Acetylcholinesterase inhibitors rapidly activate Trk neurotrophin receptors in the mouse hippocampus

NEUROPHARMACOLOGY

卷:61

Article

Autio, Henri¹  Matlik, Kert²  Rantamaki, Tomi¹  Lindemann, Lothar³  Hoener, Marius C.³  Chao, Moses⁴  Arumae, Urmas²  Castern, Eero¹ 

[1] Univ Helsinki, Ctr Neurosci, Helsinki 00790, Finland

[2] Univ Helsinki, Inst Biotechnol, Helsinki 00790, Finland

[3] F Hoffmann La Roche & Co Ltd, Roche Discovery Neurosci, CH-4070 Basel, Switzerland

[4] NYU Med Ctr, Mol Neurobiol Program, Skirball Inst Biomol Med, Nyc, NY 10016 USA

关键词: Trk receptor phosphorylation;    Donepezil;    Galantamine;    Nerve growth factor;    Acetylcholinesterase inhibitor;   

DOI  :  10.1016/j.neuropharm.2011.07.033

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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