Abstract
To determine the roles of nitric oxide in glaucomatous injury and its regulation by δ-opioid-receptor activation, animals were treated with: 1) a selective inducible nitric oxide synthase (iNOS) inhibitor (aminoguanidine; AG; 25 mg/kg, i.p.); 2) δ-opioid-receptor agonist (SNC-121; 1 mg/kg, i.p.); or 3) with both drugs simultaneously for 7 days, once daily. The loss in retinal ganglion cell (RGC) numbers and their function in glaucomatous eyes were significantly improved in the presence of AG or SNC-121; however, we did not see any significant additive or synergistic effects when animals were treated with both drugs simultaneously. The levels of nitrate-nitrite were significantly increased in the glaucomatous retina when compared with normal retina (normal retina 86±9 vs. glaucomatous retina 174±10 mM/mg protein), which was reduced significantly when animals were treated either with SNC-121 (121±7 mM/mg protein; P<0.05) or AG (128±10 mM/mg protein; P<0.05). Additionally, SNC-121-mediated reduction in nitrate-nitrite levels was not only blocked by naltrindole (a δ-opioid-receptor antagonist), but naltrindole treatment potentiated the nitrate-nitrite production in glaucomatous retina (235±4 mM/mg protein; P<0.001). As expected, naltrindole treatment also fully-blocked SNC-121-mediated retina neuroprotection. The nitrotyrosine level in the glaucomatous retina was also increased, which was significantly reduced in the SNC-121-treated animals. Additionally, the expression level of iNOS was clearly increased over the control levels in the glaucomatous retina and optic nerves, which was also reduced by SNC-121 treatment. In conclusion, our data support the notion that nitric oxide plays a detrimental role during glaucomatous injury and inhibition of nitric oxide production provided RGC neuroprotection. Furthermore, δ-opioid receptor activation regulates the production of nitric oxide via inhibiting the activity of iNOS in the retina and optic nerve.
Highlights
Glaucoma is a slowly progressing optic neuropathy that causes loss of retinal ganglion cells (RGCs), optic disc changes, and visualfield loss [1,2]
While astrocytes play a vital role in maintaining a normal physiological state in RGCs, they become activated in response to glaucomatous injury and produce neurotoxic substances like proinflammatory cytokines [7,8] and nitric oxide which leads to axonal and RGC loss [14,15,19]
Similar to our previous studies, we did not see any significant changes in intraocular pressure (IOP) of normal and glaucomatous eyes when animals were treated with a selective d-opioid-receptor agonist, SNC-121 (1 mg/Kg, i.p.), for 7 days [7] (Figure 1)
Summary
Glaucoma is a slowly progressing optic neuropathy that causes loss of retinal ganglion cells (RGCs), optic disc changes, and visualfield loss [1,2]. The mechanisms that lead to the RGC death during disease progression are unclear. During the progression of glaucoma, glial cells, mainly astrocytes within the optic nerve head (ONH) [17], play key roles in the initiation of lesions in glaucomatous optic neuropathy [18]. While astrocytes play a vital role in maintaining a normal physiological state in RGCs, they become activated in response to glaucomatous injury and produce neurotoxic substances like proinflammatory cytokines [7,8] and nitric oxide which leads to axonal and RGC loss [14,15,19]
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