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

• DOI: 10.1016/j.redox.2023.102620
• Publication Date: 2023-02-01T02:49:18Z
• Authors: Eiki Kanemaru; Yusuke Miyazaki; Eizo Marutani; Mariko Ezaka; Shunsaku Goto; Etsuo Ohshima; Donald B. Bloch; Fumito Ichinose
• Keywords: Male; Paraplegia; Medicine (General); 0303 health sciences; Delayed paraplegia; Articles from the Special Issue on Recent advances in sulfur biology and chemistry, Edited by: Dr. Peter Nagy; Glutathione Disulfide; QH301-705.5; Spinal Cord Ischemia; Hydrogen sulfide (H2S); Spinal cord ischemia; 3. Good health; Glutathione trisulfide (GSSSG); Mice, Inbred C57BL; Mice; 03 medical and health sciences; R5-920; Pantethine trisulfide (PTN-SSS); Animals; Female; Biology (General); Sulfane sulfur (S0); Administration, Intranasal; Sulfur

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.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%).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.