Inhibition of NMDA receptors and nitric oxide synthase reduces ischemic injury of the retina

Adachi, Kei; Fujita, Yasuhiko; Morizane, Chikako; Akaike, Akinori; Ueda, Masafumi; Satoh, Masamichi; Masai, Hirokazu; Kashii, Satoshi; Honda, Yoshio

doi:10.1016/s0014-2999(98)00317-3

Cited by 68 publications

(36 citation statements)

References 19 publications

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“…MK-801 is neuroprotective against glutamate-mediated toxicity in retina via blockade of NMDA receptor activity [23,1]. Differentiated RGC-5 cells were serumdeprived for 24 h, followed by 1 h pretreatment with MK-801 (3 or 10 µM).…”

Section: Homocysteine-induced Rgc Toxicity Is Mediated By Nmda Receptormentioning

confidence: 99%

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

Martin

Ola

Agarwal

et al. 2004

Molecular Brain Research

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Recent studies demonstrated that the excitotoxic amino acid homocysteine induces apoptotic death of retinal ganglion cells in vivo. In the present study, an in vitro rat retinal ganglion cell culture system was used to analyze the toxicity of acute exposure to high levels of homocysteine, the mechanism of homocysteine-induced toxicity and the usefulness of σR1 ligands as neuroprotectants. When cultured RGC-5 cells were subjected to treatment with 1 mM D, Lhomocysteine, a significant increase in cell death was detected by TUNEL analysis and analysis of activated caspase. When cells were treated with homocysteine-or glutamate in the presence of MK-801, an antagonist of the NMDA receptor, the cell death was inhibited significantly. In contrast, NBQX, an antagonist of the AMPA/Kainate receptor, and nifedipine, a calcium channel blocker, did not prevent the homocysteine-or glutamate-induced cell death. Semi-quantitative RT-PCR and immunocytochemical analysis demonstrated that RGC-5 cells exposed to homocysteine or glutamate express type 1 sigma receptor at levels similar to control cells. Treatment of RGC-5 cells with 3 µM or 10 µM concentrations of the σR1-specific ligand (+)-pentazocine inhibited significantly the apoptotic cell death induced by homocysteine or glutamate. The results suggest that homocysteine is toxic to ganglion cells in vitro, that the toxicity is mediated via NMDA receptor activation, and that the σR1-specific ligand (+)-pentazocine can block the RGC-5 cell death induced by homocysteine and glutamate.

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Section: Homocysteine-induced Rgc Toxicity Is Mediated By Nmda Receptormentioning

confidence: 99%

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

Martin

Ola

Agarwal

et al. 2004

Molecular Brain Research

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“…The activation of the Nmethyl-D-aspartate (NMDA) receptor, a subtype of the glutamate receptor (7,8), followed by excess Ca 2+ influx via NMDA receptor-operated channels is thought to be involved in the predominant mechanism of neuronal excitotoxicity. In fact, excitotoxicity caused by the elevation of glutamate concentration in the retinal extracellular space near the glutamate-receptor channels is thought to be one of the mechanisms of neuronal cell death induced by glaucoma (9) and MK-801, an NMDA receptorchannel blocker, prevents retinal damage induced by retinal ischemia-reperfusion (10,11).…”

Section: Introductionmentioning

confidence: 99%

Histological Protection by Donepezil Against Neurodegeneration Induced by Ischemia–Reperfusion in the Rat Retina

et al. 2010

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Abstract. Although a blockade of acetylcholine esterase has been reported to suppress neuronal cell death induced by exogenous glutamate and β -amyloid, information is still limited regarding the neuroprotective effects of the acetylcholine esterase inhibitor donepezil. We histologically examined the effects of donepezil on neuronal injury induced by ischemia-reperfusion. Intravenous and intravitreous treatment with donepezil 15 min prior to ischemia dramatically reduced the retinal damage. The protective effect of donepezil in the ganglion cell layer was not affected by mecamylamine, a nicotinic acetylcholine-receptor antagonist, nor scopolamine, a muscarinic acetylcholine-receptor antagonist. The protective effect of donepezil in the inner plexiform layer was reduced not by mecamylamine, but by scopolamine. Neostigmine, a choline-esterase inhibitor, and pilocarpine, a muscarinic acetylcholine-receptor agonist, have protective effects in the inner plexiform layer and the inner nuclear layer. These results suggest that not only the activation of acetylcholine receptors but also a mechanism unrelated to acetylcholine-esterase inhibition contribute to the protective effect of donepezil on the ganglion cells in the ischemic-reperfused rat retina. Donepezil may be useful as a therapeutic drug against retinal diseases that cause neuronal cell death such as glaucoma with high intraocular pressure.

