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

Sakamoto, Kenji; Ohki, Kayo; Saito, Maki; Nakahara, Tsutomu; Ishii, Kunio

doi:10.1254/jphs.09302fp

Cited by 25 publications

(16 citation statements)

References 36 publications

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“…[20][21][22][23]27,28) Briefly, animals were euthanized with an overdose of sodium pentobarbital. Both eyes were enucleated and fixed with a Davidson solution (37.5% ethanol, 9.3% paraformaldehyde, 12.5% acetic acid) for 24 h at room temperature.…”

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confidence: 99%

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Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina

Shirai

Mori

Nakahara

et al. 2015

Biological & Pharmaceutical Bulletin

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Endoplasmic reticulum stress has been reported to be involved in the pathogenesis of retinitis pigmentosa, macular degeneration and diabetic retinopathy. In the present study, we examined the effects of deferiprone, an iron chelator, on photoreceptor degeneration induced by tunicamycin (300 nmol/eye), an endoplasmic reticulum stress inducer, in the rat retina. Scotopic electroretinogram measurement and morphometric evaluation were done 7 d after the injection of tunicamycin. In the scotopic electroretinogram, intravitreal deferiprone (5 nmol/eye) injected simultaneously with tunicamycin significantly reduced the decreases in aand b-wave amplitudes induced by tunicamycin. Morphometric evaluation showed that deferiprone significantly reduced thinning of the outer nuclear layer, the inner segment and the outer segment. These results suggest that iron chelation therapy may be a good candidate for the treatment of eye diseases related to endoplasmic reticulum stress.Key words deferiprone; tunicamycin; endoplasmic reticulum stress; iron chelation Retinal degeneration involves various ocular disorders that characterized by the progressive death of retinal neurons. Although the mechanisms of photoreceptor cell death are not fully clarified, endoplasmic reticulum (ER) stress is one of candidates that cause macular degeneration, retinitis pigmentosa and diabetic retinopathy. 1) Tunicamycin is an antibiotic that inhibits the biosynthesis of N-acetylglucosaminylpyrophosphoryl polyisoprenol, a key intermediate in the formation of the asparagine-linked oligosaccharides of glycoproteins, 2) and widely known to induce ER stress.3) It has been reported that intravitreal tunicamycin causes photoreceptor-specific degeneration. 4,5) The intravitreal tunicamycin injection model is used for an animal model of photoreceptor-specific degeneration. [6][7][8][9] Increase of reactive oxygen species (ROS) is also known to cause ER stress, Parkinson's disease, 10-12) Alzheimer's disease, [11][12][13] and photoreceptor degeneration. 14) These ROS are believed to be generated at least in part by Fenton reaction, producing hydroxyl radical from hydrogen peroxide. It is well established that labile ferric iron, that does not form a complex with ferritin, is necessary for the Fenton reaction. Previous studies have demonstrated that chemical iron chelators, such as deferoxamine and VK-28, show neuroprotective effects in the animal models of Parkinson's disease 15) and Alzheimer's disease. 16)The aim of the present study was to determine whether iron chelation protects against photoreceptor degeneration induced by tunicamycin. Deferiprone (DFP), a chemical iron chelator that crosses the blood-brain barrier, 17) has shown efficacy with low toxicity in human.18) DFP has also been shown to decrease retinal labile iron without retinal toxicity in the mouse. 19) In the present study, we histologically and functionally examined whether intravitreal injection of DFP protects against tunicamycin-induced retinal degeneration. MATERIALS AND METHODSAnimals E...

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confidence: 99%

“…The environment of the animal room was kept at 25°C with a 12 h : 12 h light-dark cycle. All animals were fed and watered ad libitum.Intravitreal Injection Intravitreal injection was performed as previously described [20][21][22][23] with some modifications. Briefly, rats were anesthetized with ketamine (90 mg/kg intraperitoneally (i.p.…”

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Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina

Shirai

Mori

Nakahara

et al. 2015

Biological & Pharmaceutical Bulletin

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“…However, the mechanisms underlying the neuroprotective effects of donepezil remain unclear. Sakamoto et al (30) observed that the activation of AChRs and a mechanism unrelated to AChE inhibition contributes to the protective effect of donepezil. In experiments using rat cortical neurons, Takada et al (9) showed that the neuroprotection afforded by donepezil was prevented by methyllycaconitine (MLA), an α7-selective nAChR antagonist, but not by scopolamine, a muscarinic (m)AChR antagonist.…”

Section: Discussionmentioning

confidence: 99%

Donepezil delays photoreceptor apoptosis induced by N-methyl-N-nitrosourea in mice

Liu

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Retinitis pigmentosa (RP) is a group of inherited retinal degeneration diseases characterized by photoreceptor cell death that causes visual disturbances and eventual blindness. Intraperitoneal injection of N-methyl-N-nitrosourea (MNU) causes photoreceptor loss, and is used to create an animal model for investigating the mechanisms that cause retinal degeneration diseases. Donepezil is an acetylcholinesterase inhibitor that has a protective effect on retinal ganglion cells in vitro and in vivo, and it is understood that donepezil increases the expression of a heat shock protein 70 (Hsp70), which serves to protect neurons. Hsp70 functions as a chaperone molecule that protects cells from protein aggregation and assists in the refolding of denatured proteins. In the present study, the effects of donepezil on photoreceptor survival in mice was investigated. It was observed that donepezil upregulates the expression of Hsp70, to increase resistance to MNU-induced photoreceptor cell apoptosis by using its anti-apoptotic properties. In addition, the present study observed that Hsp70 promotes photoreceptor cell survival by upregulating the expression levels of B-cell lymphoma 2 (Bcl-2). In conclusion, the results of the present study indicate that donepezil has the potential to be used as a treatment for retinal degenerative diseases.

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“…Intravitreal Injection Intravitreal injection was performed as previously described 14,23,24) with some modifications. Briefly, rats were anesthetized with ketamine (90 mg/ kg intraperitoneally (i.p.…”

Section: Methodsmentioning

confidence: 99%

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

Cited by 25 publications

References 36 publications

Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina

Deferiprone Protects against Photoreceptor Degeneration Induced by Tunicamycin in the Rat Retina

Donepezil delays photoreceptor apoptosis induced by N-methyl-N-nitrosourea in mice

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

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