Abstract
The main objective of this study was to determine the inhibition of pro-inflammatory cytokines and their associated signaling molecules by δ-opioid receptor activation by a selective ligand, SNC-121 in chronic rat glaucoma model. Intraocular pressure was raised in rat eyes by injecting 2 M hypertonic saline into the limbal veins. SNC-121 (1 mg/kg; i. p) or Stattic (5 mg/kg; i. p) was administered in Brown Norway rats daily for 7 days. The mRNA expression of IL-1β, TNF-α, Fas, IL-6, leukemia inhibitory factor, and IFN-γ was increased significantly in the retina of ocular hypertensive animals at day 7, post injury. Administration of SNC-121 (1 mg/kg; i. p. injection) for 7 days (once a day) completely inhibited the increase in the mRNA and protein expression of pro-inflammatory cytokines. Mechanistically, we provide data showing a significant increase in the phosphorylation of STAT3 at tyrosine 705 whereas a moderate but significant increase in the total STAT3 protein expression was also seen in the retina of ocular hypertensive animals. Data illustrated that SNC-121 administration completely abrogated ocular hypertension-induced increase in STAT3Y705 phosphorylation. Interestingly, acetylation of STAT3 at lysine 685 (AcK685) was reduced in ocular hypertensive animals and subsequently increased significantly by SNC-121 treatment. Stattic, a selective STAT3 inhibitor, administration resulted in a complete attenuation in the production of IL-1β and IL-6 in ocular hypertensive animals. In conclusion, δ-opioid receptor activation suppressed the phosphorylation of STAT3 at tyrosine 705 and increased acetylation at lysine 686 and these posttranslational modifications can regulate the production of some but not all pro-inflammatory cytokines in response to glaucomatous injury.
Highlights
Glaucoma is the second leading cause of blindness worldwide in which retinal ganglion cells (RGCs) die slowly and progressively over a prolonged period of time
We have shown that activation of δ-opioid receptor reduces oxidative stress and proinflammatory cytokines in acute ischemia/reperfusion, chronic rat glaucoma model, and in the optic nerve head (ONH) astrocytes (Husain et al, 2009; Abdul et al, 2013; Akhter et al, 2013b; Husain et al, 2014)
We have shown that protein expression of IL-1β and IL-6 was remarkably increased in RGC and nerve fiber layers in ocular hypertensive animals (Figure 2), which was completely inhibited in SNC-121 treated ocular hypertensive animals
Summary
Glaucoma is the second leading cause of blindness worldwide in which retinal ganglion cells (RGCs) die slowly and progressively over a prolonged period of time. As a result, circulating immune cells can enter the retina and nerve fiber layer where the hemorrhage has been observed most prominently (Drance, 1989; Choi et al, 2007; Hwang et al, 2014). These observations advocate for a potential role of neuroinflammation in glaucoma, it is not clear if neuroinflammation is a primary cause or a compensatory response or it is entirely a secondary event during glaucoma pathology that can slowly and progressively damage RGCs
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