Anti-diabetic drug metformin dilates retinal blood vessels through activation of AMP-activated protein kinase in rats

Nadeem

et al. 2022

IJMS

Retinal cell death is responsible for irreversible vision loss in many retinal disorders. No commercially approved treatments are currently available to attenuate retinal cell loss and preserve vision. We seek to identify chemicals/drugs with thoroughly-studied biological functions that possess neuroprotective effects in the retina using a computational bioinformatics approach. We queried the National Center for Biotechnology Information (NCBI) to identify genes associated with retinal neuroprotection. Enrichment analysis was performed using ToppGene to identify compounds related to the identified genes. This analysis constructs a Pharmacome from multiple drug-gene interaction databases to predict compounds with statistically significant associations to genes involved in retinal neuroprotection. Compounds with known deleterious effects (e.g., asbestos, ethanol) or with no clinical indications (e.g., paraquat, ozone) were manually filtered. We identified numerous drug/chemical classes associated to multiple genes implicated in retinal neuroprotection using a systematic computational approach. Anti-diabetics, lipid-lowering medicines, and antioxidants are among the treatments anticipated by this analysis, and many of these drugs could be readily repurposed for retinal neuroprotection. Our technique serves as an unbiased tool that can be utilized in the future to lead focused preclinical and clinical investigations for complex processes such as neuroprotection, as well as a wide range of other ocular pathologies.

Section: Discussionmentioning

confidence: 99%

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

Nadeem

et al. 2022

IJMS

“…Metformin inhibits inflammatory reactions and angiogenesis in the retina, in addition to lowering blood glucose levels. Aside from these benefits, the retinal vasodilator influence can help prevent or delay the development of diabetic retinopathy [42]. KN-93, a calmodulin-dependent protein kinase inhibitor, prevents neuronal cell viability in an in vitro Alzheimer's disease model, according to Yilmaz.…”

Section: No Acts As a Kinase Inhibitormentioning

confidence: 99%

Importance of Protein Kinase and Its Inhibitor: A Review

Panneerselvam¹,

Kunjiappan²,

Hegde³

et al. 2021

Biochemistry

Deregulation of a broad range of protein kinases has been linked to the development and growth of cancer cells. Protein kinases are intracellular enzymes that regulate cell growth and proliferation as well as the triggering and regulation of immune responses. Protein kinases are important therapeutic targets in cancer because of their critical role in signalling mechanisms that drive malignant cell characteristics. Intensive efforts in drug research have been made in this area over the last two decades. The current study delves into the catalytic domain of a protein kinase as well as information transfer from the cell’s membrane to internal targets. It also discusses the function of protein kinases in signal transduction and their cellular signalling pathways. Furthermore, it specifically outlines a systematic method to hybrid therapies to solve the issue of protein kinase resistance. The therapeutic use of nitric oxide, as well as other targets such as Phosphoinositide 3-kinases (PI3K), Protein Kinase B (Akt), serine/threonine protein kinase (mTOR), p38 mitogen-activated protein kinases (p38 MAPK), vascular endothelial growth factor receptors (VEGFR), epidermal growth factor receptors (EGFR), and anaplastic lymphoma (ALK) etc., According to the review article, selective therapy has shown high effectiveness in the treatment of advanced cancer, with protein kinase inhibitors being a main focus of the therapy. As a result, the latest review summarized that, the current state of science with the aim of identifying a novel protein kinase inhibitor that may be utilized in the treatment of advanced cancers.

“…Previous studies have demonstrated several beneficial effects of metformin in various central nervous system disorders [ 4 , 5 , 6 ]. In the visual system, metformin exerts inhibitory effects on inflammatory responses [ 7 ] and angiogenesis [ 7 , 8 ], as well as vasodilatory effects on the retinal blood vessels [ 9 ]. Furthermore, 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 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, 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 ]. Similarly, AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside), an activator of AMPK, attenuates diabetes-induced retinal inflammation [ 7 , 14 ] and dilates retinal blood vessels [ 9 ]. Thus, activation of the AMPK system contributes to beneficial effects in the visual system.…”

Section: Introductionmentioning

confidence: 99%

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

Watanabe

Asano

Ushikubo

et al. 2021

IJMS

Self Cite

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.