March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Activation Of AMPK Protects Photoreceptors From Light Damage By Preventing Oxidative Stress, And Requires Signaling Through GP130 And STAT3
Author Affiliations & Notes
  • Lei Xu
    Ophthalmology, Univ of Florida, Gainesville, Florida
  • John D. Ash
    Ophthalmology, Univ of Florida, Gainesville, Florida
  • Footnotes
    Commercial Relationships  Lei Xu, None; John D. Ash, None
  • Footnotes
    Support  Funding support to JDA include NIH R01EY016459-06, Foundation Fighting Blindness, and Lew Wasserman Merit award and unrestricted departmental support from Research to Prevent Blindness, Inc.
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2587. doi:
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      Lei Xu, John D. Ash; Activation Of AMPK Protects Photoreceptors From Light Damage By Preventing Oxidative Stress, And Requires Signaling Through GP130 And STAT3. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2587.

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

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Abstract

Purpose: : AMPK (AMP-activated protein kinase pathway) is a serine-threonine kinase that is activated by reductions in cellular ATP levels. We have previously reported that metformin, an agonist of AMPK, can protect photoreceptors from light damage. The goal of this study was to determine the protective mechanisms.

Methods: : Metformin, an agonist of AMPK was injected daily for 7 days into BALB/cj albino mice (Jackson Laboratories, Bar Harbor, ME, U.S.A.), or gp130 knockout mice. Mice were then exposed to damaging light (4000 lux for 4 hours) following the intravitreal or subcutaneous injection of metformin. All procedures were in accord with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. To verify neuroprotective function of metformin, visual function was measured by electroretinogram (ERG) and photoreceptor protection was measured by counting the rows of photoreceptors in histological sections. To investigate the mechanism we assessed activation of phosphorylated AMPK and PGC-1 alpha by Western blots. Real time PCR was used to measure gene expression. Mitochondrial proteomics was done by MS analysis.

Results: : Both systemic and intravitreal injections of Metformin led to activation of AMPK in the retina, and prevented light induced oxidative stress including DNA and protein oxidation. The protection was partially lost in mice lacking gp130 or STAT3.

Conclusions: : We have demonstrated that metformin can prevent oxidative stress from light damage by a mechanism that includes increased mitochondrial DNA content and mitochondrial gene expression. The protection partially required the activity of the protective pathway induced by gp130 and STAT3. These results suggest that gene expression induced by STAT3 activation can interact with targets of AMPK activation to promote photoreceptor survival.

Keywords: neuroprotection • photoreceptors • signal transduction 
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