A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems.
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 anticholiner...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0118786 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850212913557536768 |
|---|---|
| author | Elizabeth K Woehrling H Rheinallt Parri Erin H Y Tse Eric J Hill Ian D Maidment G Christopher Fox Michael D Coleman |
| author_facet | Elizabeth K Woehrling H Rheinallt Parri Erin H Y Tse Eric J Hill Ian D Maidment G Christopher Fox Michael D Coleman |
| author_sort | Elizabeth K Woehrling |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a47d81910e0140fc8e08062f8a172760 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-a47d81910e0140fc8e08062f8a1727602025-08-20T02:09:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e011878610.1371/journal.pone.0118786A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems.Elizabeth K WoehrlingH Rheinallt ParriErin H Y TseEric J HillIan D MaidmentG Christopher FoxMichael D ColemanThe 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.https://doi.org/10.1371/journal.pone.0118786 |
| spellingShingle | Elizabeth K Woehrling H Rheinallt Parri Erin H Y Tse Eric J Hill Ian D Maidment G Christopher Fox Michael D Coleman A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems. PLoS ONE |
| title | A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems. |
| title_full | A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems. |
| title_fullStr | A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems. |
| title_full_unstemmed | A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems. |
| title_short | A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems. |
| title_sort | predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems |
| url | https://doi.org/10.1371/journal.pone.0118786 |
| work_keys_str_mv | AT elizabethkwoehrling apredictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT hrheinalltparri apredictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT erinhytse apredictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT ericjhill apredictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT iandmaidment apredictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT gchristopherfox apredictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT michaeldcoleman apredictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT elizabethkwoehrling predictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT hrheinalltparri predictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT erinhytse predictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT ericjhill predictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT iandmaidment predictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT gchristopherfox predictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems AT michaeldcoleman predictiveinvitromodeloftheimpactofdrugswithanticholinergicpropertiesonhumanneuronalandastrocyticsystems |