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P3–289: Histamine H3 antagonists in Alzheimer's disease: Exploring the translational disconnect between rodent models and humans
Author(s) -
Geerts Hugo,
Spiros Athan,
Roberts Patrick
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.1363
Subject(s) - acetylcholinesterase , histamine h3 receptor , donepezil , acetylcholine , cholinergic , pharmacology , neuroscience , medicine , muscarinic acetylcholine receptor , psychology , receptor , disease , chemistry , antagonist , dementia , biochemistry , enzyme
Background:HistamineH3 antagonists have shown great promise in preclinical models of Alzheimer’s disease (AD) and in scopolamine induced deficits in healthy volunteers. However, different H3 antagonists did not produce substantial improvement in clinical trials of AD.Methods:We developed a complex computer-based cortical network model with implementation of the physiology of 12 different membrane CNS targets based on a biophysically realistic multi-compartment model of 80 mpyramidal cells and 40 interneurons simulating the stability of a memory trace. The model was calibrated with multiple clinical trials for working memory tasks in healthy humans and schizophrenia patients and 28 different drug-dose-time combinations in Alzheimer patients. H3 antagonism was introduced using presynaptic increases in dopamine (DA), acetylcholine (ACh) and norepinephrine (NE), the size of which was calibrated using the clinical data in human volunteers with scopolamine. The clinical trials with H3 antagonism were simulated for different treatment durations, APOE genotypes and comedication with acetylcholinesterase inhibitors (AChE-I). Results: Assuming an 80% target engagement in the human scopolamine trial, relative values for maximal cortical release of ACh, DA and NE were 25%, 15% and 10% respectively. Further simulations in the AD case showed a dose-dependent improvement of H3 antagonism at 4 weeks, but not at longer durations. The model identified the dynamics of ACh release and clearance in the cholinergic cleft as the major difference between H3 antagonism and AChE inhibition. Chronic treatment drives the a4b2 nAChRmore into desensitization with AChE-I; with these receptors regulating GABA tone in cortical networks the resulting balance between excitation and inhibition favors AChE-I over H3 antagonists especially at progressively more severe pathology. Conclusions: This case-study illustrates the capability of a quantitative systems pharmacology approach to identify the pharmacodynamic difference of H3 antagonists in AD and scopolamine-induced deficits in healthy volunteers and preclinical studies on the other hand. A key role is attributed to the GABA tone in the cortical network, suggesting that the observed downregulation of a4b2 nAChR is a compensatory mechanism of the AD brain to reduce the GABA inhibitory tone that becomes dominant at later stages of the pathology whenmore excitatory pyramidal cells become affected.