Mechanism of the pathogenesis of glutamate neurotoxicity in retinal ischemia

Adachi, Kei; Kashii, Satoshi; Masai, Hirokazu; Ueda, Masafumi; Morizane, Chikako; Kaneda, Katsuyuki; Kume, Toshiaki; Akaike, Akinori; Honda, Yoshio

doi:10.1007/s004170050156

Cited by 104 publications

(75 citation statements)

References 42 publications

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“…(2) In the cat, a global ocular ischaemia was produced by 60 min of IOP elevation followed by 100 min of re-perfusion. 15 In this study, the vitreous amino-acid concentration was continuously monitored by a microdialysis probe positioned in the vitreous cavity. At 60-70 min of reperfusion, the vitreous glutamate concentration peaked at 6.7 times the baseline level.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, the current primate model produced only the inner retinal ischaemia by transiently occluding the central retinal artery (see Figures 1-3), while the previous studies. 14,15 produced more global ocular ischaemia by occluding the entire ocular blood supply. Thus, it is possible that vitreous glutamate elevation is only associated with much more global ocular ischaemia that affects not only the retinal blood supply but also the choroidal and even the anterior segment blood circulation.…”

Section: Discussionmentioning

confidence: 99%

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Vitreous and retinal amino acid concentrations in experimental central retinal artery occlusion in the primate

Kwon

Rickman

Baruah

et al. 2004

Eye

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Purpose Vitreous and retinal amino-acid concentrations were evaluated in a primate model of central retinal artery occlusion (CRAO) to study the role of glutamate excitotoxicity in acute retinal ischaemia. Methods Unilateral, acute CRAO was produced by temporary clamping of the central retinal artery for 190 min in four elderly rhesus monkeys. Fundus photography, fluorescein angiography, and electroretinogram were performed before and during CRAO, and after unclamping the artery. Vitreous samples were obtained before and after CRAO in both eyes, and analysed for 13 amino-acid concentrations using highpressure liquid chromatography. The animals were killed 350 min after retinal reperfusion, and the retinal tissue was submitted for amino-acid analysis. Results In all four eyes, the macula showed the 'cherry red spot'. The CRAO was confirmed by fluorescein angiography and decreased b-wave on electroretinogram. Retinal histology confirmed ischaemic changes in the inner retina. Changes in all 13 vitreous amino-acid concentrations after CRAO (including glutamate) were not significantly different between study and control eyes (P ¼ 0.09 to 0.82). All retinal amino-acid concentrations (including glutamate) were not significantly different between two eyes (P ¼ 0. 07-0.93

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Vitreous and retinal amino acid concentrations in experimental central retinal artery occlusion in the primate

Kwon

Rickman

Baruah

et al. 2004

Eye

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“…A stronger extracellular volume decrease, which should severely impair the homeostasis of extracellular ions and neuroactive substances, is apparently prevented by the "compensatory" reshaping of glial cells. This effect should be even more important under pathological conditions, such as epilepsy (Glass and Dragunow, 1995) or ischemia, that cause excessive glutamate release (Adachi et al, 1972;Osborne et al, 2004) and functional downregulation of glial glutamate uptake (Barnett et al, 2001). Thus, this mechanism may help to decrease the extent of glutamate toxicity.…”

Section: Functional Relevancementioning

confidence: 99%

“…The K ϩ and water fluxes, generated by neuronal activity and mediated by glial cells, are accompanied by swelling of cells and shrinkage of the extracellular space caused by the decreased extracellular osmolality (Dietzel et al, 1980;Jendelová and Syková, 1991;Syková, 1991). Cell volume alterations are important, particularly under pathological conditions such as epilepsy and ischemia in which overexcited neurons release large amounts of glutamate and K ϩ (Adachi et al, 1972;Glass and Dragunow, 1995;Nicholson and Syková, 1998). Increased extracellular glutamate may evoke slow swelling of retinal glial cells resulting from the influx of Na ϩ , which drives the glial glutamate transporters (Izumi et al, 1996), and high K ϩ may cause swelling of astrocytes mediated by the Na-K-2Cl cotransport (Walz and Hinks, 1985;MacVicar et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Glutamate-Evoked Alterations of Glial and Neuronal Cell Morphology in the Guinea Pig Retina

