多硫化物的鼻内给药可预防脊髓神经变性并使小鼠免于脊髓缺血后的迟发性截瘫,Redox Biology

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多硫化物的鼻内给药可预防脊髓神经变性并使小鼠免于脊髓缺血后的迟发性截瘫
Redox Biology ( IF 10.7 ) Pub Date : 2023-02-01 , DOI: 10.1016/j.redox.2023.102620
Eiki Kanemaru ₁ , Yusuke Miyazaki ₁ , Eizo Marutani ₁ , Mariko Ezaka ₁ , Shunsaku Goto ₁ , Etsuo Ohshima ₂ , Donald B Bloch ₃ , Fumito Ichinose ₁

Affiliation

背景

迟发性截瘫是胸腹主动脉手术的严重并发症。据报道，硫化氢 (H ₂ S) 在脊髓缺血小鼠模型中具有保护作用，并且 H ₂ S 的有益作用归因于多硫化物。本研究的目的是研究多硫化物对脊髓缺血后迟发性截瘫的影响。

方法和结果

通过夹紧主动脉弓和左锁骨下动脉，在雄性和雌性 C57BL/6J 小鼠中诱导脊髓缺血。谷胱甘肽三硫化物 (GSSSG)、谷胱甘肽 (GSH)、谷胱甘肽二硫化物 (GSSG) 或单独的载体在手术后 0、8、23 和 32 小时鼻内给药。所有仅用载体治疗的小鼠在手术后 48 小时内出现截瘫。GSSSG，但不是 GSH 或 GSSG，可预防 11 只雄性小鼠中的 8 只 (73%) 和 8 只雌性小鼠中的 6 只 (75%) 的截瘫。³⁴ S 标记的 GSSSG的鼻内给药迅速增加³⁴腰椎脊髓中 S 标记的硫烷硫物种。在用鼻内 GSSSG 治疗的小鼠中，硫烷硫含量增加，并且腰椎脊髓中的神经变性、小胶质细胞活化和 caspase-3 活化减少。使用小鼠初级皮层神经元的体外研究表明，GSSSG 增加了硫烷硫的细胞内水平。GSSSG，但不是 GSH 或 GSSG，在氧气和葡萄糖剥夺/复氧 (OGD/R) 后以剂量依赖性方式提高细胞活力。在 OGD/R 后，泛硫乙胺三硫化物 (PTN-SSS) 也增加了细胞内的硫烷硫并提高了细胞活力。PTN-SSS（而非泛硫乙胺）的鼻内给药可预防 9 只雄性小鼠中的 6 只 (66%) 的截瘫。

结论

多硫化物的鼻内给药使小鼠免于短暂性脊髓缺血后的迟发性截瘫。GSSSG 的神经保护作用与腰椎脊髓中多硫化物和硫烷硫含量的增加有关。通过多硫化物靶向递送硫烷硫可能被证明是治疗神经退行性疾病的一种新方法。

"点击查看英文标题和摘要"

Intranasal administration of polysulfide prevents neurodegeneration in spinal cord and rescues mice from delayed paraplegia after spinal cord ischemia

Background

Delayed paraplegia is a devastating complication of thoracoabdominal aortic surgery. Hydrogen sulfide (H₂S) was reported to be protective in a mouse model of spinal cord ischemia and the beneficial effect of H₂S has been attributed to polysulfides. The objective of this study was to investigate the effects of polysulfides on delayed paraplegia after spinal cord ischemia.

Methods and results

Spinal cord ischemia was induced in male and female C57BL/6J mice by clamping the aortic arch and the left subclavian artery. Glutathione trisulfide (GSSSG), glutathione (GSH), glutathione disulfide (GSSG), or vehicle alone was administered intranasally at 0, 8, 23, and 32 h after surgery. All mice treated with vehicle alone developed paraplegia within 48 h after surgery. GSSSG, but not GSH or GSSG, prevented paraplegia in 8 of 11 male mice (73%) and 6 of 8 female mice (75%). Intranasal administration of ³⁴S-labeled GSSSG rapidly increased ³⁴S-labeled sulfane sulfur species in the lumbar spinal cord. In mice treated with intranasal GSSSG, there were increased sulfane sulfur levels, and decreased neurodegeneration, microglia activation, and caspase-3 activation in the lumbar spinal cord. In vitro studies using murine primary cortical neurons showed that GSSSG increased intracellular levels of sulfane sulfur. GSSSG, but not GSH or GSSG, dose-dependently improved cell viability after oxygen and glucose deprivation/reoxygenation (OGD/R). Pantethine trisulfide (PTN-SSS) also increased intracellular sulfane sulfur and improved cell viability after OGD/R. Intranasal administration of PTN-SSS, but not pantethine, prevented paraplegia in 6 of 9 male mice (66%).

Conclusions

Intranasal administration of polysulfides rescued mice from delayed paraplegia after transient spinal cord ischemia. The neuroprotective effects of GSSSG were associated with increased levels of polysulfides and sulfane sulfur in the lumbar spinal cord. Targeted delivery of sulfane sulfur by polysulfides may prove to be a novel approach to the treatment of neurodegenerative diseases.

更新日期：2023-02-01

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