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

Eiki Kanemaru; Yusuke Miyazaki; Eizo Marutani; Mariko Ezaka; Shunsaku Goto; Etsuo Ohshima; Donald B. Bloch; Fumito Ichinose

Redox Biology (Apr 2023)

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

Eiki Kanemaru,
Yusuke Miyazaki,
Eizo Marutani,
Mariko Ezaka,
Shunsaku Goto,
Etsuo Ohshima,
Donald B. Bloch,
Fumito Ichinose

Affiliations

Eiki Kanemaru: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Yusuke Miyazaki: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Eizo Marutani: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Mariko Ezaka: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Shunsaku Goto: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Etsuo Ohshima: Corporate Strategy Department, Kyowa Hakko Bio Co., Ltd., Tokyo, 164-0001, Japan
Donald B. Bloch: Department of Medicine, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, 02114, USA
Fumito Ichinose: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Corresponding author. Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Thier 503, 50 Blossom St, Boston, MA, 02114, USA.

Journal volume & issue: Vol. 60
p. 102620

Abstract

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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.

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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