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Bin Lin, Wei Yang, Meng Cheng, Rong Li; Cyclooxygenase-1 (COX-1) modulates neuroinflammation in the rd10 mouse model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2019;60(9):430.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is a heterogeneous group of inherited disorders caused by a number of gene mutations that result in initial death of rods followed by cone photoreceptors. The mechanisms underlying photoreceptor death are not yet completely understood. Neuroinflammation is reported to be involved in RP progression. However, the mechanisms that trigger neuroinflammation remain unclear. Here, we investigated the role of COX-1, a key enzyme in the conversion of arachidonic acid to prostaglandins, in modulating neuroinflammation in rd10 mice.
To address the role of COX-1, we treated rd10 mice with the highly selective COX-1 inhibitor SC-560 or backcrossed COX-1 knockout mice onto rd10 background and generated a COX-1-/-/rd10 mouse line. We investigate the effect of COX-1 inhibition or deletion on the status of microglia activation and photoreceptor survival using a combination of immunocytochemistry, RT-PCR, western blot analysis, and a series of simple visual tests. To identify the key downstream mediator of COX-1 activity, we administered rd10 mice with an antagonist that blocks the prostaglandin E2 receptor (EP2).
Both pharmacological inhibition with SC-560 and genetic deletion of COX-1 reduced microgliosis, resulted in a decrease in the production of inflammatory mediators including PGE2, TNF-α, IL-1β and NF-κB, and enhanced photoreceptor cell survival, retinal function and visual performance in rd10 mice. These data supported a pathological role of COX-1 in RP. Moreover, we identified that the EP2 receptor was a key downstream effector of COX-1 neurotoxicityin rd10 mice.
We demonstrated that COX-1-mediated inflammation contributed to photoreceptor degeneration in rd10 mice, and that the COX-1/PGE2/EP2 signaling pathway played an important role in mediating neuroinflammatory responses and disease progression in rd10 mice. The therapeutic approaches centered around COX-1 inhibition might be a potential strategy for treating RP patients.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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