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Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243
Journal article   Open access   Peer reviewed

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, …
Investigative ophthalmology & visual science, Vol.55(12), pp.8330-8341
12/02/2014
DOI: 10.1167/iovs.14-15468
PMCID: PMC5102342
PMID: 25468886
url
https://doi.org/10.1167/iovs.14-15468View
Published (Version of record) Open Access

Abstract

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. 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. 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. 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.
 Dendrites - pathology Brain Injuries - drug therapy Cell Count Brain Injuries - complications Male Brain Injuries - physiopathology Blast Injuries - drug therapy Retinal Ganglion Cells - pathology Vision Disorders - physiopathology Electroretinography - drug effects Neuronal Plasticity - physiology Neuroprotective Agents - pharmacology Blast Injuries - complications Disease Models, Animal Retinal Ganglion Cells - physiology Mice, Inbred C57BL Injections, Intraperitoneal Animals Analysis of Variance Vision Disorders - prevention & control Mice Carbazoles - pharmacology Blast Injuries - physiopathology Retinal Ganglion Cells - drug effects Vision Disorders - etiology

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