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

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.

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

“…One strategy has been to target retinal extrasynaptic NMDA receptors (avoiding those located at the synapse) through either the application of specific inhibitors such as memantine [ 359 , 360 , 361 ], targeting the extrasynaptic NMDAR-associated subunit NR2B with substances such as nafamostat or sepimostat [ 362 ], or by interfering with degeneration-promoting interactions between the NMDA receptor and its extrasynaptic partners, as was achieved through inhibiting the NMDA receptor-TRPM4 interface [ 202 ]. Alternatively, modulation of pathways downstream of NMDA receptor activation may allow one to strengthen neuroprotective [ 363 , 364 ] versus apoptotic [ 365 , 366 ] signalling pathways in the retina. One method to achieve this is to target effector mechanisms downstream of physiological NMDA receptor activation, such as enhancing either calcium homeostasis through preservation of mitochondrial function [ 302 , 320 , 367 ] or the ER-mediated UPR response [ 349 , 368 ].…”

Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina

“…Studies have shown that NMDA treatment results in increased loss of RGCs, and intraocular NMDA injection is useful to study RGCs degeneration in retinal diseases [49][50][51][52][53]. The NMDA receptor is a type of glutamate receptor in the mammalian central nervous system [54].…”

Using Computational Drug-Gene Analysis to Identify Novel Therapeutic Candidates for Retinal Neuroprotection

“…Recently, our team and others similarly found evidence that patients taking metformin are associated with a decreased risk of developing retina disorders including AMD and non-proliferative DR when adjusted for age, gender, and other comorbidities [ 63 , 64 ]. It is believed that metformin demonstrates neuroprotection against glutamate-induced excitotoxicity, which is seen in neurodegenerative disorders such as glaucoma and diabetic retinopathy by promoting retinal neuronal cell survival via the MEK/ERK signaling pathway [ 65 , 66 , 67 , 68 ]. The exact function of antidiabetics in translational, preclinical, and clinical investigations to explore their possible role in novel therapeutic strategies for neuroprotection needs to be pursued.…”