September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
The 5HT1a Agonist Xaliproden Exhibits Anti-oxidant and Anti-inflammatory Properties and Protects the Retina in a Mouse Model of Geographic Atrophy
Author Affiliations & Notes
  • Alfred S Lewin
    Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States
  • Chulbul M Ahmed
    Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States
  • Manas Ranjan Biswal
    Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States
  • Hong Li
    Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States
  • Pingyang Han
    Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States
  • Footnotes
    Commercial Relationships   Alfred Lewin, AGTC,Inc (C), Shire, Inc. (C); Chulbul Ahmed, None; Manas Ranjan Biswal, None; Hong Li, None; Pingyang Han, None
  • Footnotes
    Support  BrightFocus Foundation
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4428. doi:
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    • Get Citation

      Alfred S Lewin, Chulbul M Ahmed, Manas Ranjan Biswal, Hong Li, Pingyang Han; The 5HT1a Agonist Xaliproden Exhibits Anti-oxidant and Anti-inflammatory Properties and Protects the Retina in a Mouse Model of Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4428.

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

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Abstract

Purpose : Chronic oxidative stress with concomitant inflammation have been implicated in the pathogenesis of age related macular degeneration (AMD). The purpose of this study was to test the serotonin agonist, xaliproden for protection against geographic atrophy in a mouse model. This orally available compound has been tested in clinical trials for other indications.

Methods : ARPE-19 cells were treated with paraquat, an oxidative stressor with or without xaliproden. In a separate experiment, TNF-α was added to the cells in the presence or absence of the drug. Synthesis of protective antioxidant factors and of inflammatory cytokines was assayed by RT-qPCR. Survival of cells was measured by MTS assay and microscopy. Integrity of the cell monolayer was assessed by immunostaining with ZO-1 antibody and by transepithelial electrical resistance (TEER). Mice deleted for Sod2 in the RPE were gavage fed xaliproden daily for 4 months. SD-OCT and ERG were used to analyze retinal structure. Optokinetic measurements were used to assess visual acuity. Light and electron microscopy were used to evaluate the retinal structure.

Results : Survival of cells following paraquat treatment was dependent on the dose of xaliproden. An increase in the transcript levels of NqO1, GSTM1, Nrf2, and metallothionein 1 was observed with xaliproden treatment. The induction of IL-1b, IL-6 and VEGFA in TNF-α treated cells was attenuated by xaliproden exposure. TNF-α led to a decrease in TEER that was prevented by xaliproden. Protection of the integrity of the tight junctions was also documented by ZO-1 staining. Oral dosing with xaliproden induced the expression of protective enzymes in the mouse retina. Mice with an Sod2 deletion in RPE treated with xaliproden showed improvement in visual acuity and in thickness of the outer nuclear layer, but no change in full field ERG amplitudes was observed among treatment groups. These mice showed substantial vacuolization of the RPE and disorganization of photoreceptor outer segments that was prevented by oral treatment with the drug

Conclusions : Xaliproden can protect the RPE and retina against oxidative as well as inflammatory insults, suggesting that it can be developed as an oral drug for the treatment of AMD.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Damage to the RPE and photoreceptors (left) is prevented by daily p.o.dosing with xaliproden (right).

Damage to the RPE and photoreceptors (left) is prevented by daily p.o.dosing with xaliproden (right).

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