Melatonin receptor agonist ramelteon alleviates experimental acute ocular inflammation via HIF-1Α/VEGF/E-NOS signaling

Abstract

Purpose Ramelteon (RML) is a potent, selective agonist of the high-affinity melatonin receptor 1 and 2 receptors. In addition, RML is known to have antioxidant and anti-inflammatory effects. In this study, we aimed to investigate the effects of RML on HIF-1α, VEGF and e-NOS signaling pathway in a rat model of endotoxin-induced uveitis (EIU). Methods Twenty-eight Wistar albino rats were divided into 4 groups as controls, lypopolysaccharide (LPS) group (5 mg/kg i.p.), LPS + RML group (5 mg/kg i.p and 8 mg/kg orally, respectively) and RML group (8 mg/kg orally). EIU was induced by a single intraperitoneal LPS injection. Histopathological and genetical analyses were performed. Results In histopathological analysis, LPS caused mild anterior uveitis characterized by increased surface area of iris leaflets and ciliary body due to edema, mild to moderate congestion, and inflammatory infiltrate 6 h following the injection. The pathological findings were reduced by RML. Higher inflammation levels seen in LPS group were significantly reduced in LPS + RML group. Also, HIF-1 α, eNOS and VEGF expressions increased in LPS and decreased in LPS + RML group. Conclusion RML treatment reversed the changes in the HIF-1α /eNOS/ VEGF signaling pathway in LPS-induced uveitis in rats, preventing the progression of the damage and showed positive effects.

Melatonin Exerts Prominent, Differential Epidermal and Dermal Anti-Aging Properties in Aged Human Eyelid Skin Ex Vivo

“…We recently showed that the key angiogenesis regulatory gr dothelial growth factor A (VEGF-A), is a critical driver of huma in vivo and ex vivo [3]. In line with the "angiogenesis hypothes poses that a reduction in the production of angiogenic factors and capillary density promote tissue aging [90], we were interested i atonin exerted any impact on epidermal VEGF-A protein ex mainly been discussed in the literature as a candidate anti-angi counteract pro-angiogenic VEGF-A effects [91][92][93]. However, it reported to ameliorate aging-associated impaired angiogenesis [9 and/or VEGF receptor expression under some conditions [95,9 showed that melatonin treatment significantly increased the epid level of VEGF-A (Figure 3a,b).…”

“…In line with the "angiogenesis hypothesis of aging", which proposes that a reduction in the production of angiogenic factors and subsequently decreased capillary density promote tissue aging [90], we were interested in checking whether melatonin exerted any impact on epidermal VEGF-A protein expression. Melatonin has mainly been discussed in the literature as a candidate anti-angiogenesis factor that may counteract pro-angiogenic VEGF-A effects [91][92][93]. However, it has conversely also been reported to ameliorate aging-associated impaired angiogenesis [94] and to promote VEGF and/or VEGF receptor expression under some conditions [95,96].…”

Ramelteon attenuates renal ischemia and reperfusion injury through reducing mitochondrial fission and fusion and inflammation

“…For example, ramelteon protects the brain via relieving inflammation and oxidative stress though the Nrf2 signaling pathway ( 10 ). Ramelteon attenuates LPS-induced experimental acute ocular inflammation though hypoxia-inducible factor-1α/vascular endothelial growth factor/endothelial nitric oxide synthase signaling ( 11 ). Imai et al elucidated that ramelteon may alleviate the risk of vancomycin-induced nephrotoxicity ( 12 ).…”