title: Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243.
abstract: OBJECTIVE
  Traumatic brain injury (TBI) frequently leads to chronic visual dysfunction. The purpose of this study was to investigate the effect of TBI on retinal ganglion cells (RGCs), and to test whether treatment with the novel neuroprotective compound P7C3-S243 could prevent in vivo functional deficits in the visual system.
  
  
  METHODS
  Blast-mediated TBI was modeled using an enclosed over-pressure blast chamber. The RGC physiology was evaluated using a multielectrode array and pattern electroretinogram (PERG). Histological analysis of RGC dendritic field and cell number were evaluated at the end of the study. Visual outcome measures also were evaluated based on treatment of mice with P7C3-S243 or vehicle control.
  
  
  RESULTS
  We show that deficits in neutral position PERG after blast-mediated TBI occur in a temporally bimodal fashion, with temporary recovery 4 weeks after injury followed by chronically persistent dysfunction 12 weeks later. This later time point is associated with development of dendritic abnormalities and irreversible death of RGCs. We also demonstrate that ongoing pathologic processes during the temporary recovery latent period (including abnormalities of RGC physiology) lead to future dysfunction of the visual system. We report that modification of PERG to provocative postural tilt testing elicits changes in PERG measurements that correlate with a key in vitro measures of damage: the spontaneous and light-evoked activity of RGCs. Treatment with P7C3-S243 immediately after injury and throughout the temporary recovery latent period protects mice from developing chronic visual system dysfunction.
  
  
  CONCLUSIONS
  Provocative PERG testing serves as a noninvasive test in the living organism to identify early damage to the visual system, which may reflect corresponding damage in the brain that is not otherwise detectable by noninvasive means. This provides the basis for developing an earlier diagnostic test to identify patients at risk for developing chronic CNS and visual system damage after TBI at an earlier stage when treatments may be more effective in preventing these sequelae. In addition, treatment with the neuroprotective agent P7C3-S243 after TBI protects from visual system dysfunction after TBI.
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States Departments of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Dutca
authors.affiliation: Departments of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Stasheff
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Hedberg-Buenz
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Rudd
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Batra
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Blodi
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Yorek
authors.affiliation: Department of Psychiatry, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Terry
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Malini
authors.initials: M
authors.lastname: Shankar
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Herlein
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Jacinth
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Morlock
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Noelle
authors.initials: N
authors.lastname: Williams
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States Departments of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Randy H
authors.initials: RH
authors.lastname: Kardon
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States Departments of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Anderson
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States Department of Neurology, The University of Iowa, Iowa City, Iowa, United States Department of Psychiatry, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
authors.affiliation: The Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, Iowa, United States Departments of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Harper
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001753:Blast Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002227:Carbazoles / Q000494:pharmacology*; D002452:Cell Count; D003712:Dendrites / Q000473:pathology; D004195:Disease Models, Animal; D004596:Electroretinography / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D014786:Vision Disorders / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D002227:Carbazoles; D018696:Neuroprotective Agents; C552520:P7C3 compound
keywords: blast injury; multielectrode array; neuroprotection; pattern ERG; retinal ganglion cell