Role of Cholesterol in Mediating Interaction of Antidepressant Amitriptyline with Phospholipid Membranes

Understanding the interaction between brain lipid membranes and therapeutic molecules is essential for unravelling the action mechanism of a drug. This study investigates the influence of amitriptyline hydrochloride (AMT), a tricyclic antidepressant, on lipid monolayers and multilamellar vesicles composed of brain sphingomyelin (BSM) and cholesterol (Chol). Using Langmuir monolayer and small-angle X-ray scattering (SAXS) techniques, it reveals that AMT alters the rigidity, packing density, surface potential, and structural parameters of a phospholipid membrane. The presence of cholesterol in the lipid membrane not only enhances the hydrophobicity and structural stability of the membrane but also magnifies the effect of the AMT. SAXS analyses demonstrate that AMT incorporation increases bilayer thickness while reducing the water layer between successive bilayers, highlighting its altering effects on inter- and intra-molecular hydrogen bonding. These findings provide insights into the molecular interactions between antidepressants and cholesterol-rich biomimetic brain lipid membranes, which may pave the way to a better design of drug molecules.