Cited by 54Alzheimer's disease research and treatmentsReceptor Mechanisms and SignalingNeuroscience and Neuropharmacology Research

The muscarinic M1 agonist xanomeline increases soluble amyloid precursor protein release from chinese hamster ovary-m1 cells

Eckols, Kris, Bymaster, Frank P., Mitch, Charles H., Shannon, Harlan E., Ward, John S., DeLapp, Neil W.·1995·Life Sciences

Abstract

The functionally selective M1 agonist xanomeline, which is currently undergoing clinical trials as a therapy for Alzheimer's disease, was compared to the muscarinic agonist carbachol for effects on secretion of soluble amyloid precursor protein (APPs) from Chinese hamster ovary cells transfected with the human m1 receptor (CHO-m1). Release of APPs from CHO-m1 cells was increased maximally (4-10 fold) by 100 microM carbachol (EC50 = 11 microM) and by 100 nM xanomeline (EC50 = 10 nM). Stimulation of APPs secretion by xanomeline and carbachol was blocked by preincubation with 1 microM atropine. Carbachol did not stimulate APPs secretion from non-transfected CHO cells. Pilocarpine at 1 mM also increased APPs release. The efficacy of carbachol, xanomeline and pilocarpine for stimulating APPs secretion did not differ significantly. Activation of protein kinase C (PKC) in m1 transfected cell lines by 1 microM phorbol dibutyrate (PDBu) increased APPs release, and this was inhibited 97% by the PKC inhibitor bisindolemalemide. The PKC inhibitor decreased xanomeline and carbachol-stimulated APPs secretion by only 25-30%. These results demonstrate that xanomeline increased APPs release by activation of m1 muscarinic receptors and support the possibility that cholinergic replacement therapy for Alzheimer's Disease may reduce amyloid deposition.

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Crossref · 10.1016/0024-3205(95)02064-p

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Authors
Eckols, K., Bymaster, F. P., Mitch, C. H., Shannon, H. E., Ward, J. S., & DeLapp, N. W.
Affiliations
Eli Lilly (United States) (US)
Corresponding author
DeLapp, Neil W.
Venue
Life Sciences
Publisher
Elsevier BV
Published
1995-08
Volume
57
Issue
12
Pages
1183-1190
ISSN
0024-3205 (ISSN-L)
OpenAlex
W2062267821
Cited by
53
References
18
Citations by year
2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 2
FWCI
3.47
Type
journal article
Language
en
Open access
closed
Locations
  • Life Sciences (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
xanomeline, M1 muscarinic receptor, APP secretion, carbachol, pilocarpine, protein kinase C, atropine, Alzheimer's disease, amyloid deposition
MeSH terms
Animals, Carbachol, Dose-Response Relationship, Drug, Electrophoresis, Cricetinae, Humans, Phorbols, Pyridines, Thiadiazoles, Immunoblotting, CHO Cells, Amyloid beta-Protein Precursor, Muscarinic Agonists

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