June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
TSPO agonist XBD173 protects photoreceptors in a murine model of retinal ischemia
Author Affiliations & Notes
  • Antje Grosche
    Institute of Human Genetics, University of Regensburg, Regensburg, Germany
  • Kristin Mages
    Institute of Human Genetics, University of Regensburg, Regensburg, Germany
  • Herbert Jaegle
    Department of Ophthalmology, University of Regensburg, Regensburg, Germany
  • Footnotes
    Commercial Relationships   Antje Grosche, None; Kristin Mages, None; Herbert Jaegle, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5389. doi:
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      Antje Grosche, Kristin Mages, Herbert Jaegle; TSPO agonist XBD173 protects photoreceptors in a murine model of retinal ischemia. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5389.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Translocator protein (18 kDa) (TSPO) agonists could be neuroprotective and promote regeneration by modulating the glial response to neurodegeneration. We asked how the TSPO agonist XBD173 affects the glial response to an experimental model of transient ischemia in mouse retina and how this influences neurodegeneration.

Methods : Transient ischemia in mice was induced by raising the intraocular pressure interrupting retinal blood supply for 60 min. XBD173 (10 mg/kg body weight) or vehicle was i.p. injected twice a day starting one day before surgery and once each day thereafter. Cells were quantified by DAPI and TUNEL staining of retinal slices. Microglia were investigated by Iba1, Il-1β and CD206 labeling in retinal flatmounts. Glial activation markers were analyzed by quantitative PCR on samples from microglia, neurons, endothelial, Müller cells and retinal pigment epithelium (RPE) enriched by magnetic activated cells sorting performed 7 and 14 (d) days after ischemia. Retinal function is assessed by electroretinography (ERG) in 14d postischemic mice.

Results : TSPO, target of our treatment paradigm, was highest expressed in Müller cells and RPE, at moderate levels in endothelial cells and microglia, but not in neurons. After ischemia, TSPO was up-regulated in micro- and Müllerglia. Photoreceptor degeneration stopped after initial loss (7d after surgery, 76.3± 4.3 % surviving cells compared to healthy control eye; n=3) in XBD173-treated mice 14d after surgery (75.6 ± 6.3%; n=5). In contrast, postischemic photoreceptors degeneration proceeded in untreated mice from 70.8 ± 5.9 % (n=4) 7d compared to 53.3 ± 9.0 % (n=5) at 14d post ischemia. Less microglia invaded into the 3d postischemic outer nuclear layer under XBD173 treatement. However, several marker genes indicated stronger microglia activation after XBD173 treatment (F4/80, TSPO; 5.1- and 3.4-fold higher at 14d; n=4-6). Similarly, expression profiling implied that XBD173 treatment led to stronger Müller cell activation than in untreated postischemic retinae (~3.0-fold higher GFAP expression at 7 and 14d post ischemia; n=4-6). Investigations on M1 (pro-inflammatory) or M2 (regenerative) microglial polarization patterns and assessment of retinal function by ERG are work in progress.

Conclusions : We demonstrate that XBD173 leads to an altered glial response pattern in the postischemic retina and specifically prevents secondary photoreceptor loss.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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