a(CHEBI:donepezil)

Entity

Name

donepezil

Namespace

chebi

Namespace Version

20180906

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/chebi-names.belns

Drugs currently approved to treat mild-to-moderate AD, including galantamine, donepezil, and rivastigmine, all inhibit AChE, the enzyme that hydrolyzes ACh (462). PubMed:19126755

Current licensed pharmacological treatments for AD consist largely of three acetylcholinesterase (AChE) inhibitors: rivastigmine, galantamine, and donepezil (Aguglia et al., 2004; Ritchie et al., 2004), although memantine, a blocker of L-glutamate receptors of the Nmethyl- D-aspartate (NMDA) subtype, is also deployed in late stages of the disease PubMed:19293145

In addition to nicotine, donepezil and rivastigmine, AChE inhibitors currently used as treatments for mild or moderate AD under the brand names of Aricept and Exelon, also protect cultured neuroblastoma cells from the toxic effects of Abeta. Although there is evidence that, in addition to inhibiting AChE, these ligands are also allosteric modulators of nAChRs (Schrattenholz et al., 1996; Coyle et al., 2007), it has not been established whether these AChE inhibitors protect neurons by their actions on alpha7 nAChRs rather than by simply inhibiting AChE, thereby elevating ACh in the medium. PubMed:19293145

In SHSY5Y cells, RNA interference (RNAi) knockdown of alpha7 enhanced Abeta toxicity (Qi et al., 2007), and alpha7 antagonists, but not alpha4beta2 antagonists, block galantamine protection of cultured rat neurons (Kihara et al., 2004). Donepezil protects cultured rat cortical neurons against Abeta toxicity through both alpha7 and non-alpha7 nAChRs (Takada et al., 2003). It is therefore likely that alpha7 nAChRs are the primary mediators of nicotine neuroprotection, but in some cells, non-alpha7 subtypes are also likely to contribute. PubMed:19293145

In addition to nicotine, donepezil and rivastigmine, AChE inhibitors currently used as treatments for mild or moderate AD under the brand names of Aricept and Exelon, also protect cultured neuroblastoma cells from the toxic effects of Abeta. Although there is evidence that, in addition to inhibiting AChE, these ligands are also allosteric modulators of nAChRs (Schrattenholz et al., 1996; Coyle et al., 2007), it has not been established whether these AChE inhibitors protect neurons by their actions on alpha7 nAChRs rather than by simply inhibiting AChE, thereby elevating ACh in the medium. PubMed:19293145

In SHSY5Y cells, RNA interference (RNAi) knockdown of alpha7 enhanced Abeta toxicity (Qi et al., 2007), and alpha7 antagonists, but not alpha4beta2 antagonists, block galantamine protection of cultured rat neurons (Kihara et al., 2004). Donepezil protects cultured rat cortical neurons against Abeta toxicity through both alpha7 and non-alpha7 nAChRs (Takada et al., 2003). It is therefore likely that alpha7 nAChRs are the primary mediators of nicotine neuroprotection, but in some cells, non-alpha7 subtypes are also likely to contribute. PubMed:19293145

Donepezil, which protects cultured rat cortical neurons, when applied for 4 days resulted in an up-regulation of alpha4 and alpha7 nAChRs with the result that donepezil was even more potently protective (Kume et al., 2005). PubMed:19293145

Donepezil, which protects cultured rat cortical neurons, when applied for 4 days resulted in an up-regulation of alpha4 and alpha7 nAChRs with the result that donepezil was even more potently protective (Kume et al., 2005). PubMed:19293145

Donepezil, which protects cultured rat cortical neurons, when applied for 4 days resulted in an up-regulation of alpha4 and alpha7 nAChRs with the result that donepezil was even more potently protective (Kume et al., 2005). PubMed:19293145

The AD therapeutic AChE inhibitors donepezil, galantamine, and tacrine increase BCL2 expression when applied to cultured neuronal cells (Arias et al., 2004; Takada-Takatori et al., 2006). In these cells, nicotine promotes cell survival and causes the phosphorylation of the proapoptotic protein Bcl2-associated X protein (BAX), through the PI3K/AKT pathway, reducing the movement of BAX from the cytosol to the mitochondria and inhibiting its apoptotic activity (Xin and Deng, 2005). PubMed:19293145

It has been demonstrated that treatment with donepezil is associated with significant cognitive and functional benefits over the course of 12 months in patients with moderate to severe AD PubMed:26813123

A recent functional MRI study demonstrated that people with MCI treated with the FDA-approved anticholinesterase donepezil demonstrated increased frontal cortex activation relative to untreated controls, which was positively correlated with task performance [31]. PubMed:18986241

It is likely that the therapeutic benefit of cholinesterase inhibitors occurs at least in part through activation of the nAChRs, by the direct action of increased levels and/or through a direct activation of the allosteric site on the nAChR (Maelicke et al 1995, 2000) PubMed:11230871

Cholinesterase inhibitors donepezil and rivastigmine, upregulating transport proteins P-glycoprotein and LRP1, may improve Aβ clearance in the liver of rats (Mohamed et al. 2015) PubMed:29626319

Cholinesterase inhibitors donepezil and rivastigmine, upregulating transport proteins P-glycoprotein and LRP1, may improve Aβ clearance in the liver of rats (Mohamed et al. 2015) PubMed:29626319

Cholinesterase inhibitors donepezil and rivastigmine, upregulating transport proteins P-glycoprotein and LRP1, may improve Aβ clearance in the liver of rats (Mohamed et al. 2015) PubMed:29626319

Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15 donepezil, 16 rivastigmine 17 and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have had limited effect in improving the cognitive function of AD patients and do not slow the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month PubMed:30444369

Only five drugs (Figure 1) have been approved by the U. S. Food and Drug Administration (FDA), four of which are cholinesterase inhibitors (tacrine, 15 donepezil, 16 rivastigmine 17 and galantamine 18 ) and one of which is a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine 19 ). These pharmacological agents have had limited effect in improving the cognitive function of AD patients and do not slow the progression of the disease. Clinical studies have shown that these agents temporarily stabilize cognitive impairment and help to maintain global function, delaying the need for patient palliative care by only a few month PubMed:30444369