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. © 2017 the authors