Uckermann¹,

Vargová²,

Ulbricht³

et al. 2004

J. Neurosci.

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Neuronal activity is accompanied by transmembranous ion fluxes that cause cell volume changes. In whole mounts of the guinea pig retina, application of glutamate resulted in fast swelling of neuronal cell bodies in the ganglion cell layer (GCL) and the inner nuclear layer (INL) (by ϳ40%) and a concomitant decrease of the thickness of glial cell processes in the inner plexiform layer (IPL) (by ϳ40%) that was accompanied by an elongation of the glial cells, by a thickening of the whole retinal tissue, and by a shrinkage of the extracellular space (by ϳ18%). The half-maximal effect of glutamate was observed at ϳ250 M, after ϳ4 min. The swelling was caused predominantly by AMPAkainate receptor-mediated influx of Na ϩ into retinal neurons. Similar but transient morphological alterations were induced by high K ϩ and dopamine, which caused release of endogenous glutamate and subsequent activation of AMPA-kainate receptors. Apparently, retinal glutamatergic transmission is accompanied by neuronal cell swelling that causes compensatory morphological alterations of glial cells. The effect of dopamine was elicitable only during light adaptation but not in the dark, and glutamate and high K ϩ induced stronger effects in the dark than in the light. This suggests that not only the endogenous release of dopamine but also the responsiveness of glutamatergic neurons to dopamine is regulated by light-dark adaptation. Similar morphological alterations (neuronal swelling and decreased glial process thickness) were observed in whole mounts isolated immediately after experimental retinal ischemia, suggesting an involvement of AMPA-kainate receptor activation in putative neurotoxic cell swelling in the postischemic retina.Key words: glutamate; dopamine; ATP; neuroglia; circadian phase; ischemia; retina IntroductionGlial cells play crucial roles in supporting neuronal survival and information processing (Newman and Reichenbach, 1996): they regulate the extracellular homeostasis of relevant ions including K ϩ , control the water content of the extracellular space, and mediate the rapid termination of neuronal activity by transmitter uptake from the synaptic cleft (Matsui et al., 1999). In the retina, neuronally released K ϩ , water, and glutamate are cleared from the extracellular space mainly by the radial glial (Müller) cells. Retinal glial cells display a complex pattern of K ϩ channel expression in their plasma membranes that directs the flow of neuronally released K ϩ into the glial cell bodies and farther into the vitreous and the blood vessels (Kofuji et al., 2002). Parallel water fluxes were suggested to be coupled to the transglial K ϩ fluxes (Nagelhus et al., 1999). The K ϩ and water fluxes, generated by neuronal activity and mediated by glial cells, are accompanied by swelling of cells and shrinkage of the extracellular space caused by the decreased extracellular osmolality (Dietzel et al., 1980;Jendelová and Syková, 1991;Syková, 1991). Cell volume alterations are important, particularly under pathological conditions such as ...

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“…[1][2][3][4] As a consequence of reduced blood supply, retinal cells undergo hypoxia causing a number of pathophysiological processes, including glutamate toxicity and free radical formation, that ultimately end in damage to retinal neurons and cell death by apoptosis. 1,[3][4][5][6][7] Current treatments aim at reestablishing retinal circulation before the damage leads to irreversible vision loss. This is attained by a combination of therapeutic regimens, including laser treatment, ocular massage, anticoagulants such as tissue plasminogen activator (t-PA), and vasodilators.…”

Section: Introductionmentioning

confidence: 99%

XIAP-mediated neuroprotection in retinal ischemia

et al. 2005

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Retinal ischemia results in the loss of vision in a number of ocular diseases including acute glaucoma, diabetic retinopathy, hypertensive retinopathy and retinal vascular occlusion. Recent studies have shown that most of the neuronal death that leads to loss of vision results from apoptosis. XIAPmediated gene therapy has been shown to protect a number of neuronal types from apoptosis but has never been assessed in retinal neurons following ischemic-induced cell death. We injected an adeno-associated viral vector expressing XIAP or GFP into rat eyes and 6 weeks later, rendered them ischemic by raising intraocular pressure. Functional analysis revealed that XIAP-treated eyes retained larger b-wave amplitudes than GFP-treated eyes up to 4 weeks post-ischemia. The number of cells in the inner nuclear layer (INL) and the thickness of the inner retina were significantly preserved in XIAP-treated eyes compared to GFP-treated eyes. Similarly, there was no significant reduction in optic nerve axon numbers in XIAP-treated eyes. There were also significantly fewer TUNEL (TdT-dUTP terminal nick end labeling) positive cells in the INL of XIAP-treated retinas at 24 h post-ischemia. Thus, XIAPmediated gene therapy imparts both functional and structural protection to the retina after a transient ischemic episode.

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Mechanism of the pathogenesis of glutamate neurotoxicity in retinal ischemia

Abstract: These findings indicate that nitric oxide mediates neurotoxic actions of glutamate which are responsible for ischemic injury in the retina.

Cited by 104 publications

References 42 publications

Vitreous and retinal amino acid concentrations in experimental central retinal artery occlusion in the primate

Vitreous and retinal amino acid concentrations in experimental central retinal artery occlusion in the primate

Glutamate-Evoked Alterations of Glial and Neuronal Cell Morphology in the Guinea Pig Retina

XIAP-mediated neuroprotection in retinal ischemia

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