Pharmacokinetics/pharmacodynamics and Analysis of the Effect of Β-amyloid Peptide on Acetylcholine Neurocycle and Alzheimer's Disease Medications PDF Download
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Author: Asmaa Awad
Publisher:
ISBN:
Category :
Languages : en
Pages : 143
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Book Description
Author: Asmaa Awad
Publisher:
ISBN:
Category :
Languages : en
Pages : 143
Get Book Here
Book Description
![Pharmacokinetics/pharmacodynamics and Analysis of the Effect of [beta]-amyloid Peptide on Acetylcholine Neurocycle and Alzheimer's Disease Medications PDF](https://books.google.com/books/content/images/frontcover/GJKLoAEACAAJ?fife=w80-h100)
Author: Asmaa Awad
Publisher:
ISBN:
Category :
Languages : en
Pages : 143
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Book Description
The brain of Alzheimer's disease (AD) is characterized by accumulations of [beta]-amyloid peptide aggregates which promote neurodegentartive dysfunction. Comprehensive understanding of the interaction between [beta]-amyloid aggregates and acetylcholine (ACh) neurocycle is required to uncover the physiological processes related to AD and might result in improving therapeutic approaches for AD. Pharmacokinetics (PK) and pharmacodynamics (PD) techniques were applied to allow predicting the extent of the interaction of certain doses of AD drugs and [beta]-amyloid inhibitors and levels of ACh as well. Although many researchers focused on the [beta]-amyloid interactions, the mechanisms by which [beta]-amyloid affects cholinergic neurons and reduction of ACh are still unclear. The prediction of ACh and drug concentrations in the tissues and body needs an understanding of the physiology and mechanisms of [beta]-amyloid aggregates processes and their compilation into a mechanistic model In this work, two hypotheses are proposed to investigate the dynamic behavior of the interaction between [beta]-amyloid peptide aggregates and cholinergic neurocycle and the possible therapeutic approaches through proposing pharmacokinetic/pharmacodynamics (PK/PD) models to represent the impact of [beta]-amyloid aggregates in AD. The effect of [beta]-amyloid peptide aggregates is formulated through incorporating [beta]-amyloid aggregates into non-linear model for the neurocycle of ACh where the presynaptic neuron is considered as compartment 1 and both synaptic cleft and postsynaptic neurons are considered as compartment 2. In the first hypothesis which is choline leakage hypothesis, [beta]-amyloid peptide aggregates are considered to be located in the membrane of the presynaptic neuron and create pathways inside the membrane to allow for the intracellular choline to leak outside the cholinergic system. It is observed that [beta]-amyloid aggregates via the choline leakage hypothesis could cause significant reductions of ACh and choline levels in both compartments. Furthermore, the process rates of ACh synthesis and hydrolysis have been affected negatively by a wide range of [beta]-amyloid aggregate concentrations. It is found that as the input rate of [beta]-amyloid aggregates to compartment 1 increases, the loss of choline from compartment 1 increases leading to an increase in the intracellular concentration of [beta]-amyloid.
Author: Stanislav Tuček
Publisher:
ISBN:
Category : Acetylcholine
Languages : en
Pages : 284
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Book Description
Author: Susan E. Coombs
Publisher:
ISBN:
Category :
Languages : en
Pages : 350
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Book Description
RNA aptamers selected for two disparate targets, the nicotinic acetylcholine receptor (Ulrich et al., 1998) and beta-amyloid (Abeta) peptides (Ylera et al., 2002), share a consensus sequence (Gadalla & Hess, 2006). The RNA aptamers selected for the nicotinic acetylcholine receptors fell into two classes. Class 1 aptamers inhibited the receptor and, in the presence of an activator of the receptor, Class 2 aptamers alleviated the inhibition. The short consensus sequence of Class 1 aptamers retained this activity (Sivaprakasam et al., 2010). Gadalla and Hess (2006) recognized that the same consensus sequence occurred in the RNA aptamers selected for the Abeta(1-40) peptide by Ylera et al. (2002). Some organic compounds that bind to the acetylcholine receptor, and affect its function, were assigned to either Class 1 or Class 2 (Hess et al., 2000). (+) MK-801 (dizocilpine) is a Class 1 compound. In the work reported here, the effects of (+) MK-801 and of memantine on the aggregation pathway of Abeta(1-40) and Abeta(1-42) peptides have been examined using the Thioflavin T fluorescence assay, nuclear magnetic resonance spectroscopy, and electron microscopy. Memantine is FDA-approved for the treatment of mild-moderate Alzheimer's Disease. Both compounds accelerated the initial formation of beta-sheets by the Abeta peptides, (+) MK-801 more rapidly than memantine. But in the presence of either compound a decrease in the fluorescence signal followed the initial rise, a decrease that was not observed when they were absent. The decrease may represent an abruptly formed, insoluble aggregated state, rather than a return to the initial non-beta-sheet state. In the absence of either compound, the fluorescence signal indicating beta-sheet formation reaches a plateau. NMR spectra of the soluble peptides in the presence and absence of (+) MK-801 were compared to the fluorescence measurements and showed a similar difference for the initial phase. However, no return to the monomeric form was observed, possibly suggesting that the decrease in fluorescence in the Thioflavin T assay represented the formation of insoluble aggregates. Consistent with this interpretation, electron microscopy of the insoluble peptides formed over time showed a more rapid rate of formation of clumped fibrils in the presence of (+) MK-801 than in its absence. Thus, as observed by three different techniques, (+) MK-801 and memantine increase the rate of Abeta peptide aggregation as compared to the aggregation that occurs in their absence. This raises a question: What is the effect on patients of long-term treatment with memantine? Is there an explanation for the observation that led to this study, the shared consensus sequence between aptamers selected for two different targets? This cannot yet be answered. In this study, it was recognized that the consensus sequences of the two classes of RNA aptamers targeting the acetylcholine receptor are complementary in the 5'-3' and 3'-5' directions. Is this of biological significance? The selection of two classes of aptamers is not limited to this excitatory receptor. Fluorinated RNA aptamers that target the inhibitory GABAA (alpha1, beta2, gamma2) receptor have been selected (Cui et al., 2004). They also fell into two class...
