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Lei Xu, Jiangang Wang, Li Kong, John D. Ash; Protection Of Retinal Photoreceptors By Activation Of AMPK With Metformin. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5434.
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AMPK (AMP-activated protein kinase pathway) is a serine-threonine kinase that is activated by reductions in cellular ATP levels. Activated AMPK phosphorylates multiple substrates that generally result in reduced ATP consuming activities and increased ATP production. Energy deficiency has been postulated to be a mechanism of photoreceptor degeneration. The goal of this study was to determine whether agonists of AMPK could improve photoreceptor survival through enhanced energy production.
Metformin, an agonist of AMPK was injected daily for 7 days into BALB/cj albino mice (Jackson Laboratories, Bar Harbor, ME, U.S.A.). 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 by Western blots. Mitochondria DNA copy number was assessed by determining mtDNA/nDNA ratio, using qPCR to determine the relative expression of cytochrome oxidase subunit 2(mitochondrial gene) and beta-actin (nuclear gene).
Both systemic and intravitreal injections of Metformin led to activation of AMPK in the retina, and protected photoreceptor function and structure from the light damage in a dose dependent manner.
We have demonstrated that systemic injection of Metformin can activate AMPK in the retina suggesting the drug can cross the blood retinal barrier. Metformin induced protection from light damage suggests that stimulation of the AMPK pathway is a potential therapeutic approach for delaying or preventing retinal degeneration.
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