Protective effect of metformin on rat diabetic retinopathy involves suppression of toll-like receptor 4/nuclear factor-k B expression and glutamate excitotoxicity

Alomar, Suliman Yousef; Barakat, Bassant M.; El-Dosoky, Mohamed; Atef, Hoda; Mohamed, Abdelaty Shawky; Elhawary, Reda; El-Shafey, Mohamed; Youssef, Amal M.; Elkazaz, Amany Y.; Gabr, Attia; Elaskary, Abdelhakeem; Salih, Mohamed Ali; Alolayan, Sultan Othman; Zaitone, Sawsan A.

doi:10.1016/j.intimp.2020.107193

Cited by 27 publications

(12 citation statements)

References 76 publications

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“…We evaluated the effects of NOX2 blockade on glutamate metabolism and reported a statistically significant increase in glutamate levels in the retinas of diabetic non-treated animals. As mentioned above, an increase in retinal levels of glutamate as a result of diabetes has been identified in many studies, both in diabetic patients and in animal models of DR, as an early diabetic insult [ 36 , 37 , 38 , 40 , 87 , 88 , 94 ]. This occurs as a result of various impairments in retinal glutamate metabolism, including alterations in the expression of glutamate transporters.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Effects of a Novel NOX2 Inhibitor, GLX7013170, against Glutamate Excitotoxicity and Diabetes Insults in the Retina

Dionysopoulou,

Wikstrom,

Walum

et al. 2024

Pharmaceuticals

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Glutamate excitotoxicity and oxidative stress represent two major pathological mechanisms implicated in retinal disorders. In Diabetic Retinopathy (DR), oxidative stress is correlated to NADPH oxidase (NOX), a major source of Reactive Oxygen Species (ROS), and glutamate metabolism impairments. This study investigated the role of NOX2 and the novel NOX2 inhibitor, GLX7013170, in two models of a) retinal AMPA excitotoxicity [AMPA+GLX7013170 (10−4 M, intravitreally)] and b) early-stage DR paradigm (ESDR), GLX7013170: 14-day therapeutic treatment (topically, 20 μL/eye, 10 mg/mL (300 × 10−4 M), once daily) post-streptozotocin (STZ)-induced DR. Immunohistochemical studies for neuronal markers, nitrotyrosine, micro/macroglia, and real-time PCR, Western blot, and glutamate colorimetric assays were conducted. Diabetes increased NOX2 expression in the retina. NOX2 inhibition limited the loss of NOS-positive amacrine cells and the overactivation of micro/macroglia in both models. In the diabetic retina, GLX7013170 had no effect on retinal ganglion cell axons, but reduced oxidative damage, increased Bcl-2, reduced glutamate levels, and partially restored excitatory amino acid transporter (EAAT1) expression. These results suggest that NOX2 in diabetes is part of the triad, oxidative stress, NOX, and glutamate excitotoxicity, key players in the induction of DR. GLX7013170 is efficacious as a neuroprotective/anti-inflammatory agent and a potential therapeutic in retinal diseases, including ESDR.

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Section: Discussionmentioning

confidence: 99%

Investigation of the Effects of a Novel NOX2 Inhibitor, GLX7013170, against Glutamate Excitotoxicity and Diabetes Insults in the Retina

Dionysopoulou,

Wikstrom,

Walum

et al. 2024

Pharmaceuticals

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“…Although the mechanism by which enmein suppresses glial activation was not investigated in this study, toll-like receptors (TLRs) have been shown to play a critical role in glial cell activation and subsequent hippocampal neuron excitotoxicity [ 53 ]. Furthermore, preventing TLR activation suppresses glial activation and protects against excitotoxicity [ 53 , 54 ]. Whether enmein suppresses the activation of TLRs, thereby reducing glial cell activation and further suppressing KA-induced excitotoxic injuries, should be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Enmein Decreases Synaptic Glutamate Release and Protects against Kainic Acid-Induced Brain Injury in Rats

