Breathing hydrogen sulfide prevents delayed paraplegia in mice

Manabu Kakinohana; Eizo Marutani; Kentaro Tokuda; Kotaro Kida; Shizuko Kosugi; Shingo Kasamatsu; Aurora Magliocca; Kohei Ikeda; Shinichi Kai; Masahiro Sakaguchi; Shuichi Hirai; Ming Xian; Masao Kaneki; Fumito Ichinose

doi:10.1016/j.freeradbiomed.2018.12.003

Breathing hydrogen sulfide prevents delayed paraplegia in mice

Free Radic Biol Med. 2019 Feb 1:131:243-250. doi: 10.1016/j.freeradbiomed.2018.12.003. Epub 2018 Dec 8.

Affiliations

¹ Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, USA; Department of Anesthesiology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. Electronic address: mnb-shk@med.u-ryukyu.ac.jp.
² Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, USA. Electronic address: emarutani@mgh.harvard.edu.
³ Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, USA.
⁴ Department of Chemistry, Washington State University, Pullman, Washington, USA.
⁵ Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, USA; Shriners Hospitals for Children, Boston, MA, USA.

PMID: 30529602
DOI: 10.1016/j.freeradbiomed.2018.12.003

Abstract

Delayed paraplegia complicates the recovery from spinal cord ischemia or traumatic spinal cord injury. While delayed motor neuron apoptosis is implicated in the pathogenesis, no effective treatment or preventive measures is available for delayed paraplegia. Hydrogen sulfide exerts anti-apoptotic effects. Here, we examined effects of hydrogen sulfide breathing on the recovery from transient spinal cord ischemia. Breathing hydrogen sulfide starting 23 h after reperfusion for 5 h prevented delayed paraplegia after 5 min of spinal cord ischemia. Beneficial effects of hydrogen sulfide were mediated by upregulation of anti-apoptotic Bcl-XL and abolished by nitric oxide synthase 2 deficiency. S-nitrosylation of NFkB p65 subunit, which is induced by nitric oxide derived from nitric oxide synthase 2, facilitated subsequent sulfide-induced persulfidation of p65 and transcription of anti-apoptotic genes. These results uncover the molecular mechanism of the anti-apoptotic effects of sulfide based on the interaction between nitric oxide and sulfide. Exploitation of the anti-apoptotic effects of delayed hydrogen sulfide breathing may provide a new therapeutic approach for delayed paraplegia.

Keywords: Hydrogen sulfide; Nitric oxide; Nitric oxide synthase 2; Paraplegia; Spinal cord ischemia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Inhalation
Animals
Apoptosis / drug effects
Apoptosis / genetics
Cell Line, Tumor
Gene Expression Regulation
Humans
Hydrogen Sulfide / pharmacology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons / drug effects
Neurons / metabolism
Neurons / pathology
Neuroprotective Agents / pharmacology*
Nitric Oxide / metabolism
Nitric Oxide Synthase Type II / deficiency
Nitric Oxide Synthase Type II / genetics*
Paraplegia / genetics
Paraplegia / metabolism
Paraplegia / pathology
Paraplegia / prevention & control*
Reperfusion Injury / drug therapy*
Reperfusion Injury / genetics
Reperfusion Injury / metabolism
Reperfusion Injury / pathology
Signal Transduction
Spinal Cord Ischemia / drug therapy*
Spinal Cord Ischemia / genetics
Spinal Cord Ischemia / metabolism
Spinal Cord Ischemia / pathology
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism
bcl-X Protein / genetics
bcl-X Protein / metabolism

Substances

Bcl2l1 protein, mouse
Neuroprotective Agents
Rela protein, mouse
Transcription Factor RelA
bcl-X Protein
Nitric Oxide
Nitric Oxide Synthase Type II
Nos2 protein, mouse
Hydrogen Sulfide