Melatonin maintains inner blood‐retinal barrier via inhibition of p38/TXNIP/NF‐κB pathway in diabetic retinopathy

Abstract

The pathophysiology of diabetic retinopathy (DR) was complex. Under hyperglycemic conditions, the release of proinflammatory cytokines and the adhesion of leukocytes to retinal capillaries contribute to endothelial damage and the subsequent increase in vascular permeability resulting in macular edema. Melatonin, produced in the retina to regulate redox reactions and dopamine metabolism, plays protective roles against inflammation and oxidative stress. Considering its anti‐inflammatory and antioxidative properties, melatonin was speculated to exert beneficial effects in DR. In this study, we characterized the protective effects of melatonin on the inner blood–retinal barrier (iBRB), as well as the possible mechanisms in experimental DR. Results showed that in diabetic rat retinas, the leakage of iBRB and the expression of inflammatory factors (VEGF, TNF‐α, IL‐1β, ICAM‐1, and MMP9) increased dramatically, while the expression of tight junction proteins (ZO‐1, occludin, JAM‐A, and claudin‐5) decreased significantly. The above changes were largely ameliorated by melatonin. The in vivo data were confirmed in vitro. In addition, the protein expressions of p38 MAPK, NF‐κB, and TXNIP were upregulated significantly in diabetes and were downregulated following melatonin treatment. Melatonin could maintain the iBRB integrity by upregulating the expression of tight junction proteins via inhibiting p38/TXNIP/NF‐κB pathway, thus decreasing the production of inflammatory factors. This study may shed light on the development of melatonin‐based DR therapy.

Effects of Melatonin on Diabetic Neuropathy and Retinopathy

“…The DM model resulted in the development of hyperglycemia, reduction of a and b waves and oscillatory potential amplitude of electroretinography (ERG), and an increase in GFAP and vascular endothelial growth factor (VEGF) levels. Data from previous studies corroborate the alterations in a and b waves of the ERG by DM [ 52 , 53 ]. MEL did not affect glucose metabolism, but did prevent a decrease in the a wave, b wave [ 51 , 53 ] and the amplitude of the oscillatory potential of the ERG of diabetic rats.…”

“…Data from previous studies corroborate the alterations in a and b waves of the ERG by DM [ 52 , 53 ]. MEL did not affect glucose metabolism, but did prevent a decrease in the a wave, b wave [ 51 , 53 ] and the amplitude of the oscillatory potential of the ERG of diabetic rats. In addition, MEL prevented the increase in GFAP levels in Müller cells and VEGF in the retina.…”

“…The model induced hyperpermeability of the BRB and increased expression of genes linked to hypoxia and angiogenesis (HIF1-α and HIF1-β), all of which were reversed by MEL (0.5–1 mM). Tang et al [ 53 ] also found an increase in leakage of the retinal blood vessels in the BRB due to hyperglycemia, while treatment with intravitreal MEL (30 µg) maintained the integrity of the barrier. Glucose also altered the expression of genes involved in mitochondrial function.…”

Circular Ribonucleic Acid circFTO Promotes Angiogenesis and Impairs Blood–Retinal Barrier Via Targeting the miR-128-3p/Thioredoxin Interacting Protein Axis in Diabetic Retinopathy

“…Previous studies have also reported that TXNIP was highly expressed in diabetic complications (Xu et al, 2013;Lv et al, 2020). For example, the inhibition of the p38/TXNIP/NF-κB pathway by melatonin is suggested to maintain the inner blood-retinal barrier in DR (Tang et al, 2021). Moreover, TXNIP overexpression has been demonstrated to activate autophagy and apoptosis in the rat müller cells treated with high glucose in DR (Ao et al, 2021).…”

Melatonin Maintains Inner Blood–Retinal Barrier by Regulating Microglia via Inhibition of PI3K/Akt/Stat3/NF-κB Signaling Pathways in Experimental Diabetic Retinopathy

“…At 2 h after STZ injection, the right eye of rats was intravitreally injected with melatonin (30 μg/eye, 2 μl; Sigma-Aldrich), while the left eye was injected with the equivalent volume of normal saline. Intravitreal injection of melatonin was repeated every week based on our previous study ( 18 ), and the rats were killed at 8 weeks after diabetes onset. The rats that failed to develop diabetes and with intraocular damages (e.g., traumatic cataract, intraocular hemorrhage, inflammation) were excluded from the experiments.…”