title: Dl-3-n-butylphthalide improves functional recovery in rats with spinal cord injury by inhibiting endoplasmic reticulum stress-induced apoptosis.
abstract: Endoplasmic reticulum (ER) stress-induced apoptosis occurs in the spinal cord following traumatic spinal cord injury (SCI). Dl-3-n-butylphthalide (NBP) exerts an neuroprotective effects against both ischemic brain injury and neurodegenerative diseases; however, the relationship between ER stress-induced apoptosis and the therapeutic effect of NBP in SCI remains unclear. In this study, moderate spinal cord injuries were induced in Sprague-Dawley (SD) rats with a vascular clip. NBP was administered by oral (80 mg/kg/d) gavage 2 h before injury and then once daily for 28 d thereafter. Neurological recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) locomotion rating scale, the inclined plane test, and the footprint analysis. Neuronal cell death was examined by TUNEL staining at 7 days post-injury. ER stress and apoptosis-related proteins were quantified by immunofluorescence staining and western blotting bothin vivoandin vitro. Our results showed that NBP significantly decreased spinal cord lesion cavity area and improved locomotor recovery in SD rats after SCI. NBP also decreased neuronal apoptosis and inhibited activation of the caspase 3 cascade. Upregulation of ER stress-related proteins, such as GRP78, ATF-6, ATF-4, PDI, XBP-1, and CHOP, was reversed by NBP treatment in SD rats with SCI. Similarly, NBP effectively ameliorated ER stress and apoptosis-related protein expression induced by incubation with thapsigargin (TG) in PC12 cells. Our findings demonstrate that NBP treatment alleviates secondary SCI by inhibiting ER stress-induced apoptosis, thereby promoting neurological and locomoter functional recovery.
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical UniversityWenzhou 325035, Zhejiang, PR China; Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical UniversityWenzhou 325035, Zhejiang, PR China.
authors.forename: Zili
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical UniversityWenzhou 325035, Zhejiang, PR China; Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical UniversityWenzhou 325035, Zhejiang, PR China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University Wenzhou 325035, Zhejiang, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University Wenzhou 325035, Zhejiang, PR China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical UniversityWenzhou 325035, Zhejiang, PR China; Department of Orthopaedics, Taizhou Hospital, Wenzhou Medical UniversityLinhai 317000, Zhejiang, PR China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical UniversityWenzhou 325035, Zhejiang, PR China; Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical UniversityDongyang 322100, Zhejiang, PR China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University Wenzhou 325035, Zhejiang, PR China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Li
authors.affiliation: Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University Wenzhou 325035, Zhejiang, PR China.
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Affiliated Cixi People's Hospital, Wenzhou Medical University Ningbo 315300, PR China.
authors.forename: Fenzan
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Ningbo Medical Treatment Center Li Hui-Li Hospital Ningbo 315040, PR China.
authors.forename: Xie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Affiliated Cixi People's Hospital, Wenzhou Medical University Ningbo 315300, PR China.
authors.forename: Songlin
authors.initials: S
authors.lastname: Tong
authors.affiliation: Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University Dongyang 322100, Zhejiang, PR China.
authors.forename: Maofeng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University Wenzhou 325035, Zhejiang, PR China.
authors.forename: Zhouguang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University Wenzhou 325035, Zhejiang, PR China.
authors.forename: Huacheng
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University Wenzhou 325035, Zhejiang, PR China.
authors.forename: Huazi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical UniversityWenzhou 325035, Zhejiang, PR China; Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical UniversityWenzhou 325035, Zhejiang, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
keywords: Dl-3-n-butylphthalide; ER stress; apoptosis; spinal cord injury