Contribution of endogenous glycine site NMDA agonists to excitotoxic retinal damage in vivo

Hama, Yasuhiro; Katsuki, Hiroshi; Tochikawa, Yoshinaga; Suminaka, Chihiro; Kume, Toshiaki; Akaike, Akinori

doi:10.1016/j.neures.2006.07.008

Cited by 34 publications

(30 citation statements)

References 38 publications

(52 reference statements)

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“…A great number of NMDA type ionotropic glutamate receptors can be detected in the ganglion cell layer of the retina [14,15]. Retinal ischemia, various experimental glaucoma models, diabetic or optic neuropathy are often associated with neurodegeneration of retinal ganglion cells and amacrine cells, which may undergo apoptosis in the inner nuclear layer [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

et al. 2015

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Rat posterior eyecups containing the retina were prepared, loaded with [(3)H]glycine and superfused in order to determine its release originated from glycinergic amacrine cells and/or glial cells. Deprivation of oxygen and glucose from the Krebs-bicarbonate buffer used for superfusion evoked a marked increase of [(3)H]glycine release, an effect that was found to be external Ca(2+)-independent. Whereas oxygen and glucose deprivation increased [(3)H]glycine release, its uptake was reduced suggesting that energy deficiency shifts glycine transporter type-1 operation from normal to reverse mode. The increased release of [(3)H]glycine evoked by oxygen and glucose deprivation was suspended by addition of the non-competitive glycine transporter type-1 inhibitor NFPS and the competitive inhibitor ACPPB further suggesting the involvement of this transporter in the mediation of [(3)H]glycine release. Oxygen and glucose deprivation also evoked [(3)H]glutamate release from rat retina and the concomitantly occurring release of the NMDA receptor agonist glutamate and the coagonist glycine makes NMDA receptor pathological overstimulation possible in hypoxic conditions. [(3)H]Glutamate release was suspended by addition of the excitatory amino acid transporter inhibitor TBOA. Sarcosine, a substrate inhibitor of glycine transporter type-1, also increased [(3)H]glycine release probably by heteroexchange shifting transporter operation into reverse mode. This effect of sarcosine was also external Ca(2+)-independent and could be suspended by NFPS. Energy deficiency in retina induced by ouabain, an inhibitor of the Na(+)-K(+)-dependent ATPase, and by rotenone, a mitochondrial complex I inhibitor added with the glycolytic inhibitor 2-deoxy-D-glucose, led to increase of retinal [(3)H]glycine efflux. These effects of ouabain and rotenone/2-deoxy-D-glucose could also be blocked by NFPS pointed to the preferential reverse mode operation of glycine transporter type-1 as a consequence of impaired cellular energy homeostasis. Immunohistochemical studies revealed that glycine transporter type-1, of which reverse mode operation assures [(3)H]glycine release, is expressed in amacrine cells in the inner nuclear and plexiform layers of the retina and also in Müller macroglia cells. We conclude that disruption of the balanced normal/reverse mode operation of glycine transporter type-1 is likely a significant factor contributing to neurotoxic processes of the retina. The possibility to inhibit glycine transporter type-1 mediated glycine efflux by drugs more potently than glycine uptake might offer some therapeutic potential for the treatment of various neurodegenerative disorders of the retina.

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Section: Introductionmentioning

confidence: 99%

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

et al. 2015

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“…Previous evidence also supported that endogenous D-serine, particularly generated from neuronal cells, much contributed to neuronal death following various CNS insults. It was found that D-serine acted as a dominant co-agonist for NMDA receptor-elicited neuronal death in hippocampal and cortical slice cultures [14,31], and also involved in neuronal degeneration in the amyotrophic lateral sclerosis [34,35]. Besides, a large number of D-serine-containing astrocytes were widely observed in brains of this mouse pilocarpine model, it is possible that D-serine released from astrocytes might also be involved in inducing the neuronal death.…”

Section: Discussionmentioning

confidence: 85%

Up-regulation of d-serine Might Induce GABAergic Neuronal Degeneration in the Cerebral Cortex and Hippocampus in the Mouse Pilocarpine Model of Epilepsy

et al. 2009

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Epilepsy is a serious neurological disorder with neuronal loss and spontaneous recurrent seizures, but the neurochemical basis remains largely unclear. We hypothesize that D-serine, a newly identified endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptor, may trigger excitotoxicity and neuronal damage in epileptogenesis. By using a mouse pilocarpine model, immunohistochemistry, Fluoro-Jade staining and double-labeling, the present study revealed up-regulation of D-serine expression in a proportion (41%) of neurons in the cerebral cortex and hippocampus. The D-serine-positive neurons occurred at 4 h, reached peak levels at 12-24 h, and gradually went down at 3-14 days. Moreover, most of D-serine-positive neurons were GABAergic (98%), underwent degenerating death (93%), and were accompanied enhancing phosphorylation of NMDA receptor subunit 1. This study has provided new evidence that up-regulation of D-serine production might induce GABAergic neuronal degeneration through excitotoxic mechanism in the pilocarpine model and may be involved in early pathogenesis and recurrent seizure of chronic epilepsy.

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“…Thes e findings sugg e s t that glycine site stimula tio n by endo g e n o u s ligand s is obligat o ry for NMDA-induc e d retin al dam a g e [121].…”

Section: Sc H I Z O P H R E N I Amentioning

confidence: 81%

Syntheses, Transformations and Pharmaceutical Applications of Kynurenic Acid Derivatives

Fülöp

Szatmári

Vámos

et al. 2009

CMC

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KEYWORDS: Kynur e ni c acid, Kynure nic acid deriva tive s, Neu rologic al disor d e r s , Schizop h r e n i a , Retinal dam a g e , Diabe t e s mellitus, Hyper t e n s i o n Abstr a c tThe synth e s e s and tran sfo r m a t i o n s of 4-hydroxyq ui n olin e-2-carboxylic acid, kynur e ni c acid, are review e d , and speci al att e n tio n is paid to the phar m a c olo gic al activities and pha r m a c e u t i c al applica tio n s of its derivative s.

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Contribution of endogenous glycine site NMDA agonists to excitotoxic retinal damage in vivo

Cited by 34 publications

References 38 publications

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

Up-regulation of d-serine Might Induce GABAergic Neuronal Degeneration in the Cerebral Cortex and Hippocampus in the Mouse Pilocarpine Model of Epilepsy

Syntheses, Transformations and Pharmaceutical Applications of Kynurenic Acid Derivatives

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