A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems

Abstract

The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine whether a relevant in vitro model may aid the identification of anticholinergic responses to drugs and the prediction of anticholinergic risk during polypharmacy. In this preliminary study we employed a co-culture of human-derived neurons and astrocytes (NT2.N/A) derived from the NT2 cell line. NT2.N/A cells possess much of the functionality of mature neurons and astrocytes, key cholinergic phenotypic markers and muscarinic acetylcholine receptors (mAChRs). The cholinergic response of NT2 astrocytes to the mAChR agonist oxotremorine was examined using the fluorescent dye fluo-4 to quantitate increases in intracellular calcium [Ca2+]i. Inhibition of this response by drugs classified as severe (dicycloverine, amitriptyline), moderate (cyclobenzaprine) and possible (cimetidine) on the Anticholinergic Cognitive Burden (ACB) scale, was examined after exposure to individual and pairs of compounds. Individually, dicycloverine had the most significant effect regarding inhibition of the astrocytic cholinergic response to oxotremorine, followed by amitriptyline then cyclobenzaprine and cimetidine, in agreement with the ACB scale. In combination, dicycloverine with cyclobenzaprine had the most significant effect, followed by dicycloverine with amitriptyline. The order of potency of the drugs in combination frequently disagreed with predicted ACB scores derived from summation of the individual drug scores, suggesting current scales may underestimate the effect of polypharmacy. Overall, this NT2.N/A model may be appropriate for further investigation of adverse anticholinergic effects of multiple medications, in order to inform clinical choices of suitable drug use in the elderly.

Publication DOI: https://doi.org/10.1371/journal.pone.0118786
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > Clinical and Systems Neuroscience
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
Aston University (General)
Additional Information: Copyright: © 2015 Woehrling et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: British Brain Research Fund, United Kingdom (United Kingdom Registered Charity: 1140361), Grant Number: 012013
Uncontrolled Keywords: General Agricultural and Biological Sciences,General Biochemistry,Genetics and Molecular Biology,General Medicine
Publication ISSN: 1932-6203
Last Modified: 29 Oct 2024 13:06
Date Deposited: 19 Aug 2019 09:45
Full Text Link: http://journals ... al.pone.0118786
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2015-03-04
Authors: Woehrling, Elizabeth K.
Parri, H. Rheinallt (ORCID Profile 0000-0002-1412-2688)
Tse, Erin H.Y.
Hill, Eric J. (ORCID Profile 0000-0002-9419-1500)
Maidment, Ian D. (ORCID Profile 0000-0003-4152-9704)
Fox, G. Christopher
Coleman, Michael D. (ORCID Profile 0000-0002-5510-6852)

Download

[img]

Version: Published Version

License: Creative Commons Attribution

| Preview

Export / Share Citation


Statistics

Additional statistics for this record