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Alterations of Kynurenic Acid Synthesis in the Retina in Response to Retinal Ganglion Cell Damage in Experimental Glaucoma
Rejdak R.1,2, Schuettauf F.1, Zarnowski T.2, Turski W. A.3, Shenk Y.1, Zagorski Z.2, Zrenner E.1
1Department of Pathophysiology of Vision and Neuro-Ophthalmology, Division of Experimental Ophthalmology, University Eye Hospital, Tübingen
2Tadeusz Krwawicz Chair of Ophthalmology and 3Department of Pharmacology, Medical University, Lublin/PL
Purpose: Kynurenic acid (KYNA) is the only known endogenous glutamate receptor antagonist and it is synthesised in the brain by two kynurenine aminotransferases (KAT I and KAT II). KYNA and KATs are present in the retina (Rejdak et al. Neuroreport 2001). The present study examines the modulation of retinal kynurenic acid content in animal models of glaucoma.
Method: In the first part of the study the death of rat retinal ganglion cells (RGC) was induced with intravitral NMDA injections in adult Brown Norway rats. Surviving RGC were retrogradely labeled with fluorogold and counted in wholemounts of retinas 2, 7 and 14 days after injection. Retinal KYNA content was measured by HPLC at the same time points. In addition we studied alterations in KYNA synthesis in the retina of DBA/2J mice during ageing. The DBA/2J mouse is a promising animal model of glaucoma. Mice of this strain spontaneously develop time-dependent RGC loss. Retinas were obtained from DBA/2J mice of different ages: 3, 6, 8 and 11 months. Retinal KYNA content was measured with HPLC. Immunohistochemistry was performed on retinal sections using specific antibodies against KAT I and KAT II. Double-labelling studies were performed using a specific monoclonal antibody against glutamine synthetase as a marker for Müller cells.
Results: We observed that RGC numbers decreased significantly 2, 7 and 14 days after NMDA injection in rats if compared to control retinas. KYNA concentration increased significantly two days after NMDA-injection. However, 7 and 14 days after injection retinal KYNA content was found markedly decreased in NMDA-treated eyes as compared to controls. Double labelling studies performed in the retina of DBA2J mice showed that expression of both KAT I and KAT II decreased in the retina of DBA/2J mice during ageing. KYNA content decreased significantly (p=0.03) in the retina of 6 month old DBA/2J mice and continued to decrease (p=0.008) in the retina of 11 months old animals as compared to controls.
Conclusions: KYNA synthesis changes in response to RGC loss in animal model systems of glaucoma. It is therefore conceivable that KYNA deficiency is causally related to the pathology of neurodegenerative retinal diseases.
This work was supported by the european union under the marie curie individual fellowship to Dr. med. Robert Rejdak (contract number: QLK2-CT-2002-51562)
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