Protection of retinal ganglion cells by kynurenic acid

Abstract

Purpose : Tryptophan degradation through the kynurenine pathway (KP) generates metabolites that affect cellular physiology. Kynurenine 3-monooxygenase (KMO) is an enzyme of the KP, it produces the neurotoxic 3OH-kynurenine. We investigated the role of KMO in retinal ganglion cell (RGC) death in mice subjected to retinal ischemia/reperfusion (I/R) injury.

Methods : The KP metabolites were measured by liquid chromatography/mass spectrometry (LC-MS/MS). Fasting blood glucose (FBG) measurement, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed. I/R injury was induced by elevating the intraocular pressure to 70 mm Hg for 60 min followed by reperfusion. RGC numbers in the retina were counted in the flatmounts of retina by staining for Brn3a or RBPMS. Kynurenic acid (KYNA) was administered intravenously or intravitreally to test its neuroprotection in mice subjected to I/R injury.

Results : The KMO mRNA and enzyme activity were present in the WT mice but not in KMO KO mice. The levels of kynurenine (Kyn), anthranilic acid (AA) and KYNA were higher in the serum of KMO KO mice compared to WT mice. The FBG levels were 1.3- 1.9 times higher in KMO KO mice relative to WT mice, but the body weight, OGTT and ITT results were similar between WT and KMO KO mice. The P1 amplitude in the pattern electroretinogram attributable to RGCs was higher in KMO KO than WT mice. The retinas of KMO KO mice had higher levels of Kyn, AA and KYNA compared to WT mice, but were unaffected by the I/R injury. The I/R injury caused a greater loss of RGCs in WT mice compared to KMO KO mice. Intravenous as well as intravitreal administration of KYNA protected RGCs in WT mice after I/R injury.

Conclusions : Our study suggested that the absence of KMO protects RGCs from the I/R injury, which is likely due to higher levels of the neuroprotective KYNA. Increasing the retinal KYNA levels could be a strategy to prevent RGC death in glaucoma.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.