a(CHEBI:tacrine)

Entity

Name

tacrine

Namespace

chebi

Namespace Version

20180906

Namespace URL

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

This file encodes the article Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia by Choi et al, 2014

The APOE-epsilon4 gene-dose effect was also found to correlate with the loss of nAChR binding sites in patients with AD, as well as a reduced respon- siveness to the therapeutic AChE inhibitor tacrine (Poirier et al., 1995). Within an AD cohort, APOE-epsilon4 dose dependently correlates with higher losses of ChAT but not with losses in alpha4beta2 nAChRs (Lai et al., 2006). 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

The APOE-epsilon4 gene-dose effect was also found to correlate with the loss of nAChR binding sites in patients with AD, as well as a reduced respon- siveness to the therapeutic AChE inhibitor tacrine (Poirier et al., 1995). Within an AD cohort, APOE-epsilon4 dose dependently correlates with higher losses of ChAT but not with losses in alpha4beta2 nAChRs (Lai et al., 2006). PubMed:19293145

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

Since an enhanced activity of acetylcholinesterase has been measured in cerebrospinal fluid following long-term treatment with tacrine (Nordberg et al 1999), possibly as a result of an increased acetylcholinesterase gene expression, it might be an advantage to use drugs interacting with nAChRs PubMed:11230871

In addition, PET studies also have revealed an improvement in nAChRs in AD patients during long-term treatment with cholinesterase inhibitors such as tacrine and NXX- 066 (Nordberg 2000; Nordberg et al 1992, 1998) PubMed:11230871

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