In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease.
Of 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living.
At the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P < 0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment.
In this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.
"Findings of reduced cholinergic activity and loss of cholinergic neurons in the brains of individuals with Alzheimer's disease (AD) formed the rationale for the development of acetylcholinesterase inhibitors as drugs to ameliorate the dementia associated with AD (Davis et al., 1992; Rogers et al., 1998; Francis et al., 1999; Tariot et al., 2000; Csernansky et al., 2002). Donepezil, an acetylcholinesterase inhibitor, is one of the most popular approved therapies for AD. "
[Show abstract][Hide abstract] ABSTRACT: Donepezil, an acetylcholinesterase inhibitor, is an approved drug for the treatment of Alzheimer's disease (AD). Although extensive studies have demonstrated the symptomatic efficacy of donepezil treatment in patients with AD, the effects of donepezil, if any, on the AD process are not known. In this study, we sought to determine whether long-term administration of donepezil would slow amyloid plaque deposition or confer neuronal protection in a mouse model of AD. We used quantitative light and electron microscopy to investigate the effects of long-term administration (from 3 to 9 months of age for 6 months of treatment) of donepezil (1, 2, 4 mg/kg, in drinking water) on tissue amyloid-beta (Abeta) protein, plaque deposition, synaptic protein (synaptophysin), and synapse density in the hippocampus of Tg2576 mice. Administration of the 4 mg/kg dose of donepezil, as compared to vehicle and lower doses of donepezil, significantly reduced brain tissue soluble Abeta(1-40) and Abeta(1-42), Abeta plaque number, and burden at the study end point in Tg2576 mice. The dose of 4 mg/kg of donepezil also significantly increased synaptic density in the molecular layer of the dentate gyrus in Tg2576 mice. However, a significant change of the synaptophysin-positive bouton in the hippocampus was not observed. These results suggest that a higher dose of donepezil may have a measurable impact on tissue level of Abeta protein and plaque deposition and may prevent synapse loss in the Tg2576 mouse model of AD.
Brain research 09/2009; 1303:169-78. DOI:10.1016/j.brainres.2009.09.097 · 2.84 Impact Factor
"The mAChRs are G protein-coupled receptors (GPCRs) with five subtypes termed M 1 through M 5 that respond to the endogenous neurotransmitter acetylcholine (ACh); M 1 , M 3 , and M 5 couple to G q , whereas M 2 and M 4 couple via G i/o to downstream signaling pathways and associated effector systems (Wess, 1996; Langmead et al., 2008). It is interesting that mAChR agonists and acetylcholinesterase inhibitors have established efficacy in improving cognitive performance in patients with AD (Davis et al., 1992; Bodick et al., 1997; Rogers et al., 1998; Raskind et al., 1999). In addition, the mAChR agonist xanomeline has robust efficacy in reducing delusions, hallucinations, and other psychotic symptoms in patients with AD (Bodick et al., 1997) and schizophrenia (Shekhar et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Activators of M(1) muscarinic acetylcholine receptors (mAChRs) may provide novel treatments for schizophrenia and Alzheimer's disease. Unfortunately, the development of M(1)-active compounds has resulted in nonselective activation of the highly related M(2) to M(5) mAChR subtypes, which results in dose-limiting side effects. Using a functional screening approach, we identified several novel ligands that potentiated agonist activation of M(1) with low micromolar potencies and induced 5-fold or greater leftward shifts of the acetylcholine (ACh) concentration-response curve. These ligands did not compete for binding at the ACh binding site, indicating that they modulate receptor activity by binding to allosteric sites. The two most selective compounds, cyclopentyl 1,6-dimethyl-4-(6-nitrobenzo[d][1,3]-dioxol-5-yl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (VU0090157) and (E)-2-(4-ethoxyphenylamino)-N'-((2-hydroxynaphthalen-1-yl)methylene)acetohydrazide (VU0029767), induced progressive shifts in ACh affinity at M(1) that were consistent with their effects in a functional assay, suggesting that the mechanism for enhancement of M(1) activity by these compounds is by increasing agonist affinity. These compounds were strikingly different, however, in their ability to potentiate responses at a mutant M(1) receptor with decreased affinity for ACh and in their ability to affect responses of the allosteric M(1) agonist, 1-[1'-(2-tolyl)-1,4'-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one. Furthermore, these two compounds were distinct in their abilities to potentiate M(1)-mediated activation of phosphoinositide hydrolysis and phospholipase D. The discovery of multiple structurally distinct positive allosteric modulators of M(1) is an exciting advance in establishing the potential of allosteric modulators for selective activation of this receptor. These data also suggest that structurally diverse M(1) potentiators may act by distinct mechanisms and differentially regulate receptor coupling to downstream signaling pathways.
"Perhaps, if more attention were focused on the issues underlying the sub-populations of responders and the wide individual variations of the most effective dose, we might gain the required insight to improve treatment responses in this treatment-resistant patient population. While some in the AD field might argue that this concept was indeed tested in one of the earliest tacrine trials (Davis et al. 1992), in fact, this trial only tested two different doses per subject (and a very limited dose range) and thus hardly tested the concept identified in aged monkeys (Bartus 1979c; Bartus and Dean 1988c) for a wide variation exists (i.e., an order of magnitude ) in peak effective doses between individual subjects. "
[Show abstract][Hide abstract] ABSTRACT: Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical-neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review.
A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer's disease (AD) but for many other disorders involving cognitive deficits.
Collectively, our research provided first evidence of the following: aged primates can be used as 'models' for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed.
Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.