Epidemiology has identified a few nonaging, nongenetic factors that do fit in with the hypothesis. Head injury, for example, might influence AD by increasing amyloid production. Diabetes or insulin-resistance syndrome might affect AD by reducing inhibition of GSK-3 and increasing tau pathology. It will be interesting over the forthcoming years to see Inhibitors,research,lifescience,medical how other factors, and the genetic factors in particular, which will be identified following the systematic genome scans, enhance our understanding of the cascade. For now, however, it is clear that substantial parts of the cascade of events leading

to neuronal death and dementia are understood, and, most importantly, the race is now on Inhibitors,research,lifescience,medical to convert these targets for therapies into compounds that might delay, prevent, or possibly even reverse this devastating disease. Selected abbreviations and acronyms AD Alzheimer’s disease apo E apolipoprotein E APP amyloid precursor protein BACE beta-site APP-cleaving enzyme DRAP Down’s region aspartic protease FTDP-17 frontotemporal dementia and selleck chem MEK162 parkinsonism linked to chromosome 17 GSK-3 glycogen synthase kinase-3 NFT neurofibrillary tangle PHF paired helical filaments PKC protein kinase C PP2A type 2A protein phosphatase PS-1, -2 presenilin-1 and -2 PSP progressive supranuclear palsy TPK1 tau protein kinase 1
Early in the Inhibitors,research,lifescience,medical course of Alzheimer’s disease (AD) treatment research, the cholinergic

system was recognized as the most severely affected Inhibitors,research,lifescience,medical neurotransmitter system and therapeutic strategies were developed to restore cholinergic

function in AD. While agents with various kinds of procholinergic action (eg, acetylcholine precursors, cholinesterase inhibitors [ChEIs], and muscarinic and nicotinic receptor agonists) have been evaluated for efficacy in AD, only the ChEIs have thus far demonstrated clinically Inhibitors,research,lifescience,medical Sorafenib Tosylate molecular weight significant cognitive effects. The ChEIs are the only agents to have consistently demonstrated efficacy in numerous multicenter, well-controlled trials in AD, and have been approved by many national regulatory authorities. Thus, ChEIs represent the first class of efficacious pharmacological approaches to AD treatment, and one that is likely to be used clinically in the indefinite future, since clinical applications of research into drugs with other mechanisms have not advanced as rapidly as many of us had hoped. Cholinergic hypothesis The well-established cholinergic defects in AD include: Carfilzomib (i) decline of cholinergic basocortical projections; (ii) reduced activity of cerebral cortical choline acetyltransferase (ChAT), the key acetylcholine (ACh) synthesis enzyme; and (iii) cholinergic cell body loss in the nucleus basalis. The cholinergic hypothesis proposes that the cognitive deficits of AD are related to the observed decrease in central acetylcholinergic activity, and that increasing intrasynaptic ACh could enhance cognitive function and clinical well-being.

selleck chem inhibitor benzodiazepine Assays First-generation benzodiazepine screening assays of the 1970s used one of three antigenic targets [36,37] – diazepam, nordiazepam,

or oxazepam – with a recent shift towards using multiple benzodiazepines as antigenic targets (Additional file 1, tab T). The original choice of diazepam, nordiazepam, or oxazepam also followed from historical trends in usage of benzodiazepines. Diazepam was the most prescribed medication overall Inhibitors,research,lifescience,medical in the United States for over a decade (Additional file 2). Other commonly prescribed benzodiazepines of the 1970s, including chlordiazepoxide and clorazepate, are metabolized to nordiazepam and oxazepam (Additional file 2, figure S2-D). Using diazepam, nordiazepam, or oxazepam as target compounds thus fit the prescribing patterns of the 1970s well, either by targeting

the most commonly prescribed benzodiazepine of that time (diazepam) or targeting metabolites common to multiple benzodiazepines. Inhibitors,research,lifescience,medical However, three benzodiazepines (alprazolam, clonazepam, and lorazepam) are currently more commonly prescribed in the United States than diazepam (Additional file 2, figure S2-C; Table ​Table3)3) [29]. None of these three ‘newer’ benzodiazepines are metabolized to nordiazepam or oxazepam; in addition, each has lower similarity to diazepam than does nordiazepam (Tanimoto similarities to diazepam: nordiazepam, 0.780; lorazepam, Inhibitors,research,lifescience,medical 0.673; clonazepam, 0.656; alprazolam, 0.610). The Inhibitors,research,lifescience,medical marketed benzodiazepine screening immunoassays therefore have difficulty in detection of clonazepam and lorazepam usage, as compared to the use of diazepam or other early generation benzodiazepines. Figure ​Figure2B2B plots the cross-reactivities of marketed benzodiazepine assays towards diazepam, nordiazepam, oxazepam, 7-aminoclonazepam, and lorazepam Ponatinib IC50 glucuronide (note that cross-reactivity Inhibitors,research,lifescience,medical is not reported for all of these compounds for some of the assays). The upper brackets for diazepam, nordiazepam, and oxazepam in Figure ​Figure2B2B indicate the maximum urine concentrations detected in

individual consuming a single diazepam dose of 10 mg or less [38]. As can be seen, even a single diazepam dose can result in urine concentration of diazepam and multiple metabolites that exceed the positive cutoff for benzodiazepine screening immunoassays (Figure ​(Figure2B).2B). Detection would be predicted to be even easier in patients on chronic therapy, where steady-state Entinostat urine concentrations of diazepam and multiple metabolites would accumulate to even higher concentrations. Currently marketed benzodiazepine screening assays have limited sensitivity to detecting use of clonazepam. Although marketed benzodiazepine assays have reasonably good sensitivity to clonazepam (parent drug), sensitivity is much lower to the major urinary metabolite 7-aminoclonazepam (Additional file 1, tab C).