Contribution of endogenous glycine site NMDA agonists to excitotoxic retinal damage in vivo.
N-Methyl-d-aspartate (NMDA) receptors, which play an important role in neuronal excitotoxicity, require not only agonists at the glutamate-binding site but also co-agonists at the glycine site for their activation. Here we examined the role of endogenous agonists at the glycine site of NMDA receptors in excitotoxic retinal damage in vivo. To quantify the number of surviving retinal ganglion cells (RGCs), we injected a retrograde tracer, fluoro-gold, into the superior colliculus bilaterally and subsequently counted RGCs on whole-mounted retinas. Co-injection of 5,7-dichlorokynurenic acid (300 nmol), a competitive antagonist at the glycine site of NMDA receptors, rescued RGCs from damage induced by 200 nmol NMDA. On the other hand, RGC death induced by 20 nmol NMDA was enhanced by addition of glycine (10 nmol), D-serine (10 nmol) or a competitive glycine transporter-1 inhibitor, sarcosine (0.3 or 3 nmol). Moreover, application of d-serine-degrading enzyme, D-amino acid oxidase (30 mU), partially suppressed RGC death induced by 20 nmol NMDA. These results suggest that the severity of excitotoxic retinal damage in vivo depends on the levels of both glycine and D-serine.
Hama
Yasuhiro
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Katsuki
Hiroshi
H
Tochikawa
Yoshinaga
Y
Suminaka
Chihiro
C
Kume
Toshiaki
T
Akaike
Akinori
A
D000581:Amidohydrolases / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000502:physiology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012164:Retinal Diseases / Q000139:chemically induced* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D012694:Serine / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016202:N-Methylaspartate; D000581:Amidohydrolases; C407355:D-amino acid amidase; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D005998:Glycine