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Shahid Husain, Sudha Singh; Protein acetylation in δ-opioid receptor mediated RGC neuroprotection. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1592.
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This study was designed to determine that activation of δ-opioid receptor enhances protein acetylation to attenuate glaucomatous injury in chronic rat glaucoma model.
Brown Norway rats were used to elevate intraocular pressure (IOP) by injecting 50 µL of 2 M hypertonic saline into the limbal veins. Animals were treated with δ-opioid receptor agonist, SNC-121 (1 mg/kg; i.p) daily for 7 days. Pattern electroretinograms (PERG) and retinal ganglion cells (RGCs) in flat mount were counted 4-6 week post injury. The retinas and optic nerves were analyzed for acetyl-histone H3 acetylation and total HDAC (Class I and II) activity following SNC-121 treatment. The changes in phospho-cyclic AMP-response element binding protein (p-CREB) were determined by Western blotting and immunohistochemistry. PCR array kit was used to measure changes in the variety of genes including neurotrophins, neuropeptides and their respective receptors after SNC-121 treatment.
Administration of selective δ-opioid-receptor agonist, SNC-121 (1 mg/kg), once-a-day for 7-days provides prolonged (42 days) neuroprotection as measured by PERG and RGC counting. Acetyl-histone H3 levels were elevated in both retina (200 ± 35; p<0.05) and optic nerve (175 ± 42; p<0.05) in rats treated with SNC-121 when compared to tissues from control rats. Additionally, total HDAC activity was suppressed in both the retina and optic nerve from rats treated with SNC-121. We also have seen a significant decrease by 51% (p<0.05) and 79% (p<0.05) in the levels of activated (phosphorylated) CREB in the retina and optic nerve head, respectively, in ocular hypertensive eyes. Rats treated with SNC-121 for 7-days demonstrated a significant increase in the CREB phosphorylation in both the retina and optic nerve tissues of ocular hypertensive eyes that persisted through the 42-day ocular hypertensive study period. We also found that gene expression of nerve growth factor, ciliary neurotrophic factor, and brain-derived neurotrophic factor were up-regulated by SNC-121 treatment when measured by 84-gene RT profilerTM PCR array kit.
These data provide evidence that neuroprotection induced by δ-opioid agonist involves hyperacetylation of retina and optic nerve and provide a strong rationale that the activation of δ-opioid receptor can lead to epigenetic changes associated with long-term RGC neuroprotection.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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