title: Treatment with amnion-derived cellular cytokine solution (ACCS) induces persistent motor improvement and ameliorates neuroinflammation in a rat model of penetrating ballistic-like brain injury.
abstract: OBJECTIVE
  The present work compared the behavioral outcomes of ACCS therapy delivered either intravenously (i.v.) or intracerebroventricularly (i.c.v.) after penetrating ballistic-like brain injury (PBBI). Histological markers for neuroinflammation and neurodegeneration were employed to investigate the potential therapeutic mechanism of ACCS.
  
  
  METHODS
  Experiment-1, ACCS was administered either i.v. or i.c.v. for 1 week post-PBBI. Outcome metrics included behavioral (rotarod and Morris water maze) and gross morphological assessments. Experiment-2, rats received ACCS i.c.v for either 1 or 2 weeks post-PBBI. The inflammatory response was determined by immunohistochemistry for neutrophils and microglia reactivity. Neurodegeneration was visualized using silver staining.
  
  
  RESULTS
  Both i.v. and i.c.v. delivery of ACCS improved motor outcome but failed to improve cognitive outcome or tissue sparing. Importantly, only i.c.v. ACCS treatment produced persistent motor improvements at a later endpoint. The i.c.v. ACCS treatment significantly reduced PBBI-induced increase in myeloperoxidase (MPO) and ionized calcium binding adaptor molecule 1 (Iba1) expression. Concomitant reduction of both Iba1 and silver staining were detected in corpus callosum with i.c.v. ACCS treatment.
  
  
  CONCLUSIONS
  ACCS, as a treatment for TBI, showed promise with regard to functional (motor) recovery and demonstrated strong capability to modulate neuroinflammatory responses that may underline functional recovery. However, the majority of beneficial effects appear restricted to the i.c.v. route of ACCS delivery, which warrants future studies examining delivery routes (e.g. intranasal delivery) which are more clinically viable for the treatment of TBI.
authors.affiliation: Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Deng-Bryant
authors.affiliation: Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Readnower
authors.affiliation: Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, USA.
authors.forename: Lai Yee
authors.initials: LY
authors.lastname: Leung
authors.affiliation: Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Cunningham
authors.affiliation: Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Shear
authors.affiliation: Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tortella
mesh_terms: D000650:Amnion; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000008:administration & dosage*; D004195:Disease Models, Animal; D020197:Head Injuries, Penetrating / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008840:Microfilament Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D012996:Solutions
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D012996:Solutions; D009195:Peroxidase
keywords: Amnion-derived cellular cytokine solution; microglia; morris water maze; neurodegeneration; neuroinflammation; neutrophil; penetrating ballistic-like brain injury; rotarod