Technologies

Lipoxins LXA4 and LXB4 as potential treatment for glaucoma and other neuronal injury related pathologies

Neuroprotective agents represent an intensive research field and an area of high interest for pharmaceutical development. Lipoxins are known pro-resolving lipid mediators that act locally in paracrine or autocrine manners to dampen inflammation. A team of researchers from the University Health Network and the University of California at Berkeley have discovered a new role for lipoxin signaling directly on neuronal homeostasis and survival. Both endogenous lipoxins LXA ₄ and LXB ₄ demonstrate direct neuroprotective effects in a neuronal cell line, primary cortical neurons, and cultured retinal ganglion cells (RGCs). Interestingly, the much less well-studied LXB ₄ demonstrates superior neuroprotective action compared to LXA ₄ (Fig.1). In an acutein vivoretinal injury model LXB ₄ was similarly more potent than LXA ₄ . Finally, in a challenging 15-week rat model of chronic glaucoma, LXB ₄ was therapeutically delivered to the eye and via IP injection starting from week 8. RGC function and survival was significantly better in LXB ₄ -treated retinas compared to vehicle, as shown in Figs. 1 & 2. Importantly, there was no observed effect of LXB ₄ treatment on intraocular pressure, eliminating a potential indirect effect.

Fig. 1. Therapeutic administration of LXB ₄ protects RGC function following chronic IOP injury. (a)Schematic of the experimental design showing ERG and OCT readings every 4 weeks following suture induce IOP. LXB ₄ administration started at week 8, and retinal flatmounting and RGC counting was performed at week 15.(b)Average waveforms for RGC (pSTR) responses at week 15 for LXB ₄ and vehicle groups, and(c)relative change in RGC function across 15 weeks. Starting at week 12, there was a significant and increasing rescue of LXB ₄ treated eyes compared to vehicle (* p < 0.05; n=8 per group, bars are S.D., the shaded area indicates the treatment period).

Fig.2.Quantification of RGC density revealed the suture induced loss was significantly rescued by LXB ₄ treatment compared to vehicle in both the outer and inner retinas (***p < 0.001 compared to vehicle, n=8, bars are S.E.M.).