Martínez-Martel Ignacio, Bai Xue, Kordikowski Rebecca, Leite-Panissi Christie R A, Pol Olga
Grup de Neurofarmacologia Molecular, Institut de Recerca Sant Pau, 08041 Barcelona, Spain.
Grup de Neurofarmacologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain.
Antioxidants (Basel). 2024 Jul 17;13(7):856. doi: 10.3390/antiox13070856.
Chemotherapy-provoked peripheral neuropathy and its associated affective disorders are important adverse effects in cancer patients, and its treatment is not completely resolved. A recent study reveals a positive interaction between molecular hydrogen (H) and a heme oxygenase (HO-1) enzyme inducer, cobalt protoporphyrin IX (CoPP), in the inhibition of neuropathic pain provoked by nerve injury. Nevertheless, the efficacy of CoPP co-administered with hydrogen-rich water (HRW) on the allodynia and emotional disorders related to paclitaxel (PTX) administration has not yet been assessed. Using male C57BL/6 mice injected with PTX, we examined the effects of the co-administration of low doses of CoPP and HRW on mechanical and thermal allodynia and anxiodepressive-like behaviors triggered by PTX. Moreover, the impact of this combined treatment on the oxidative stress and inflammation caused by PTX in the amygdala (AMG) and dorsal root ganglia (DRG) were studied. Our results indicated that the antiallodynic actions of the co-administration of CoPP plus HRW are more rapid and higher than those given by each of them when independently administered. This combination inhibited anxiodepressive-like behaviors, the up-regulation of the inflammasome NLRP3 and 4-hydroxynonenal, as well as the high mRNA levels of some inflammatory mediators. This combination also increased the expression of NRF2, HO-1, superoxide dismutase 1, glutathione S-transferase mu 1, and/or the glutamate-cysteine ligase modifier subunit and decreased the protein levels of BACH1 in the DRG and/or AMG. Thus, it shows a positive interaction among HO-1 and H systems in controlling PTX-induced neuropathy by modulating inflammation and activating the antioxidant system. This study recommends the co-administration of CoPP plus HRW as an effective treatment for PTX-provoked neuropathy and its linked emotive deficits.
化疗引起的周围神经病变及其相关情感障碍是癌症患者重要的不良反应，其治疗尚未完全解决。最近一项研究揭示了分子氢（H₂）与血红素加氧酶（HO-1）诱导剂钴原卟啉IX（CoPP）在抑制神经损伤引起的神经性疼痛方面存在积极相互作用。然而，CoPP与富氢水（HRW）联合使用对紫杉醇（PTX）给药相关的痛觉过敏和情绪障碍的疗效尚未得到评估。我们使用注射了PTX的雄性C57BL/6小鼠，研究了低剂量CoPP与HRW联合使用对PTX引发的机械性和热痛觉过敏以及焦虑抑郁样行为的影响。此外，还研究了这种联合治疗对PTX在杏仁核（AMG）和背根神经节（DRG）中引起的氧化应激和炎症的影响。我们的结果表明，CoPP与HRW联合使用的抗痛觉过敏作用比单独使用时更快且更强。这种联合治疗抑制了焦虑抑郁样行为、炎性小体NLRP3和4-羟基壬烯醛的上调以及一些炎症介质的高mRNA水平。这种联合治疗还增加了DRG和/或AMG中NRF2、HO-1、超氧化物歧化酶1、谷胱甘肽S-转移酶μ1和/或谷氨酸-半胱氨酸连接酶修饰亚基的表达，并降低了BACH1的蛋白水平。因此，它显示了HO-1和H₂系统在通过调节炎症和激活抗氧化系统来控制PTX诱导的神经病变方面存在积极相互作用。本研究推荐CoPP与HRW联合使用作为治疗PTX引起的神经病变及其相关情绪缺陷的有效方法。
