奋性的影响。抢先ELB 00824，而不是吡格列酮，减少奥沙利铂诱导的冷和机械异常性疼痛和氧化应激。ELB 0824抑制奥沙利铂诱导的IB 4 −神经元放电。在人结肠癌细胞系（HCT 116）和人口腔癌细胞系（HSC-3）中，ELB 00824未引起运动失调或镇静/成瘾或降低奥沙利铂的抗肿瘤活性（采用基于MTS的细胞增殖试验测量）。我们的研究结果表明，ELB 00824预防奥沙利铂诱导的疼痛，可能是通过抑制神经元超敏反应和氧化应激。
Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs. CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARγ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, acute or chronic CIPN was introduced by short or long-term treatment of oxaliplatin in BALB/c mice. CIPN mice were treated with either a novel blood-brain barrier (BBB) penetrable PPARγ agonist ELB00824, or a BBB non-penetrable PPARγ agonist pioglitazone, or vehicle. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring byproducts of protein oxidation (carbonyl and 3-Nitrotyrosine) and lipid peroxidation [Thiobarbituric acid reactive substances (TBARS)], as wells as gene expression of Cat, Sod2, Ppargc1a. The effects of ELB00824 on nociceptor excitability were measured using whole-cell electrophysiology of isolated dorsal root ganglion neurons. Preemptive ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4− neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress.
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影响因子：
3.9
作者：
G KK;Thaggikuppe Krishnamurthy P;Ammu V V V RK;Vishwanath K;Narenderan ST;Babu B;Krishnaveni N
通讯作者：
Krishnaveni N
影响因子：
4.6
作者：
Chang KL;Pee HN;Yang S;Ho PC
通讯作者：
Ho PC
脑脊液奥沙利铂会导致奥沙利铂全身给药引起的急性疼痛
影响因子：
8.8
作者：
Huang, Zhen-Zhen;Li, Dai;Xin, Wen-Jun
通讯作者：
Xin, Wen-Jun
影响因子：
3.1
作者：
Heppner, TJ;Bonev, AD;Nelson, MT
通讯作者：
Nelson, MT
影响因子：
--
作者：
Jain, Vivek;Jaggi, Amteshwar Singh;Singh, Nirmal
通讯作者：
Singh, Nirmal