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Systemic L-Kynurenine Administration Partially Protects Against NMDA

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Systemic L-Kynurenine Administration Partially Protects Against NMDA Systemic L-Kynurenine Administration Partially Protects Against NMDA, But Not Kainate-Induced Degeneration of Retinal Ganglion Cells, and Reduces Visual Discrimination Deficits in Adult Rats Christian K. Vonuerk* MichaelR. Kreutz* Evan B. Dreyer,-f and Bernhard A. Sabel* Purpose. Kynurenic acid (KYNA), an endogenous tryptophan metabolite, is an N-methyl-D- aspartate (NMDA) antagonist active at the glycine-binding site of the NMDA-receptor com- plex. The authors investigated whether systemic administration of a biochemical precursor of KYNA, L-kynurenine (L-Kyn), could block NMDA- or kainic acid (KA)-induced cell death in adult rat retinal ganglion cells (RGCs) and protect NMDA-treated animals from lesion- induced visual deficits. Methods. Rats were injected with 20-nmol NMDA or 5-nmol KA intraocularly. To quantify the number of surviving RGCs, the retrograde tracer horseradish-peroxidase was injected into the superior colliculus contralateral to the lesioned eye. Surviving RGCs were counted on wholemounted retinae in a centroperipheral gradient, as well as in the four quadrants, using a computer-assisted image analysis system. Results. The NMDA-injections resulted in an approximately 82% RGC loss in the adult rat retina compared with control retinae and a cell loss of approximately 50% in KA-treated retinae. Pretreatment with L-Kyn significantly reduced NMDA-induced RGC degeneration to values of approximately 60%, but KA toxicity was not significantly affected by L-Kyn pretreat- ment. Intraocular injections of NMDA resulted in an impairment of visual discrimination behavior, which partially recovered within a period of approximately 3 weeks. However, when treated systemically with L-Kyn, brightness discrimination was significantly improved as com- pared with NMDA-treated rats. Conclusions. These findings show that systemic administration of L-Kyn in adult rats can block NMDA-induced retinal ganglion cell death in vivo and preserves brightness discrimination performance. Invest Ophthalmol Vis Sci. 1996; 37:2382-2392. •Secondary cell loss due to brain damage after stroke central nervous system. Excitatory amino acids, such or trauma is not only the result of mechanical tissue as glutamate, have been suggested to act as a major damage but also due to excitotoxic insults. Activation neurotransmitters for most classes of neurons in the of excitatory amino acid receptors has been postulated retina.6"8 Lucas and Newhouse9 first established that to play a key role in stroke, degenerative disorders, glutamate is a potent toxin for neurons in the inner epilepsy, ischemia, and hypoglycemia.1"5 retina. In the past decade, various glutamate receptor 10 The retina is the most accessible portion of the subtypes have been reported in retinal cell types, and specific glutamate receptor agonists were shown to induce distinct lesions. Moreover, it was shown that From the * Institute, of Medical Psychology, Medical Faculty, Olto-von-Cumcke- the mammalian retina is highly susceptible to N- UniversUy of Magdeburg, Magdeburg, Cennany; and the f Department of methyl-D-aspartate (NMDA) toxicity.""14 The NMDA- Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, boston, Massachusetts. induced neuronal degeneration was found to be dose Supported by a grant from the Deutsche Forschungsgemeinschaft (Sa 433/3-1). dependent and mainly restricted to the innermost reti- Submitted for publication February 20, 1996; revised July S, 1996; accepted July 9, 1996. nal layers, whereas more distal layers were less af- Proprietary interest category: N. fected.13 This pattern closely resembles the cell loss Reprint requests: H. A. Sabel, Institute of Medical Psychology, Medical Faculty, Otto- von-Cuericke University, Uipuger Sir. 44, 39120 Magdeburg, Germany. that is observed in several retinal disease states such Investigative Ophthalmology & Vislal Sci. c:, November 1996, Vol. 37. No. 12 2382 Copyright © Association for Resea ch in ' on and Ophthalmology Downloaded from iovs.arvojournals.org on 09/28/2021 Systemic Htynurenine Protects Against Excitotoxicity 2383 as ischemia14 and glaucoma.lllD Furthermore, it was Kyn.22 This is of pharmacologic interest because it has proposed that retinal glutamate neurotoxicity is been shown that KYNA is able to block excitotoxin caused predominantly by overactivation of NMDA re- lesions created in vivo during development.20 ceptors, pointing to their crucial role in retinal degen- erative disorders.16 Retinal lesions induced by exposure to kainic acid MATERIALS AND METHODS 1718 (KA) were first characterized in the chicken. Kai- Treatments nic acid is a powerful excitotoxin when injected intra- ocularly and causes