title: Effect of amiloride on endoplasmic reticulum stress response in the injured spinal cord of rats.
abstract: After traumatic spinal cord injury (SCI), endoplasmic reticulum (ER) stress exacerbates secondary injury, leading to expansion of demyelination and reduced remyelination due to oligodendrocyte precursor cell (OPC) apoptosis. Although recent studies have revealed that amiloride controls ER stress and leads to improvement in several neurological disorders including SCI, its mechanism is not completely understood. Here, we used a rat SCI model to assess the effects of amiloride on functional recovery, secondary damage expansion, ER stress-induced cell death and OPC survival. Hindlimb function in rats with spinal cord contusion significantly improved after amiloride administration. Amiloride significantly decreased the expression of the pro-apoptotic transcription factor CHOP in the injured spinal cord and significantly increased the expression of the ER chaperone GRP78, which protects cells against ER stress. In addition, amiloride treatment led to a significant decrease in ER stress-induced apoptosis and a significant increase of NG2-positive OPCs in the injured spinal cord. Furthermore, in vitro experiments performed to investigate the direct effect of amiloride on OPCs revealed that amiloride reduced CHOP expression in OPCs cultured under ER stress. These results suggest that amiloride controls ER stress in SCI and inhibits cellular apoptosis, contributing to OPC survival. The present study suggests that amiloride may be an effective treatment to reduce ER stress-induced cell death in the acute phase of SCI.
authors.affiliation: Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kuroiwa
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Katoh
authors.forename: Kaori
authors.initials: K
authors.lastname: Suyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsuyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imai
authors.forename: Joji
authors.initials: J
authors.lastname: Mochida
mesh_terms: D000584:Amiloride / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism*; D013904:Thoracic Vertebrae; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000584:Amiloride; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP
keywords: apoptosis; glial cells; in vivo; rat; spinal cord injury