Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243

Laura M. Dutca, Steven F. Stasheff, Adam Hedberg-Buenz, Danielle S. Rudd, Nikhil Batra, Frederick R. Blodi, Matthew S. Yorek, Terry Yin, Malini Shankar, Judith A. Herlein, Jacinth Naidoo, Lorraine Morlock, Noelle Williams, Randy H. Kardon, Michael G. Anderson, Andrew A. Pieper, Matthew M. Harper

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Purpose: 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.

Original languageEnglish (US)
Pages (from-to)8330-8341
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume55
Issue number12
DOIs
StatePublished - Dec 2 2014

Fingerprint

Retinal Ganglion Cells
Cell Physiological Phenomena
Wounds and Injuries
Neuroprotective Agents
Pathologic Processes
Therapeutics
Traumatic Brain Injury
Routine Diagnostic Tests
Dendritic Cells
Cell Count
Outcome Assessment (Health Care)
Light
Pressure
Brain

Keywords

  • Blast injury
  • Multielectrode array
  • Neuroprotection
  • Pattern ERG
  • Retinal ganglion cell

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243. / Dutca, Laura M.; Stasheff, Steven F.; Hedberg-Buenz, Adam; Rudd, Danielle S.; Batra, Nikhil; Blodi, Frederick R.; Yorek, Matthew S.; Yin, Terry; Shankar, Malini; Herlein, Judith A.; Naidoo, Jacinth; Morlock, Lorraine; Williams, Noelle; Kardon, Randy H.; Anderson, Michael G.; Pieper, Andrew A.; Harper, Matthew M.

In: Investigative Ophthalmology and Visual Science, Vol. 55, No. 12, 02.12.2014, p. 8330-8341.

Research output: Contribution to journalArticle

Dutca, LM, Stasheff, SF, Hedberg-Buenz, A, Rudd, DS, Batra, N, Blodi, FR, Yorek, MS, Yin, T, Shankar, M, Herlein, JA, Naidoo, J, Morlock, L, Williams, N, Kardon, RH, Anderson, MG, Pieper, AA & Harper, MM 2014, 'Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243', Investigative Ophthalmology and Visual Science, vol. 55, no. 12, pp. 8330-8341. https://doi.org/10.1167/iovs.14-15468
Dutca, Laura M. ; Stasheff, Steven F. ; Hedberg-Buenz, Adam ; Rudd, Danielle S. ; Batra, Nikhil ; Blodi, Frederick R. ; Yorek, Matthew S. ; Yin, Terry ; Shankar, Malini ; Herlein, Judith A. ; Naidoo, Jacinth ; Morlock, Lorraine ; Williams, Noelle ; Kardon, Randy H. ; Anderson, Michael G. ; Pieper, Andrew A. ; Harper, Matthew M. / Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243. In: Investigative Ophthalmology and Visual Science. 2014 ; Vol. 55, No. 12. pp. 8330-8341.
@article{71d6503aff0549a59634b45340f92239,
title = "Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243",
abstract = "Purpose: 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.",
keywords = "Blast injury, Multielectrode array, Neuroprotection, Pattern ERG, Retinal ganglion cell",
author = "Dutca, {Laura M.} and Stasheff, {Steven F.} and Adam Hedberg-Buenz and Rudd, {Danielle S.} and Nikhil Batra and Blodi, {Frederick R.} and Yorek, {Matthew S.} and Terry Yin and Malini Shankar and Herlein, {Judith A.} and Jacinth Naidoo and Lorraine Morlock and Noelle Williams and Kardon, {Randy H.} and Anderson, {Michael G.} and Pieper, {Andrew A.} and Harper, {Matthew M.}",
year = "2014",
month = "12",
day = "2",
doi = "10.1167/iovs.14-15468",
language = "English (US)",
volume = "55",
pages = "8330--8341",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "12",

}

TY - JOUR

T1 - Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243

AU - Dutca, Laura M.

AU - Stasheff, Steven F.

AU - Hedberg-Buenz, Adam

AU - Rudd, Danielle S.

AU - Batra, Nikhil

AU - Blodi, Frederick R.

AU - Yorek, Matthew S.

AU - Yin, Terry

AU - Shankar, Malini

AU - Herlein, Judith A.

AU - Naidoo, Jacinth

AU - Morlock, Lorraine

AU - Williams, Noelle

AU - Kardon, Randy H.

AU - Anderson, Michael G.

AU - Pieper, Andrew A.

AU - Harper, Matthew M.

PY - 2014/12/2

Y1 - 2014/12/2

N2 - Purpose: 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.

AB - Purpose: 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.

KW - Blast injury

KW - Multielectrode array

KW - Neuroprotection

KW - Pattern ERG

KW - Retinal ganglion cell

UR - http://www.scopus.com/inward/record.url?scp=84919372230&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919372230&partnerID=8YFLogxK

U2 - 10.1167/iovs.14-15468

DO - 10.1167/iovs.14-15468

M3 - Article

C2 - 25468886

AN - SCOPUS:84919372230

VL - 55

SP - 8330

EP - 8341

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 12

ER -