title: GAPDH/Siah1 cascade is involved in traumatic spinal cord injury and could be attenuated by sivelestat sodium.
abstract: The glyceraldehyde-3-phosphate dehydrogenase (GAPDH)/Siah1 signaling pathway has been recognized as a sensor of nitric oxide (NO). It is associated with a variety of injurious conditions, suggesting its therapeutic potential for spinal cord injury (SCI). Sivelestat sodium (SIV), a neutrophil elastase (NE) inhibitor initially used to treat acute lung injury, has been known to protect against compression-induced and ischemic SCI. However, little is known about the relationship between the GAPDH/Siah1 cascade and SIV. Thus, we aimed to assess the role of GAPDH/Siah1 cascade in traumatic SCI and its possible link with SIV. Rats were assigned to four groups: sham group, SCI group, 5-mg/kg SIV group, and 10-mg/kg SIV. The traumatic SCI was induced by dropping a 10-g impactor from a height of 25mm on the dorsal surface of T9 and T10. SIV was injected intraperitoneally immediately after surgery. Our results showed that the nuclear translocation of GAPDH was induced together with the nuclear translocation of Siah1 and the formation of the GAPDH/Siah1 complex in the spinal cord after traumatic SCI. However, the activation of the GAPDH/Siah1 cascade was attenuated by treatment with SIV. We also found that SIV suppressed apoptosis, NE and inducible nitric oxide synthase (iNOS) protein expressions, the number of NE and iNOS immunostained cells, the production of interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α), and the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) signaling in the spinal cord. The behavioral tests showed that SIV promoted functional recovery after traumatic SCI as reflected in the sustained increase in the Basso-Beattie-Bresnahan (BBB) scores throughout the observation period. In conclusion, our results reveal GAPDH/Siah1 as a novel signaling pathway during the progression of SCI, which can be blocked by SIV.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Huo
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: hldong6@hotmail.com.
authors.forename: Hai-Long
authors.initials: HL
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: Su_luccy@126.com.
authors.forename: Bin-Xiao
authors.initials: BX
authors.lastname: Su
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C069195:sivelestat; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D005998:Glycine
keywords: GAPDH; Siah1; sivelestat sodium; spinal cord injury