title: The effects of dexmedetomidine pretreatment on the pro- and anti-inflammation systems after spinal cord injury in rats.
abstract: Excessive inflammatory responses play important roles in the aggravation of secondary damage to an injured spinal cord. Dexmedetomidine (DEX), a selective α2-adrenoceptor agonist, has recently been implied to be neuroprotective in clinical anesthesia, but the underlying mechanism is elusive. As signaling through Toll-like receptor 4 (TLR4) and nicotinic receptors (nAChRs, notably α7nAChR) play important roles in the pro- and anti-inflammation systems in the central nervous system, respectively, this study investigated whether and how they were modulated by DEX pretreatment in a rat model of spinal cord compression. The model was used to mimic perioperative compressive spinal cord injury (SCI) during spinal correction. DEX preconditioning improved locomotor scores after SCI, which was accompanied by increased α7nAChR and acetylcholine (Ach, an endogenous ligand of α7nAChR) expression as well as PI3K/Akt activation. However, there was a decrease in Ly6h (a negative regulator for α7nAChR trafficking), TLR4, PU.1 (a critical transcriptional regulator of TLR4), HMGB1 (an endogenous ligand of TLR4), and caspase 3-positive cells, which was prevented by intrathecal preconditioning with antagonists of either α2R, α7nAChR or PI3K/Akt. In addition, application of an α7nAChR agonist produced effects similar to those of DEX after SCI, while application of an α7nAChR antagonist reversed these effects. Furthermore, both α7nAChR and TLR4 were mainly co-expressed in NeuN-positive cells of the spinal ventral horn, but not in microglia or astrocytes after SCI. These findings imply that the α2R/PI3K/Akt/Ly6h and α7nAChR/PI3K/Akt/PU.1 cascades are required for upregulated α7nAChR and downregulated TLR4 expression by DEX pretreatment, respectively, which provided a unique insight into understanding DEX-mediated neuroprotection.
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Rong
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Lianyungang City, Lianyungang, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Lianyungang City, Lianyungang, China.
authors.forename: Jiying
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Yishan
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Rao
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Zuoxia
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Bailing
authors.initials: B
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: YuE
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China. Electronic address: mazhengliang1964@nju.edu.cn.
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu, China. Electronic address: liuyueseu@163.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020927:Dexmedetomidine / Q000008:administration & dosage*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009187:Myelitis / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D018836:Inflammation Mediators; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D064569:alpha7 Nicotinic Acetylcholine Receptor; D020927:Dexmedetomidine
keywords: Dexmedetomidine; Inflammation; Neuroprotection; Spinal cord injury; Toll-like receptor 4; α7 nicotinic acetylcholine receptor