Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats.

Koki Watanabe,Akane Morita,Kunio Ishii,Kenji Sakamoto,Asami Mori,Hiroko Ushikubo,Tsutomu Nakahara,Daiki Asano

doi:10.3390/ijms22094439

Abstract

Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its protective effects. Male Sprague–Dawley rats (7 to 9 weeks old) were used in this study. Following intravitreal injection of NMDA (200 nmol/eye), the number of neuronal cells in the ganglion cell layer and parvalbumin-positive amacrine cells decreased, whereas the number of CD45-positive leukocytes and Iba1-positive microglia increased. Metformin attenuated these NMDA-induced responses. The neuroprotective effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK). The AMPK activator, AICAR, exerted a neuroprotective effect in NMDA-induced retinal injury. The MEK1/2 inhibitor, U0126, reduced the neuroprotective effect of metformin. These results suggest that metformin protects against NMDA-induced retinal neurotoxicity through activation of the AMPK and MEK/extracellular signal-regulated kinase (ERK) signaling pathways. This neuroprotective effect could be partially attributable to the inhibitory effects on inflammatory responses.

Highlights

Metformin, an anti-hyperglycemic drug of the biguanide class, controls blood glucose levels by increasing insulin sensitivity and enhancing glucose uptake in the liver, and is widely used in the treatment of type 2 diabetes mellitus [1]
The present study demonstrates that metformin protects against the death of RGCs and amacrine cells in N-methyl-D-aspartic acid (NMDA)-induced excitotoxicity
The AMPK activator, AICAR, exerted a neuroprotective effect against NMDAinduced retinal injury. These results suggest that metformin exerts its protective effect through activation of the AMPK system in the retina

Summary

Introduction

An anti-hyperglycemic drug of the biguanide class, controls blood glucose levels by increasing insulin sensitivity and enhancing glucose uptake in the liver, and is widely used in the treatment of type 2 diabetes mellitus [1]. In addition to its glucose-lowering effect, metformin exerts positive effects in several non-diabetes-related diseases [2]. Previous studies have demonstrated several beneficial effects of metformin in various central nervous system disorders [4,5,6]. Metformin exerts inhibitory effects on inflammatory responses [7] and angiogenesis [7,8], as well as vasodilatory effects on the retinal blood vessels [9]. Metformin protects against retinal neuronal damage in diabetic animals [10,11] and maintains the integrity of the photoreceptors and retinal pigment epithelium, through the activation of AMPK, in animal models of retinitis pigmentosa and age-related macular degeneration [12,13]. Activation of the AMPK system contributes to beneficial effects in the visual system

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