Ezaka Mariko, Marutani Eizo, Miyazaki Yusuke, Kanemaru Eiki, Selig Martin K, Boerboom Sophie L, Ostrom Katrina F, Stemmer-Rachamimov Anat, Bloch Donald B, Brenner Gary J, Ohshima Etsuo, Ichinose Fumito
Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
Antioxidants (Basel). 2022 Oct 27;11(11):2122. doi: 10.3390/antiox11112122.
Peripheral neuropathy is a dose-limiting side effect of chemotherapy with paclitaxel. Paclitaxel-induced peripheral neuropathy (PIPN) is typically characterized by a predominantly sensory neuropathy presenting with allodynia, hyperalgesia and spontaneous pain. Oxidative mitochondrial damage in peripheral sensory neurons is implicated in the pathogenesis of PIPN. Reactive sulfur species, including persulfides (RSSH) and polysulfides (RSH), are strong nucleophilic and electrophilic compounds that exert antioxidant effects and protect mitochondria. Here, we examined the potential neuroprotective effects of glutathione trisulfide (GSSSG) in a mouse model of PIPN. Intraperitoneal administration of paclitaxel at 4 mg/kg/day for 4 days induced mechanical allodynia and thermal hyperalgesia in mice. Oral administration of GSSSG at 50 mg/kg/day for 28 days ameliorated mechanical allodynia, but not thermal hyperalgesia. Two hours after oral administration, S-labeled GSSSG was detected in lumber dorsal root ganglia (DRG) and in the lumber spinal cord. In mice treated with paclitaxel, GSSSG upregulated expression of genes encoding antioxidant proteins in lumber DRG, prevented loss of unmyelinated axons and inhibited degeneration of mitochondria in the sciatic nerve. In cultured primary neurons from cortex and DRG, GSSSG mitigated paclitaxel-induced superoxide production, loss of axonal mitochondria, and axonal degeneration. These results indicate that oral administration of GSSSG mitigates PIPN by preventing axonal degeneration and mitochondria damage in peripheral sensory nerves. The findings suggest that administration of GSSSG may be an approach to the treatment or prevention of PIPN and other peripheral neuropathies.
周围神经病变是紫杉醇化疗的剂量限制性副作用。紫杉醇诱导的周围神经病变（PIPN）通常以主要为感觉神经病变为特征，表现为痛觉过敏、痛觉超敏和自发疼痛。外周感觉神经元中的氧化线粒体损伤与PIPN的发病机制有关。包括过硫化物（RSSH）和多硫化物（RSH）在内的反应性硫物种是具有强亲核性和亲电性的化合物，具有抗氧化作用并保护线粒体。在此，我们在PIPN小鼠模型中研究了三硫化谷胱甘肽（GSSSG）的潜在神经保护作用。以4mg/kg/天的剂量腹腔注射紫杉醇4天可诱导小鼠出现机械性痛觉过敏和热痛觉超敏。以50mg/kg/天的剂量口服GSSSG 28天可改善机械性痛觉过敏，但不能改善热痛觉超敏。口服给药两小时后，在腰段背根神经节（DRG）和腰段脊髓中检测到S标记的GSSSG。在用紫杉醇治疗的小鼠中，GSSSG上调了腰段DRG中编码抗氧化蛋白的基因表达，防止了无髓轴突的丢失，并抑制了坐骨神经中线粒体的退化。在来自皮层和DRG的原代培养神经元中，GSSSG减轻了紫杉醇诱导的超氧化物产生、轴突线粒体丢失和轴突退化。这些结果表明，口服GSSSG可通过防止外周感觉神经中的轴突退化和线粒体损伤来减轻PIPN。这些发现表明，给予GSSSG可能是一种治疗或预防PIPN和其他周围神经病变的方法。