Huang

Chiu

et al. 2021

IJMS

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This study investigated the effects of enmein, an active constituent of Isodon japonicus Hara, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes) and evaluated its neuroprotective potential in a rat model of kainic acid (KA)-induced glutamate excitotoxicity. Enmein inhibited depolarization-induced glutamate release, FM1-43 release, and Ca2+ elevation in cortical nerve terminals but had no effect on the membrane potential. Removing extracellular Ca2+ and blocking vesicular glutamate transporters, N- and P/Q-type Ca2+ channels, or protein kinase C (PKC) prevented the inhibition of glutamate release by enmein. Enmein also decreased the phosphorylation of PKC, PKC-α, and myristoylated alanine-rich C kinase substrates in synaptosomes. In the KA rat model, intraperitoneal administration of enmein 30 min before intraperitoneal injection of KA reduced neuronal cell death, glial cell activation, and glutamate elevation in the hippocampus. Furthermore, in the hippocampi of KA rats, enmein increased the expression of synaptic markers (synaptophysin and postsynaptic density protein 95) and excitatory amino acid transporters 2 and 3, which are responsible for glutamate clearance, whereas enmein decreased the expression of glial fibrillary acidic protein (GFAP) and CD11b. These results indicate that enmein not only inhibited glutamate release from cortical synaptosomes by suppressing Ca2+ influx and PKC but also increased KA-induced hippocampal neuronal death by suppressing gliosis and decreasing glutamate levels by increasing glutamate uptake.

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“…After 8 days’ acclimatization, six animals serving as the vehicle group were injected with an equal volume of citrate buffer. For the rest of the animals, diabetes mellitus was induced by 2 STZ injections (30 mg/kg) following a recent schedule [ 37 , 38 ] in fasted rats. Then, fasting blood glucose level was determined using a GlucoDr.…”

Section: Methodsmentioning

confidence: 99%

Computational and Experimental Approaches Exploring the Role of Hesperetin in Improving Autophagy in Rat Diabetic Retinopathy

Alshaman,

Kolieb,

El-Sayed

et al. 2024

Biomedicines

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Diabetic retinopathy (DR) is a debilitating diabetic disorder of the retinal microvasculature and the main cause of avoidable blindness in old people. Hesperetin is a plant flavanone largely abundant in citrus species with neuroprotective properties in animal models. This study aimed to explore the neuroprotective and autophagy-enhancing effect of hesperetin in rats with DR. Twenty-four male rats were utilized and allocated to groups: (i) the vehicle group, (ii) DR group and (iii–iv) the DR + hesperetin (50 and 100 mg/kg) groups. Treatment with hesperetin continued for 6 weeks. After the rats were euthanized, their eyes were dissected to detect the biochemical and histological changes in the retinas. Quantification of autophagy markers, beclin 1/LC3/p62, and inflammation markers was performed. Histopathologic changes were investigated after staining with hematoxylin and eosin and periodic acid–Schiff (PAS). Results demonstrated that hesperetin decreased the PAS staining in diabetic rats and attenuated histopathological changes and restored retinal organization and thickness of layers in hematoxylin and eosin staining. Moreover, hesperetin reduced the level of mRNA expression for TNF-α (4.9-fold), IL-1β (4.15-fold), IL-6 (4.6-fold) and NFκB (5.2-fold), as well as the protein level. This was accompanied by induction of autophagy proteins, beclin 1 and LC3-II. Our results afford evidence that hesperetin is effective in alleviating the pathology of DR via suppressing the inflammatory burden and induction of autophagy. After extensive clinical examinations, hesperetin may prove to be a useful option for treatment of DR.

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Protective effect of metformin on rat diabetic retinopathy involves suppression of toll-like receptor 4/nuclear factor-k B expression and glutamate excitotoxicity

Cited by 27 publications

References 76 publications

Investigation of the Effects of a Novel NOX2 Inhibitor, GLX7013170, against Glutamate Excitotoxicity and Diabetes Insults in the Retina

Investigation of the Effects of a Novel NOX2 Inhibitor, GLX7013170, against Glutamate Excitotoxicity and Diabetes Insults in the Retina

Enmein Decreases Synaptic Glutamate Release and Protects against Kainic Acid-Induced Brain Injury in Rats

Computational and Experimental Approaches Exploring the Role of Hesperetin in Improving Autophagy in Rat Diabetic Retinopathy

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