Diabetes drug suppresses retinal angiogenesis in mice

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Metformin, an anti-diabetes drug, may partially suppress the formation of neovascular tufts on the retinal surface by blocking the mTORC1 signaling pathway

Image credit: AdobeStock/neirfy

(Image credit: AdobeStock/neirfy)

In an experimental murine study, Rina Yagasaki, PhD, and colleagues from the Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan, found that metformin, an anti-diabetes drug, may partially suppress the formation of neovascular tufts on the retinal surface by blocking the mTORC1 signaling pathway.1

The authors explained that while metformin is used to treat diabetes,the drug has other beneficial effects. “The effects of metformin,” Yagasaki explained, “are mainly mediated by the AMP-activated protein kinase (AMPK)-dependent pathway. AMPK activation interferes with the action of the mammalian target of rapamycin complex 1 (mTORC1), and blocking the mTORC1 pathway suppresses pathological retinal angiogenesis.

Because of thee effects, the investigators examined how the drugs affects pathological angiogenesis and mTORC1 activity in the retinas of mice with oxygen-induced retinopathy (OIR).

Murine model of OIR

To create the mouse model of OIR, the animals were exposed to 80% oxygen from postnatal day 7 to postnatal day 10. The OIR mice then were treated with metformin, rapamycin (an inhibitor of mTORC1), or the vehicle from postnatal days 10 to 12 or 14.

On postnatal days 10, 13, or 15, the investigators evaluated the following: formation of neovascular tufts, revascularization in the central avascular areas, expression of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) 2, and phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTORC1 activity.

Yagasaki and colleagues observedneovascular tufts and vascular growth in the central avascular areas in the retinas of mice with OIR on postnatal day 15. The results showed that from postnatal days 10 to 14 metformin attenuated the formation of the neovascular tufts but not the revascularization in the central avascular areas. Metformin did not significantly inhibit the expression of VEGF and VEGFR2, but it reduced the pS6 immunoreactivity in vascular cells at the sites of angiogenesis. Rapamycin blocked the phosphorylation of ribosomal protein S6 and markedly reduced the formation of neovascular tufts.

The investigators concluded, “These results suggested that metformin partially suppressed the formation of neovascular tufts on the retinal surface by blocking the mTORC1 signaling pathway. Metformin may exert beneficial effects against the progression of ocular diseases in which abnormal angiogenesis is associated with the pathogenesis.”

Reference
1. Yagasaki R, Morita A, Mori A, Sakamoto K, Nakahara, T. Anti-diabetic drug metformin suppresses pathological retinal angiogenesis via blocking the mTORC1 signaling pathway in mice (metformin suppresses pathological angiogenesis). Curr Eye Res. 2024;49:505–512; https://doi.org/10.1080/02713683.2024.2302865
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