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Zhongqiao Lu, Wangzi Li, Wei Liu, Mingchang Zhang; Oral administration of metformin protects retinal ganglion cells after optic nerve crush in mice by the cAMP/Epac1/p-CaMKII pathway. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4050.
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© ARVO (1962-2015); The Authors (2016-present)
Traumatic optic neuropathy is an acute injury of the optic nerve secondary to ocular trauma in which retinal ganglion cells (RGCs) undergo apoptosis and necroptosis, eventually resulting in irreversible loss of visual function. The purpose of this study was to determine whether RGCs can be protected from death by the widely used antidiabetic drug metformin in a mouse model of optic nerve crush (ONC), and to investigate the mechanisms underlying its neuroprotective effects.
ONC was performed by a transient crush of optic nerve behind the eye ball in C57BL/6J mice. Metformin (20mg/kg) or its vehicle was given daily through oral gavage. Eye balls were collected 9 hours to 7 days after ONC. The inflammatory response was determined by adherence and infiltration of leukocytes. Cyclic AMP (cAMP), exchange protein directly activated by cAMP 1 (Epac1), phospho-calcium/calmodulin-dependent protein kinase II (p-CaMKII), receptor-interacting protein kinase 3 (RIP3), phosphor-tau, inflammatory molecules, and RGC injury were determined by immunohistochemistry, Western blot, or quantitative PCR.
In the early stage (9 hours) after the ONC injury, fewer leukocytes were found to adhere in blood vessels and infiltrate in metformin/ONC retinas compared to the vehicle/ONC (n=3, p<0.01). Then we demonstrated that ONC-induced retinal neuronal apoptosis and necroptosis were alleviated 3 days after ONC. At 7 days after ONC, there was 49.5% RGC loss in mice given vehicle and such loss was reduced to 31.3% in mice given metformin (n=5, p<0.01). Mechanistically, the protective effects of metformin may be mediated by its downregulation of cAMP/Epac1/p-CaMKII levels, leading to decreased tau phosphorylation and attenuated inflammatory response after ONC.
Our results are consistent with our hypothesis that oral administration of metformin decreased tau phosphorylation, alleviated retinal inflammatory response and eventually protected RGCs against ONC. These findings would provide possible treatments to preserve RGCs and visual function for the patients suffering ocular trauma.
This is a 2020 ARVO Annual Meeting abstract.
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