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Shahid Husain, Sudha Singh; Delta Opioids Provide RGC Neuroprotection Via Adenylyl Cyclase (AC) Superactivation. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6400.
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© ARVO (1962-2015); The Authors (2016-present)
This study was designed to determine the role of AC Superactivation in delta opioid-receptors-mediated RGC neuroprotection during 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 treated with delta opioid-receptor agonist, SNC-121 (1 mg/kg; i.p) daily for 7 days. Pattern electroretinograms (PERG), retinal ganglion cells (RGCs) in flat mount, and axons were counted 4-6 week post injury. The changes in the cAMP levels and phospho-cyclic AMP-response element binding protein (p-CREB) were determined by ELISA, Western blotting, and immunohistochemistry.
We measured the cAMP levels in the retina at 1, 7, 14, and 42 days, post-glaucomatous injury in normal, glaucomatous, and SNC-121-treated (1 mg/kg; 7 days, once daily) glaucomatous eyes. The level of cAMP was decreased by 32% in the glaucomatous eyes, but significantly increased in SNC-121-treated normal and glaucomatous eyes. We found this data very interesting and highly unexpected as opioids generally inhibit cAMP formation because they are linked to Gi-proteins. As we expected, acute treatment by SNC-121 decreased cAMP formation significantly at day 1. However, chronic treatment with a δ-opioid agonist for 7 days increased the levels of cAMP, which was further elevated significantly at the 14th day, while SNC-121 treatment had been stopped at day 7. These data form a strong rationale for the existence of "AC Superactivation" within the retina. The p-CREB was also significantly reduced in glaucomatous eyes at day 42. Glaucomatous injury caused significant (p<0.05) reduction in pattern ERG (PERG), axonal, and RGC numbers at day 42, post glaucomatous injury. PERG deficits, axonal, and RGC survival were significantly improved by SNC-121 treatment.
These data provide evidence that cAMP/CREB pathway plays a key role in RGC neuroprotection during glaucomatous injury. Data also provide novel information about the “AC Superactivation” in the retina, which will open new avenues for RGC neuroprotection.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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