Woehrling, Elizabeth K., Parri, H. Rheinallt, Tse, Erin H.Y., Hill, Eric J., Maidment, Ian D., Fox, G. Christopher and Coleman, Michael D. (2015). A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems. PLoS ONE, 10 (3),
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 |
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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 |
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: | 05 Aug 2024 13:45 |
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 ( ![]() Tse, Erin H.Y. Hill, Eric J. ( ![]() Maidment, Ian D. ( ![]() Fox, G. Christopher Coleman, Michael D. ( ![]() |