Neuroprotective effect of donepezil, a nicotinic acetylcholine-receptor activator, on cerebral infarction in rats

Fujiki, Minoru; Kobayashi, Hidenori; Uchida, Susumu; Inoüe, Ryo; Ishii, Keisuke

doi:10.1016/j.brainres.2005.02.063

Cited by 51 publications

(48 citation statements)

References 17 publications

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“…However, neither mecamylamine nor scopolamine blocked the neuroprotective effects of donepezil on the retinal ganglion cells in the present study, suggesting that activation of nicotinic acetylcholine receptors or muscarinic acetylcholine receptors is not related to the neuroprotective effects of donepezil in the ganglion cells of the ischemic-reperfused rat retina. The similar phenomenon was reported in cultured retinal ganglion cells injured by glutamate (17) and the brain infarction in the rat left middle cerebral artery occlusion model (27). In contrast, neostigmine and pilocarpine showed neuroprotection in INL and IPL, and so nicotine did in INL, suggesting that stimulation of muscarinic receptors leads to neuroprotection in IPL and INL and that stimulation of nicotinic receptors leads to neuroprotection only in INL in the ischemic-reperfused rat retina.…”

Section: Dicussionsupporting

confidence: 80%

“…According to these previous data, not only intravenous but also oral donepezil will be effective. In fact, orally administered donepezil (12 mg/kg) was reported to reduce infarct size in the ischemic-reperfused rat brain (27). Therefore, donepezil has advantages over other new chemicals presently in development as medicines for treatment of retinal injury induced by high ocular pressure.…”

Section: Dicussionmentioning

confidence: 99%

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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: Dicussionsupporting

confidence: 80%

Section: Dicussionmentioning

confidence: 99%

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

et al. 2010

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“…The subsequent action of downstream signaling pathways, including the phosphatidylinositol 3-kinase-Akt signaling pathway and the MAPK pathway, makes neurons more sensitive to the protection by donepezil [98,100] . Consistent with this finding, Fujiki and co-workers found that the reduction of cerebral infarct and traumatic brain injury after donepezil administration was prevented by coinjection with mecamylamine, indicating that protection of donepezil is mediated by nAChR activation [96,97] . Moreover, another study showed that donepezil could markedly inhibit lipopolysaccharide-induced enhancement of AChE activity and suppress the elevated expression of IL-2 in several brain regions in mice [101] .…”

Section: Donepezilmentioning

confidence: 58%

“…Fujiki et al reported that pretreatment with a single oral dose of donepezil significantly attenuated cerebral infarction induced by permanent MCAO in rats [96] . Similarly, treatment with a single oral dose of donepezil immediately after mild traumatic brain injury also significantly attenuated neuronal death and cognitive impairment [97] .…”

Section: Donepezilmentioning

confidence: 99%

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

2009

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Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.

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“…The interaction of donepezil with the 1 receptor has been demonstrated at the behavioral level, since the selective 1 receptor antagonist N-[2- (3,4-dichlorophenyl)ethyl]-Nmethyl-2-(dimethylamino)ethylamine (BD1047) or an antisense probe targeting the 1 receptor blocked the antiamnesic effect of donepezil against dizocilpine-induced learning impairments in mice (Maurice et al, 2006), a behavioral response identifying 1 receptor agonist activity (Maurice et al, 1994a). Donepezil and other cholinesterase inhibitors showed neuroprotective effects in both in vivo or in vitro models of glutamate neurotoxicity, through a mechanism involving mainly an indirect activation of ␣ 4 ␤ 2 -and ␣ 7 -nicotinic receptors (Takada et al, 2003;Fujiki et al, 2005). However, the putative involvement of the 1 receptor in the neuroprotective activity of donepezil was never examined.…”

mentioning

confidence: 99%

Antiamnesic and Neuroprotective Effects of Donepezil against Learning Impairments Induced in Mice by Exposure to Carbon Monoxide Gas

Meunier

Ieni²,

Maurice³

2006

J Pharmacol Exp Ther

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Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the 1 receptor, an intracellular neuromodulatory protein.In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference 1 agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e., 7 to 8 days after CO, all drugs showed antiamnesic properties. Preadministration of the 1 receptor antagonist N- [2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO exposure (preinsult protection) or by injection 1 h after the last CO exposure (postinsult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO exposure. Preadministration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO exposure, only igmesine and donepezil induced effective neuroprotection, and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent antiamnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult, and its pharmacological actions as both an acetylcholinesterase inhibitor and 1 receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent postinsult protecting agent compared with more selective cholinesterase inhibitors.

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Neuroprotective effect of donepezil, a nicotinic acetylcholine-receptor activator, on cerebral infarction in rats

Cited by 51 publications

References 17 publications

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

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

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

Antiamnesic and Neuroprotective Effects of Donepezil against Learning Impairments Induced in Mice by Exposure to Carbon Monoxide Gas

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