title: Acetylcholinesterase inhibitors rapidly activate Trk neurotrophin receptors in the mouse hippocampus.
abstract: Acetylcholinesterase inhibitors are first-line therapies for Alzheimer's disease. These drugs increase cholinergic tone in the target areas of the cholinergic neurons of the basal forebrain. Basal forebrain cholinergic neurons are dependent upon trophic support by nerve growth factor (NGF) through its neurotrophin receptor, TrkA. In the present study, we investigated whether the acetylcholinesterase inhibitors donepezil and galantamine could influence neurotrophin receptor signaling in the brain. Acute administration of donepezil (3 mg/kg, i.p.) led to the rapid autophosphorylation of TrkA and TrkB neurotrophin receptors in the adult mouse hippocampus. Similarly, galantamine dose-dependently (3, 9 mg/kg, i.p.) increased TrkA and TrkB phosphorylation in the mouse hippocampus. Both treatments also increased the phosphorylation of transcription factor CREB and tended to increase the phosphorylation of AKT kinase but did not alter the activity of MAPK42/44. Chronic treatment with galantamine (3 mg/kg, i.p., 14 days), did not induce changes in hippocampal NGF and BDNF synthesis or protein levels. Our findings show that acetylcholinesterase inhibitors are capable of rapidly activating hippocampal neurotrophin signaling and thus suggest that therapies targeting Trk signaling may already be in clinical use in the treatment of AD.
authors.affiliation: Neuroscience Center, University of Helsinki, P.O. Box 56, 00790 Helsinki, Finland.
authors.forename: Henri
authors.initials: H
authors.lastname: Autio
authors.forename: Kert
authors.initials: K
authors.lastname: Mätlik
authors.forename: Tomi
authors.initials: T
authors.lastname: Rantamäki
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
authors.forename: Moses
authors.initials: M
authors.lastname: Chao
authors.forename: Urmas
authors.initials: U
authors.lastname: Arumäe
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004797:Enzyme-Linked Immunosorbent Assay; D005702:Galantamine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D047468:Immunoprecipitation; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D005702:Galantamine; D014443:Tyrosine; D000077265:Donepezil; D020917:Receptor, trkA; D020813:Receptor, trkB