SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process

Abstract

Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.

Evaluation of Local Retinal Function in Light-Damaged Rats Using Multifocal Electroretinograms and Multifocal Visual Evoked Potentials

“…Compared to the control group, the LD group showed thinning of the ILM-RPE, ONL, and ONL-RPE, especially in the superior retina. This is consistent with the characteristics of the LD model reported in other studies [17,25,26]. The measurement area of the mfERG and mfVEP, set at the viewing angle of 40 degrees in this study, was the region with a diameter of approximately 2.3 mm from the optic nerve head.…”

“…Different retinal responses between the superior and inferior retinas were recorded using mfERGs with well-defined region-dependent light damage. Some experiments on the effects of drugs using LD models have reported that drugs were observed to be effective on the inferior retina and not on the superior retina, causing severe damage [17]. Detecting local degeneration in the early phase of LD using ERG is challenging.…”

“…Photoreceptor degeneration was induced as previously described [17]. Briefly, rats were dark-adapted for 24 h before light exposure.…”

“…Various animal models with photoreceptor degeneration, including transgenic animals, have been developed. Photoreceptor degeneration models have used the carcinogen N-methyl-N-nitrosourea (MNU) [12][13][14], continuous light-damaged (LD) models [15][16][17][18], and animals with photoreceptor degeneration caused by genetic mutations, such as Royal College of Surgeons (RCS) rats [19][20][21], transgenic rats [22], mice [23], and rabbits [24]. Among these, a variation in degeneration exists between the superior and inferior retina, with a more pronounced degeneration observed in the superior retina [25][26][27].…”

Effects of Different Spectrum of LEDs on Retinal Degeneration Through Regulating Endoplasmic Reticulum Stress

“…LIRD is extensively used in zebrafish or rodents to affect the photoreceptors 32 , 33 and has been used in an albino background, 34 – 36 which is very susceptible to LIRD, because albino animals lack melanin in the RPE, which absorbs light passing through the retina. Nevertheless, few experiments have been conducted to analyze LIRD in albino guinea pigs.…”