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Shahid Husain, Yasir Abdul, Sudha Singh, Carolyn Peterseim; Neuroprotective Targets of Delta Opioid-Receptor in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2180.
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This study was designed to determine the downstream targets of delta opioid-receptors for neuroprotection in glaucomatous injury.
Brown Norway rats were used to elevate intraocular pressure (IOP) by injecting 50 µL of 2M hypertonic saline into the circumferential limbal veins. IOP was recorded as the average of 6-8 consecutive measurements prior to surgery (baseline IOP) and weekly after treatment, using a calibrated Tonolab tonometer. Animals were either treated with delta opioid-receptor agonist, SNC-121 or SNC-80 (1 mg/kg; i.p) or Br-cAMP (1 mg/kg; i.p), daily for 7 days. Pattern electroretinograms (PERG), retinal ganglion cells in flat mount, and axons were counted 4-6 week post injury. The changes in the expression patterns of PI3K/Akt and phospho-cyclic AMP-response element binding protein (p-CREB) were determined by Western blotting and immunohistochemistry.
PERG amplitudes were significantly reduced in ocular-hypertensive eyes (16.78±1.23 µvolts) when compared to normal eyes (22.24±1.42 µvolts) the 6th week, post injury. PERG deficits in hypertensive eyes were significantly improved by SNC-121 treatment (21.70±1.03 µvolts; P<0.05). There was a significant loss of RGCs and axons in the hypertensive eyes and the loss in RGCs and axons was fully blocked in SNC-121-treated animals by the 6th week, post injury. We found that SNC-121 activate and phosphorylate PI3K/Akt pathway and cyclic AMP-response element binding protein (CREB). A PI3K/Akt inhibitor, LY-294002 (1 mg/kg), fully blocked SNC-121 mediated retina neuroprotection. Moreover, PERG were significantly improved by Br-cAMP treatment when measured on 6th week, post injury.
These data provide initial evidence that PI3K/Akt and CREB, a transcription factor, are the potential neuroprotective targets of delta opioid-receptors in glaucomatous injury. Data also provide clues that PI3K/Akt pathway and CREB may have negatively regulated the neurodegenerative pathways in SNC-121-induced retina neuroprotection.
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