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Section: -3)mentioning

confidence: 99%

“…9) MK-801, an NMDA receptor channel blocker, has been reported to prevent retinal damage induced by retinal ischemia-reperfusion. 10,11) Activation of NMDA receptors depolarizes neurons and subsequently activates voltage-dependent Ca 2+ channels (VDCCs).12,13) We previously reported that cilnidipine, a dual L/N-type Ca 2+ channel blocker, has a beneficial effect on retinal ischemia-reperfusion injury.14) Therefore, activation of VDCCs after stimulation of NMDA receptor is likely involved in the mechanism of retinal excitotoxic injury.Nilvadipine, a dihydropyridine L-type VDCC blocker, has selective and long-lasting effects on cerebral arteries compared with other calcium channel blockers such as nicardipine, nifedipine and diltiazem.15) Nilvadipine was effective in several experimental models of cerebral ischemia. 16,17) In addition, nilvadipine has been reported to inhibit glutamate-induced apoptotic cell death by blocking Ca 2+ influx via L-type VDCC in the purified retinal ganglion cells, 18) and to have beneficial effects on the retinal ischemia-reperfusion injury.…”

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confidence: 99%

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Histological Protection by Nilvadipine against Neurotoxicity Induced by NOC12, a Nitric Oxide Donor, in the Rat Retina

Kuroki

Mori

Nakahara

et al. 2014

Biological & Pharmaceutical Bulletin

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In the present study, we histologically examined the effects of nilvadipine on neuronal injury induced by intravitreal (i.v.) N-methyl-D-aspartate (NMDA) (200 nmol/eye) and intravitreal NOC12 (400 nmol/eye), a nitric oxide donor, in the rat retina. Morphometric evaluation at 7 d after injection of NMDA or NOC12 showed that treatment with nilvadipine (1 mg/kg, i.v.) 15 min prior to injection of NMDA or NOC12 dramatically reduced the retinal damage. These results suggest that nilvadipine protects neurons against excitotoxic injury in the rat retina in vivo at least in part via an antioxidative effect. 1-3)Glutamate is the principal excitatory neurotransmitter in the central nervous system, including retina. 4,5) However, stimulation of some of the glutamate receptor by excess amount of glutamate under pathologic conditions such as hypoxia 6) and ischemia-reperfusion 1) is toxic to neuronal cells. The activation of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor, 7,8) followed by excess Ca 2+ influx via NMDA receptor-operated channels is thought to be involved in the predominant mechanism of neuronal excitotoxicity. In fact, excitotoxicity caused by the elevation of glutamate concentration in the retinal extracellular space near the glutamate receptor channels is thought to be one of the mechanisms of neuronal cell death induced by glaucoma. 9) MK-801, an NMDA receptor channel blocker, has been reported to prevent retinal damage induced by retinal ischemia-reperfusion. 10,11) Activation of NMDA receptors depolarizes neurons and subsequently activates voltage-dependent Ca 2+ channels (VDCCs).12,13) We previously reported that cilnidipine, a dual L/N-type Ca 2+ channel blocker, has a beneficial effect on retinal ischemia-reperfusion injury.14) Therefore, activation of VDCCs after stimulation of NMDA receptor is likely involved in the mechanism of retinal excitotoxic injury.Nilvadipine, a dihydropyridine L-type VDCC blocker, has selective and long-lasting effects on cerebral arteries compared with other calcium channel blockers such as nicardipine, nifedipine and diltiazem.15) Nilvadipine was effective in several experimental models of cerebral ischemia. 16,17) In addition, nilvadipine has been reported to inhibit glutamate-induced apoptotic cell death by blocking Ca 2+ influx via L-type VDCC in the purified retinal ganglion cells, 18) and to have beneficial effects on the retinal ischemia-reperfusion injury.19) Nilvadipine increases blood velocity and blood flow in the optic nerve head, choroid and retina of rabbits, and had little effect on systemic blood pressure in subjects without hypertension. 20)In contrast to cilnidipine and nilvadipine, we previously reported that amlodipine, another dihydropyridine L-type VDCC blocker, did not inhibit retinal injury induced by ischemia-reperfusion, 14) suggesting that other mechanism than blocking Ca 2+ influx via L-type VDCC may be important for retinal neuroprotection against excitotoxiciity by L-type VDCC blockers. In fact, clinidipine blocks no...

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Inhibition of NMDA receptors and nitric oxide synthase reduces ischemic injury of the retina

Cited by 68 publications

References 19 publications

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

Histological Protection by Donepezil Against Neurodegeneration Induced by Ischemia–Reperfusion in the Rat Retina

Histological Protection by Nilvadipine against Neurotoxicity Induced by NOC12, a Nitric Oxide Donor, in the Rat Retina

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