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Sudha Singh, Mohammad Pathan, Naseem Akhter, Melissa Nix, Shahid Husain; Ocular Hypertension-Induced MMPs Production Within Optic Nerve: A Regulatory Role of δ-Opioid-Receptors. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1971.
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This study was designed to determine the changes in the matrix metalloproteinases (MMPs) production in optic nerve head (ONH) and purified ONH astrocytes in response to ocular-hypertension and TNF-α-induced injury, respectively. We also have determined if δ-opioid-receptors activation counterbalances the production of MMPs.
Brown Norway rats were used to elevate intraocular pressure (IOP) by injecting 50 µL of 2 M hypertonic saline into the circumferential 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-mounts were counted at week-6 post injury. Primary cultures of human ONH astrocytes were isolated and purified by immunopanning. Cells were treated with SNC-121 (1μM), 15 minutes prior to TNF-α (25 ng/mL) treatment for 24 hours. The expression of MMP-1, MMP-2, and MMP-3 were determined by immunohistochemistry and Western blotting.
PERG amplitudes and RGCs were reduced by 18% and 28%, respectively, in ocular-hypertensive eyes. PERG deficits and reduction in RGCs in hypertensive eyes were significantly (P<0.05) improved by δ-opioid-receptor agonist, SNC-121, treatment. MMP-1, MMP-2, and MMP-3 production in ocular-hypertensive optic nerve was increased by 51 ± 7%, 232 ± 24%, and 79 ± 8%, respectively, at 7 days post injury. The production of MMPs was fully inhibited in the presence of SNC-121. In addition, TNF-α (25 ng/mL) treatment of ONH astrocytes increased the MMP-1, MMP-2, and MMP-3 secretion by 124 ± 45%, 149 ± 76%, and 53 ± 5%, respectively, at 24 hours, which was completely inhibited in the presence of SNC-121.
These data provide concrete evidence that increase in δ-opioidergic-receptor activity by SNC-121 provides retina neuroprotection, as determined by PERG and RGCs counting. Mechanistic data provide clues that MMPs are produced within the optic nerve, in an early stage of glaucomatous injury, which will further destabilize the optic nerve by excessive remodeling. These detrimental signaling molecules directly and/or indirectly weaken axons and lead to the RGC death. Delta-opioid receptor agonists represent a novel class of drugs/agents that counteract detrimental events within the optic nerve and prevent the loss of RGCs.
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