Mechanisms of α7-nicotinic receptor up-regulation and sensitization to donepezil induced by chronic donepezil treatment

Takada‐Takatori, Yuki; Kume, Toshiaki; Ohgi, Yuta; Fujii, Takeshi; Niidome, Takuro; Sugimoto, Hachiro; Akaike, Akinori

doi:10.1016/j.ejphar.2008.06.027

Cited by 29 publications

(25 citation statements)

References 28 publications

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“…59) Thus, the neuroprotective action observed with acetylcholinesterase inhibitor treatment (10 mM, 24 h) in previous studies does not involve nAChR up-regulation; however, we observed significant up-regulation of a4-and a7-nAChR protein levels with longer treatment, after 4 days' chronic treatment with donepezil. 59,60) We also observed a significant increase in the proportion of neurons expressing a4-and a7-nAChR after chronic treatment with donepezil and galantamine. These results are in good accordance with an in vivo study which showed that chronic administration of donepezil and galantamine at dose levels analogous to those used to treat patients with Alzheimer's disease significantly increased nAChR density in the frontal cortex and hippocampus of aged rats.…”

Section: Nicotinic Receptor Up-regulation By Acetylcholinesterase Inhmentioning

confidence: 54%

“…Treatment with PP2 (10 mM), AG490 (10 mM), LY294002 (10 mM) and inhibitors of Fyn, JAK2 and PI3K, respectively, significantly inhibited donepezil-induced up-regulation, suggesting the involvement of the a7-nAChR-PI3K pathway. 60) Furthermore, donepezil-induced up-regulation was significantly inhibited by treatment with PD98059 (50 mM), an inhibitor of kinase of mitogen-activated protein kinase (MAPK). Donepezil-induced functional up-regulation of nAChR as shown by the enhancement of nicotine-induced increase of [Ca 2ϩ ] i , was also significantly inhibited by MLA (10 nM), PP2 (10 mM), AG490 (10 mM), LY294002 (10 mM) and PD98059 (50 mM) treatment.…”

Section: Mechanism Of Nicotinic Receptor In Acetylcholinesterase Inhimentioning

confidence: 99%

“…69) The mechanism of donepezil-induced nAChR up-regulation has been studied using primary cultures of rat cortical neurons. 59,60) Chronic treatment with donepezil did not alter the level of a4-and a7-nAChR mRNAs examined by reverse transcription polymerase chain reaction, demonstrating that donepezil up-regulates nAChR by post-translational mechanisms.…”

Section: Mechanism Of Nicotinic Receptor In Acetylcholinesterase Inhimentioning

confidence: 99%

“…Treatment with MLA (10 nM), a selective antagonist of a7-nAChR, significantly inhibited the chorinic donepezil (10 mM) treatment-induced up-regulation of a7-nAChR, as examined by immunoblotting. 60) Then, using specific inhibitors, we investigated the involvement of the a7-nAChR-PI3K pathway in the up-regulation of nAChR. Treatment with PP2 (10 mM), AG490 (10 mM), LY294002 (10 mM) and inhibitors of Fyn, JAK2 and PI3K, respectively, significantly inhibited donepezil-induced up-regulation, suggesting the involvement of the a7-nAChR-PI3K pathway.…”

Section: Mechanism Of Nicotinic Receptor In Acetylcholinesterase Inhimentioning

confidence: 99%

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Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

Takada‐Takatori

Kume

Izumi

et al. 2009

Biological & Pharmaceutical Bulletin

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Protection of neurons from neuronal damage and cell death in neurodegenerative disease is a major challenge in neuroscience research. Donepezil, galantamine and tacrine are acetylcholinesterase inhibitors used for the treatment of Alzheimer's disease, and were believed to be symptomatic drugs whose therapeutic effects are achieved by slowing the hydrolysis of acetylcholine at synaptic termini. However, recent accumulated evidence strongly suggests that these acetylcholinesterase inhibitors also possess neuroprotective properties whose mechanism is independent of acetylcholinesterase inhibition. We have shown that acetylcholinesterase inhibitors protect neurons from glutamate-induced neurotoxicity in the primary culture of rat cortical neurons. It was also found that acetylcholinesterase inhibitor treatment induces up-regulation of nicotinic receptor expression levels, a property which may also have some bearing on their therapeutic effects. We next showed that a a4 and a a7-nicotinic receptors play important roles in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation. Our results also demonstrate the important roles of the phosphatidylinositol 3-kinase pathway downstream of nicotinic receptors in protecting neurons from death and up-regulating nicotinic receptors. This review summarizes recent findings on the roles of the nicotinic receptor in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation.

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Section: Nicotinic Receptor Up-regulation By Acetylcholinesterase Inhmentioning

confidence: 54%

Section: Mechanism Of Nicotinic Receptor In Acetylcholinesterase Inhimentioning

confidence: 99%

Section: Mechanism Of Nicotinic Receptor In Acetylcholinesterase Inhimentioning

confidence: 99%

Section: Mechanism Of Nicotinic Receptor In Acetylcholinesterase Inhimentioning

confidence: 99%

See 2 more Smart Citations

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

Takada‐Takatori

Kume

Izumi

et al. 2009

Biological & Pharmaceutical Bulletin

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“…Several studies have found that donepezil can up-regulate the expression of nAChR and activate them, especially α4 and α7 receptor subtypes [98,99] . 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] .…”

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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Nicotinic Acetylcholine Receptor Signaling: Roles in Neuroprotection

Kume

Takada‐Takatori

2018

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

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Glutamate neurotoxicity is involved in various neurodegenerative disorders including brain ischemic stroke, trauma, and Alzheimer's and Parkinson's diseases. In addition to excitatory neuronal death, neuroinflammation accompanied by the activation of glial cells has been shown to be induced by these disorders. We previously reported the roles of nicotinic acetylcholine receptors (nAChRs) in the survival of central nervous system neurons during excitotoxic events and neuroinflammation. Nicotine and other nAChR agonists protected cortical neurons against glutamate neurotoxicity via α4-and α7-nAChRs in cultures of neurons obtained from the cerebral cortex of fetal rats. In addition, donepezil, a therapeutic acetylcholinesterase inhibitor currently being used for the treatment of Alzheimer's disease, protected neuronal cells from glutamate neurotoxicity. Moreover, nicotine and donepezil induced the upregulation of nAChRs. Thus, we propose that nicotine as well as donepezil prevents glutamate neurotoxicity through Α4-and α7-nAChRs and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In addition to the beneficial effect on neuronal cells, we have reported the responses of astrocytes to bradykinin, an inflammatory mediator, and the effect of nAChR stimulation on these responses using cultured cortical astrocytes. Bradykinin induced a transient increase of intracellular calcium concentration ([Ca 2+ ] i ) in cultured astrocytes. Both nicotine and donepezil reduced this bradykinin-induced [Ca 2+ ] i increase. This reduction was inhibited not only by mecamylamine, an nAChR antagonist, but also by PI3K and Akt inhibitors. These results suggest that nAChR stimulation suppresses the inflammatory response induced by bradykinin via the PI3K-Akt pathway in astrocytes.

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Mechanisms of α7-nicotinic receptor up-regulation and sensitization to donepezil induced by chronic donepezil treatment

Cited by 29 publications

References 28 publications

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

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

Nicotinic Acetylcholine Receptor Signaling: Roles in Neuroprotection

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