Intravitreal Administration of Docosahexaenoic Acid derived Neuroprotectin D1 Promotes Photoreceptor Cell Survival in A Murine Model of Retinal Degeneration.

Abstract

Purpose : Neuroprotectin D1 (NPD1), a biosynthetic product derived from docosahexaenoic acid (DHA), is generating a significant interest in neuroprotective bioactivity in retinal degenerative diseases. We have reported endogenous formations and important regulatory functions of the specialized proresolving mediators (SPMs) in the eyes, such as LXA₄. The endogenous role of NPD1 in retinal degeneration has not been explored. Here, we show that intravitreal administration of NPD1 promotes photoreceptor cells survival, and extends the functionality of retina, accompanying enhanced production of pigment epithelium-derived factor (PEDF) in the retina of a murine model of retinal degeneration.

Methods : We performed the intravitreal injections according to the timing by measuring the thickness of the outer nuclear layer of rd1 mice. rd1 mice were treated with PBS or NPD1, respectively. Electroretinography testing was performed to evaluate the visual function of the eyes. Retinas were harvested for immunohistochemistry and neurotrophin production analysis. The structure of the retina was compared between the PBS group and NPD1 group. Apoptotic photoreceptors were evaluated by TUNEL labeling.

Results : Photoreceptors degeneration in the retina of rd1 mice starts from postnatal day 7 (P7), peaks on P14, and completes on P28. We therefore started the injections into P7 rd1 mice. At 28d post-injection, ERG testing was performed and tiny a-wave and b-wave indicating that photoreceptors in NPD1 group are weakly functional, compared with flat signals in PBS group. IHC analysis of the retinas shows that the ONL is 1.74-fold thicker in the NPD1 treated retinas. Rare TUNEL-positive cells were detected at P28, since most of the photoreceptors had already degenerated. The retinas with numerous photoreceptors were evaluated at P14. The number of TUNEL-positive cells in the ONL was significantly lower (41%) in NPD1 treated group compared to PBS treated group at P14. Production of PEDF is 192% at mRNA level and 178% at protein level higher than the PBS group, respectively.

Conclusions : This study provides evidence for a novel functional effect of NPD1 following intravitreal injection in murine eyes with retinal degeneration. Therapeutic strategies with SPMs are required for further exploration.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.