Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice.

Rooban B Nahomi,Paul S Maclean,Dorota L Stankowska,Ram H Nagaraj,Julie A Houck,Johanna Rankenberg,Mina B Pantcheva,Ginger C Johnson,Stefan Rakete,Mi-Hyun Nam

doi:10.3390/ijms21051795

Abstract

Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose.

Highlights

Glaucoma affects nearly 60 million people worldwide and approximately 8 million people are blind from this disease [1]
We found that the insulin tolerance test (ITT) and body weights were comparable between the wild type (WT) and kynurenine 3-monooxygenase (KMO) KO mice
To determine whether the kynurenic acid (KYNA) is neuroprotective in the retina, we first investigated whether it is permeable to the blood retinal barrier, KYNA has been reported to be poorly permeable to the blood brain barrier [29,30]

Summary

Introduction

Glaucoma affects nearly 60 million people worldwide and approximately 8 million people are blind from this disease [1]. Axonal degeneration and the subsequent death of retinal ganglion cells (RGCs) are the primary reaIsnot.nJ.sMfoolr. Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose

Objectives

Methods

Results