substantial cell death in the inner All animal experiments were performed in accor- nuclear layer while essentially sparing photoreceptor dance with the standards of the Association for Re- and ganglion cells.13'819 Hence, retinal KA excitotoxi- search in Vision and Ophthalmology. Hooded rats city is associated with a marked decrease in choline (300 to 350 g; PVG-Mol, Moellegard, Denmark) were acetyltransferase activity, indicating that cholinergic housed two animals per cage (wooden bedding) on a amacrine cells are the most vulnerable cell type to a 12:12 hour, dark-light cycle, food and water available KA insult.20 However, because the conclusions that ad libitum. Animals underwent surgery under general retinal ganglion cell (RGCs) are less susceptible to KA anesthesia using halothane or 7% intraperitoneal toxicity were based on the estimation of cell size and chloralhydrate injection. Intraocular injections were not on retrograde labeling of RGC, these data have performed with a heat-pulled glass pipette connected to be treated with caution. Furthermore, prelabeled to a microsyringe (model 105; Drummond Microdis- RGC in vitro are susceptible to KA neurotoxicity by a penser, Life Sciences International GmbH, Frankfurt, mechanism that seems to involve NMDA receptors Germany). All intraocular injections were made and the presence of an endogenous glutamate recep- through the dorsal limbus, each over a period of ap- tor agonist.21 proximately 1 minute. The NMDA and KA were dis- solved in phosphate-buffered saline and administrated Efforts to develop new pharmacologic treatment at a dose of 20 nmol in 2 /J,\ for each eye. The L-Kyn have focused on the development of glutamate recep- sulfate salt (Sigma-Aldrich Chemie GmbH, Diesenho- tor antagonists to prevent neuronal cell loss and de- fen, Germany) was dissolved in saline and then ad- generation. Further progress has partly been ham- justed to pH 7.4. All animals were injected with three pered by the lack of adequate in vivo models, where single doses of L-Kyn (100 mg/kg): 120 minutes be- the functional consequences of drug interventions can fore, 30 minutes before, and 30 minutes after NMDA be tested under appropriate conditions. The laminar (n = 8) or KA (n = 8) application. Control subjects organization of retinal neurons and their well-studied {n = 5) received three single injections of saline intra- synaptic connections provide excellent preconditions peritoneally and 2 pA phosphate-buffered saline intra- for studies on functional consequences of excitotoxi- ocularly. In some animals, the effect of L-Kyn on RGC city. number also was examined without subsequent excito- In the present study, we investigated the effect of toxin application. NMDA and KA excitotoxicity on retrogradely labeled ganglion cells in retinal whole mount preparations. In addition, we studied whether a pretreatment with Assessment of Retrograde Horseradish- systemic L-kynurenine (L-Kyn) attenuates NMDA-in- Peroxidase Transport duced excitotoxicity in the retina and whether such a To determine the number ofsundving RGCs, 48 hours neuroprotective effect has functional consequences as after intraocular injection, anesthetized rats were shown by visual discrimination performance. L-Kyn is placed in a stereotaxic frame (Stoelting, Woodale, IL). an endogenous metabolite of tryptophan metabolism A portion of the skull was removed, exposing the neo- that passes the blood-brain barrier and is metabolized cortex overlying the tectum on the side contralateral subsequently to kynurenic acid (KYNA), which, in to the lesioned eye. Seven intracerebral injections of turn, acts as a competitive antagonist at the glycine 0.7 fi\ horseradish peroxidase each (HRP; Boehringer binding site of the NMDA receptor complex.22 The Mannheim, Oberkochen, Germany; 30% [wt/vol] precursor L-Kyn is transported selectively across the HRP dissolved in 2% [vol/vol] dimethyl sulfoxide) blood-brain barrier by the large neutral amino acid were made targeting all layers of the contralateral su- carrier system,23 and the subsequent synthesis of KYNA perior colliculus. Each injection was made over a dura- is catalyzed by kynurenine aminotransferase. This en- tion of 2 minutes. Forty-eight hours after HRP applica- zyme has been found in both rat and human brain24'23 tion, the rats were processed to obtain retinal whole and is thought to be localized in glial cells within the mounts. central nervous system.2<3"2S Extracellular KYNA levels The protocol for the preparation of retinal whole in the central nervous system can be increased dramat- mounts was similar to that first described by Perry ically by peripheral administration of its precursor, L- and Linden.30 Briefly, rats were given a lethal dose of Downloaded from iovs.arvojournals.org on 09/28/2021 2384 Investigative Ophthalmology & Visual Science, November
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