Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

SIG-1451, A Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Inhibiting Microglial Activation

Yuki Kikuchi
,
Eriko Sugano
,
Shiori Yuki
,
Kitako Tabata
,
Yuka Endo
,
Yuya Takita
,
Reina Onoguchi
,
Taku Ozaki
ORCID logo ,
Tomokazu Fukuda
,
Yoshihiro Takai
,
Takahiro Kurose
,
Koichi Tanaka
,
Yoichi Honma
,
Eduardo Perez
ORCID logo ,
Maxwell Stock
,
Jose Fernandez
,
Masanori Tamura
,
Michael Voronkov
,
Jeffry B Stock
,
Hiroshi Tomita
* ORCID logo
Version 1 : Received: 16 May 2022 / Approved: 17 May 2022 / Online: 17 May 2022 (08:03:11 CEST)

A peer-reviewed article of this Preprint also exists.

Kikuchi, Y.; Sugano, E.; Yuki, S.; Tabata, K.; Endo, Y.; Takita, Y.; Onoguchi, R.; Ozaki, T.; Fukuda, T.; Takai, Y.; Kurose, T.; Tanaka, K.; Honma, Y.; Perez, E.; Stock, M.; Fernández, J.R.; Tamura, M.; Voronkov, M.; Stock, J.B.; Tomita, H. SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process. Int. J. Mol. Sci. 2022, 23, 8802. Kikuchi, Y.; Sugano, E.; Yuki, S.; Tabata, K.; Endo, Y.; Takita, Y.; Onoguchi, R.; Ozaki, T.; Fukuda, T.; Takai, Y.; Kurose, T.; Tanaka, K.; Honma, Y.; Perez, E.; Stock, M.; Fernández, J.R.; Tamura, M.; Voronkov, M.; Stock, J.B.; Tomita, H. SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process. Int. J. Mol. Sci. 2022, 23, 8802.

Abstract

Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress, decreased phagocytic activity, and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory drug developed for treating atopic dermatitis and known to inhibit toll-like receptor 4, on light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once a 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 protected against this decrease in retinal thickness and increase in ERG am-plitude. 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 upregu-lation 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 protects photoreceptor cells by attenuating light damage progression through inhibiting inflammatory responses.

Keywords

age-related macular degeneration; light-induced photoreceptor degeneration; anti-inflammatory drug; toll-like receptor 4

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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