Pharmacodynamics of cholinesterase inhibitors suggests add-on therapy with a low-dose carbamylating inhibitor in patients on long-term treatment with rapidly reversible inhibitors.
Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-β peptide (Aβ) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Aβ aggregation, most likely by competing with the Aβ peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Aβ and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders.
Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska Institute, Stockholm, Sweden.
Taher
T
Darreh-Shori
Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska Institute, Stockholm, Sweden Faculty of Psychology and Educational Sciences, Semnan University, Semnan, Iran.
Sharokh Makvand
SM
Hosseini
Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Karolinska Institute, Stockholm, Sweden Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Agneta
A
Nordberg
D000110:Acetylcholinesterase / Q000134:cerebrospinal fluid; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D052160:Benzothiazoles; D015153:Blotting, Western; D002091:Butyrylcholinesterase / Q000134:cerebrospinal fluid; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077265:Donepezil; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005453:Fluorescence; D005500:Follow-Up Studies; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010830:Physostigmine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013844:Thiazoles; D013997:Time Factors
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D013844:Thiazoles; C009462:thioflavin T; D000077265:Donepezil; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C092280:phenserine
Add-on therapy; Alzheimer's disease; carbamylating ChEIs; cholinesterase inhibitors (ChEIs); donepezil; peripheral anionic site; phenserine; rivastigmine