title: Does enoxaparin interfere with HMGB1 signaling after TBI? A potential mechanism for reduced cerebral edema and neurologic recovery.
abstract: BACKGROUND
  Enoxaparin (ENX) has been shown to reduce cerebral edema and improve neurologic recovery after traumatic brain injury (TBI), through blunting of cerebral leukocyte (LEU) recruitment. High mobility group box 1 (HMGB1) protein may induce inflammation through LEU activation. We hypothesized that ENX after TBI reduces LEU-mediated edema through blockade of HMGB1 signaling.
  
  
  METHODS
  Twenty-three CD1 mice underwent severe TBI by controlled cortical impact and were randomized to one of four groups receiving either monoclonal antibody against HMGB1 (MAb) or isotype (Iso) and either ENX (1 mg/kg) or normal saline (NS): NS + Iso (n = 5), NS + MAb (n = 6), ENX + Iso (n = 6), ENX + MAb (n = 6). ENX or NS was administered 2, 8, 14, 23 and 32 hours after TBI. MAb or Iso (25 μg) was administered 2 hours after TBI. At 48 hours, cerebral intravital microscopy served to visualize live LEU interacting with endothelium and microvascular fluorescein isothiocyanate-albumin leakage. The Neurological Severity Score (NSS) graded neurologic recovery; wet-to-dry ratios determined cerebral/lung edema. Analysis of variance with Bonferroni correction was used for statistical analyses.
  
  
  RESULTS
  ENX and MAb similarly reduced in vivo pial LEU rolling without demonstrating additive effect. In vivo albumin leakage was greatest in vehicle-treated animals but decreased by 25% with either MAb or ENX but by 50% when both were combined. Controlled cortical impact-induced cerebral wet-to-dry ratios were reduced by MAb or ENX without additive effect. Postinjury lung water was reduced by ENX but not by MAb. Neurologic recovery at 24 hours and 48 hours was similarly improved with ENX, MAb, or both treatments combined.
  
  
  CONCLUSIONS
  Mirroring ENX, HMGB1 signaling blockade reduces LEU recruitment, cerebrovascular permeability, and cerebral edema following TBI. ENX further reduced lung edema indicating a multifaceted effect beyond HMGB1 blockade. Further study is needed to determine how ENX may play a role in blunting HMGB1 signaling in brain injury patients.
authors.affiliation: From the Division of Traumatology, Surgical Critical Care and Emergency Surgery (S.L., R.E., K.K., J.M., K.N., J.L.P.), Department of Neurosurgery, Center for Brain Injury, and Repair (V.E.J., K.D.B., D.H.S., J.L.P.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and Department of Neurosurgery (S.L.), Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Shengjie
authors.initials: S
authors.lastname: Li
authors.forename: Rachel
authors.initials: R
authors.lastname: Eisenstadt
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kumasaka
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Johnson
authors.forename: Joshua
authors.initials: J
authors.lastname: Marks
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Nagata
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Browne
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Smith
authors.forename: Jose L
authors.initials: JL
authors.lastname: Pascual
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000925:Anticoagulants / Q000008:administration & dosage; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D001930:Brain Injuries / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D017984:Enoxaparin / Q000008:administration & dosage*; D024243:HMGB1 Protein / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000069416:Intravital Microscopy; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000502:physiology*; D020127:Recovery of Function / Q000502:physiology*; D012677:Sensation / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D017984:Enoxaparin; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse