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Shahid Husain, Yasir Abdul; Delta-Opioid Agonist Targets TNF-α and NF-B During Retinal Ischemic Injury. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5323.
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To study the neuroprotective role of a Δ-opioid agonist, SNC-121, and determine potential targets in the optic nerve and retina for neuroprotection against retinal ischemic injury.
Retinal ischemia was induced in Brown Norway rats by raising intraocular pressure (IOP) above systolic blood pressure (155-160mmHg) for 45 minutes. Rats were treated with the Δ-opioid-receptor agonist, SNC-121 (0.1-1 mg/kg; i.p.), 30 minutes post-ischemia, and daily up to 7 days. To quantitate post-ischemic functional recovery, electroretinograms (ERG) were performed seven days following ischemic injury. Structural integrity of the retinal layers was determined by hematoxylin-eosin staining. Selected rats were treated with a Δ-opioid-receptor antagonist, naltrindole (3 mg/kg, i.p.), 15 minutes prior to the SNC-121 treatment. TNF-alpha and NF-ΚB were measured by immunohistochemistry and Western blot analyses.
In eyes subjected to 45 minutes of ischemia, mean b-wave amplitudes were significantly reduced when compared to the control eyes (control eyes 646±75 vs. ischemic eyes 321±59 μvolts; P<0.05), as determined by ERG measurement 7 days following retinal ischemia. In contrast, the b-wave amplitudes were significantly greater in the animals treated with SNC-121 for 7 days (ischemic eyes 321±59 vs. SNC-121 + ischemic eyes 508±50 μvolts, P<0.05). SNC-121-mediated retina neuroprotection was completely abolished when animals were treated with a highly selective Δ-opioid-receptor antagonist, naltrindole (3 mg/kg), 15 minutes prior to SNC-121 treatment (SNC-121 + ischemic eyes 508±50 vs. naltrindole + SNC-121 + ischemic eyes 348±57 μvolts; P<0.05). In addition, degeneration of the inner retina resulted in 36% reduction in overall retina thickness, and this reduction was almost fully recovered in SNC-121-treated animals. Pretreatment with naltrindole reversed the structural retina protection induced by SNC-121. There was a robust increase in TNF-α and NF-ΚB production in the optic nerve and inner retina layers 4-hours post-ischemia. The production of both TNF-α and NF-ΚB was attenuated in the presence of SNC-121.
These results provide evidence that post-ischemia activation of Δ-opioid-receptors provides retina neuroprotection. Current data also demonstrate that production of TNF-α and NF-ΚB are early events in ischemic injury, which are opposed by Δ-opioid-receptor-activation. Overall, these results provide evidence that the Δ-opioidergic system exhibits the potential to protect the retina against ischemic injury.
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