June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Mechanisms of RGC Neuroprotection Mediated by ST266
Author Affiliations & Notes
  • Reas Sulaimankutty
    Ophthalmology, Univ of Pennsylvania, Scheie Eye Institute, Philadelphia, Pennsylvania, United States
  • Kimberly Dine
    Ophthalmology, Univ of Pennsylvania, Scheie Eye Institute, Philadelphia, Pennsylvania, United States
  • Larry R Brown
    Noveome Biotherapeutics Inc, Pittsburgh, Pennsylvania, United States
  • Kenneth S Shindler
    Ophthalmology, Univ of Pennsylvania, Scheie Eye Institute, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Reas Sulaimankutty, None; Kimberly Dine, None; Larry Brown, Noveome Biotherapeutics, Inc (E); Kenneth Shindler, Noveome Biotherapeutics, Inc (F), Noveome Biotherapeutics, Inc (C), Noveome Biotherapeutics, Inc (R)
  • Footnotes
    Support  NIH Grant EY019014; Research to Prevent Blindness; and the F. M. Kirby Foundation
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3322. doi:
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      Reas Sulaimankutty, Kimberly Dine, Larry R Brown, Kenneth S Shindler; Mechanisms of RGC Neuroprotection Mediated by ST266. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3322.

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

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Abstract

Purpose : Optic neuritis occurs during multiple sclerosis (MS) and induces retinal ganglion cell (RGC) loss. Thus, neuroprotective therapies are needed. We previously showed that intranasally delivered ST266, the biological secretome of Amnion-derived Multipotent Progenitor cells, attenuated loss of vision and RGCs in experimental optic neuritis, but mechanisms of its actions are not known. Potential mechanisms by which ST266 prevents RGC loss were examined in the experimental autoimmune encephalomyelitis (EAE) model of MS.

Methods : EAE was induced in C57/BL6 mice by immunization with myelin oligodendroglial glycoprotein peptide. Mice were treated daily with 6 µL intranasal PBS or ST266 beginning day 15 through sacrifice (days 22, 30 or 42). Optic nerves were stained with mitochondrial superoxide indicator MitoSOX red. Western blot analysis was performed on proteins isolated from retinas or optic nerves. ST266-mediated RGC neuroprotection was further examined in primary retinal cell cultures exposed to 5µM staurosporine ± ST266 for 24 hrs. ST266 neuroprotective effects were challenged with exposure to specific inhibitors of SIRT1 and pAKT.

Results : MitoSOX red staining showed that ST266 treatment lead to a reduction (p<0.01) in reactive oxygen species in EAE optic nerves on days 22 and 42. Western blot analysis showed that ST266 treated EAE mice had increased expression of SIRT1 deacetylase (day 22, p<0.05) and of mitochondrial coenzyme PGC1α (days 22 and 30, p<0.05) in the retina, as compared to PBS treated EAE mice. Retinal and optic nerve levels of mitochondrial enzyme SDHβ increased by day 30 (p<0.05). Levels of pAKT were also higher (p<0.05) in retinas of EAE mice treated with ST266 on day 30; however, phosphorylation of PDK1 was not increased. In retinal cultures, treatment with ST266 (diluted 1:20) significantly attenuated RGC loss, and co-administration of either the SIRT1 inhibitor EX527 (2µM) or pAKT inhibitor X (7µM), blocked the protective effect of ST266.

Conclusions : Increased SIRT1 expression and mitochondrial enzymes in ST266-treated EAE mice suggest ST266 stimulation of SIRT1 deacetylase activity promotes RGC survival through increased mitochondrial biogenesis and reduction of oxidative stress. In vitro studies using specific inhibitors confirm that ST266 stimulated SIRT1 and pAKT signaling mediate RGC survival. Together results demonstrate two mechanisms involved in ST266-mediated neuroprotection.

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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