Toll-like receptor 4 inhibitor protects against retinal ganglion cell damage induced by optic nerve crush in mice.
Toll-like receptor 4 (TLR4) plays key roles in innate immune responses and inflammatory reactions. TAK-242 (resatorvid) is a small-molecule cyclohexene derivative that selectively inhibits TLR4 signaling pathways and suppresses inflammatory reactions. Here we investigated the protective effects of TAK-242 against optic nerve crush (ONC) which induces axonal injury like glaucoma in mice. TAK-242 was injected intravitreally immediately after ONC. The effect of TAK-242 was evaluated by measuring the number of fluorogold-labeled retinal ganglion cells (RGCs) at 10 days after ONC. Furthermore, the expression levels of phosphorylated-nuclear factor-kappa B (p-NF-κB) and phosphorylated-p38 (p-p38) were measured by Western blotting. In addition, we examined activated astrocytes by immunostaining. TAK-242 significantly abrogated the loss of RGCs associated with ONC. Moreover, the expression levels of p-NF-κB and p-p38 were significantly reduced by TAK-242 treatment. Furthermore, TAK-242 and C34, a TLR4 inhibitor, significantly reduced astrocyte activation in the ganglion cell and inner plexiform layers, compared with vehicle treatment. These findings indicate that TAK-242 inhibits not only the TLR4 signaling pathway but also astrocyte activation downstream of this pathway, suggesting that the inhibition of TLR4 signaling is a promising candidate for the treatment of glaucoma.
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Yukimichi
Y
Nakano
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Electronic address: shimazawa@gifu-pu.ac.jp.
Masamitsu
M
Shimazawa
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Kazuki
K
Ojino
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Hiroshi
H
Izawa
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Hiroto
H
Takeuchi
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Yuki
Y
Inoue
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Kazuhiro
K
Tsuruma
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Electronic address: hidehara@gifu-pu.ac.jp.
Hideaki
H
Hara
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D020221:Optic Nerve Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D016328:NF-kappa B; D013449:Sulfonamides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; C528900:glial fibrillary astrocytic protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
Glaucoma; Optic nerve crush; Retinal ganglion cell; TAK-242; Toll-like receptor 4