From heart to brain: cognitive potential of propranolol and diltiazem through cholinergic enhancement via butyrylcholinesterase inhibition
Year: 2025
Type: article
Abstract: Background Butyrylcholinesterase (BChE) has emerged as a promising therapeutic target in the treatment of Alzheimer’s disease (AD), particularly in its later stages when acetylcholinesterase (AChE) activity declines. Drug repurposing offers a strategic approach to identify novel BChE inhibitors among existing FDA-approved compounds. Objective This study aimed to evaluate the cholinesterase inhibitory potential of propranolol and diltiazem—two widely used cardiovascular drugs—through in silico modelling and in vitro and ex vivo enzyme-inhibition kinetic. Methods Molecular docking was performed using AutoDock Vina to assess the binding affinity of propranolol and diltiazem to AChE and BChE. In vitro screening and inhibition were measured using a modified Ellman’s assay with human recombinant AChE and plasma-derived BChE. Ex-vivo IC 50 and K i values were determined through kinetic analyses in pooled plasma samples, and inhibition modes were characterized using nonlinear regression models. Results Both propranolol and diltiazem selectively inhibited BChE, with minimal activity against AChE. At 100 μM, BChE inhibition exceeded 80% for both compounds, while AChE inhibition was limited to 18% (propranolol) and 2% (diltiazem). Propranolol exhibited a K i of 0.19 µM, comparable to the selective BChE inhibitor ethopropazine (K i = 0.15 µM), and acted as a competitive inhibitor. Diltiazem exhibited a higher K i of 2.3 µM. These effects were observed at concentrations within or near reported brain levels for propranolol, suggesting potential in vivo relevance. Conclusion Propranolol and diltiazem demonstrate selective BChE inhibition, with propranolol showing potency comparable to established potent BChE inhibitors. Given their established safety profiles and CNS activity, these compounds represent promising candidates for repurposing in the treatment of AD and other cognitive disorders. Further in vivo studies are warranted to explore their therapeutic potential.
Source: Frontiers in Pharmacology
Institutions: Karolinska Institutet, Indian Institute of Technology BHU
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W4416160705