title: Retinoic Acid Induced-Autophagic Flux Inhibits ER-Stress Dependent Apoptosis and Prevents Disruption of Blood-Spinal Cord Barrier after Spinal Cord Injury.
abstract: Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB) which leads to infiltration of blood cells, an inflammatory response, and neuronal cell death, resulting spinal cord secondary damage. Retinoic acid (RA) has a neuroprotective effect in both ischemic brain injury and SCI, however the relationship between BSCB disruption and RA in SCI is still unclear. In this study, we demonstrated that autophagy and ER stress are involved in the protective effect of RA on the BSCB. RA attenuated BSCB permeability and decreased the loss of tight junction (TJ) molecules such as P120, β-catenin, Occludin and Claudin5 after injury in vivo as well as in Brain Microvascular Endothelial Cells (BMECs). Moreover, RA administration improved functional recovery in the rat model of SCI. RA inhibited the expression of CHOP and caspase-12 by induction of autophagic flux. However, RA had no significant effect on protein expression of GRP78 and PDI. Furthermore, combining RA with the autophagy inhibitor chloroquine (CQ) partially abolished its protective effect on the BSCB via exacerbated ER stress and subsequent loss of tight junctions. Taken together, the neuroprotective role of RA in recovery from SCI is related to prevention of of BSCB disruption via the activation of autophagic flux and the inhibition of ER stress-induced cell apoptosis. These findings lay the groundwork for future translational studies of RA for CNS diseases, especially those related to BSCB disruption.
authors.affiliation: 1. Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China ; 2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1. Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China ; 2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: 2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Libing
authors.initials: L
authors.lastname: Ye
authors.affiliation: 1. Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China ; 2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Sipin
authors.initials: S
authors.lastname: Zhu
authors.affiliation: 3. Department of Bioengineering and the McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Noah R
authors.initials: NR
authors.lastname: Johnson
authors.affiliation: 2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Zhouguang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 4. Department of Neurosurgery, Cixi People's Hospital, Wenzhou Medical University, Ningbo, 315300, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wei
authors.affiliation: 5. Department of Emergency, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Daqing
authors.initials: D
authors.lastname: Chen
authors.affiliation: 6. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Cao
authors.affiliation: 7. Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Fu
authors.affiliation: 2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: 1. Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Hua-Zi
authors.initials: HZ
authors.lastname: Xu
authors.affiliation: 2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism*; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D014212:Tretinoin
keywords: autophagy; blood-spinal cord barrier (BSCB); endocytoplasmic reticulum (ER) stress; retinoic acid (RA); spinal cord injury (SCI)