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

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...

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Autores principales: Watanabe, Koki, Asano, Daiki, Ushikubo, Hiroko, Morita, Akane, Mori, Asami, Sakamoto, Kenji, Ishii, Kunio, Nakahara, Tsutomu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123037/
https://www.ncbi.nlm.nih.gov/pubmed/33922757
http://dx.doi.org/10.3390/ijms22094439
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author Watanabe, Koki
Asano, Daiki
Ushikubo, Hiroko
Morita, Akane
Mori, Asami
Sakamoto, Kenji
Ishii, Kunio
Nakahara, Tsutomu
author_facet Watanabe, Koki
Asano, Daiki
Ushikubo, Hiroko
Morita, Akane
Mori, Asami
Sakamoto, Kenji
Ishii, Kunio
Nakahara, Tsutomu
author_sort Watanabe, Koki
collection PubMed
description 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.
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spelling pubmed-81230372021-05-16 Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats Watanabe, Koki Asano, Daiki Ushikubo, Hiroko Morita, Akane Mori, Asami Sakamoto, Kenji Ishii, Kunio Nakahara, Tsutomu Int J Mol Sci Article 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. MDPI 2021-04-23 /pmc/articles/PMC8123037/ /pubmed/33922757 http://dx.doi.org/10.3390/ijms22094439 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Watanabe, Koki
Asano, Daiki
Ushikubo, Hiroko
Morita, Akane
Mori, Asami
Sakamoto, Kenji
Ishii, Kunio
Nakahara, Tsutomu
Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats
title Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats
title_full Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats
title_fullStr Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats
title_full_unstemmed Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats
title_short Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats
title_sort metformin protects against nmda-induced retinal injury through the mek/erk signaling pathway in rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123037/
https://www.ncbi.nlm.nih.gov/pubmed/33922757
http://dx.doi.org/10.3390/ijms22094439
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