Modulating a model membrane of sphingomyelin by a tricyclic antidepressant drug

• Published in: Chemistry and physics of lipids 2024-09, Vol.263, p.105419, Article 105419
• Main Authors: Kaushik, Devansh, Hitaishi, Prashant, Kumar, Ashwani, Sen, Debasis, Kamil, Syed M., Ghosh, Sajal K.
• Format: Article
• Language: English
• Subjects: Amitriptyline; Amitriptyline - chemistry; Amitriptyline - metabolism; Amitriptyline - pharmacology; Antidepressive Agents, Tricyclic - chemistry; Antidepressive Agents, Tricyclic - pharmacology; Isotherm; Lipid membrane; Rheology; SAXS; Scattering, Small Angle; Sphingomyelins - chemistry; Static Electricity; Surface potential; X-Ray Diffraction
• ISSN: 0009-3084; 1873-2941; 1873-2941
• DOI: 10.1016/j.chemphyslip.2024.105419

Tricyclic medicine such as amitriptyline (AMT) hydrochloride, initially developed to treat depression, is also used to treat neuropathic pain, anxiety disorder, and migraines. The mechanism of functioning of this type of drugs is ambiguous. Understanding the mechanism is important for designing new drug molecules with higher pharmacological efficiency. Hence, in the present study, biophysical approaches have been taken to shed light on their interactions with a model cellular membrane of brain sphingomyelin in the form of monolayer and multi-lamellar vesicles. The surface pressure-area isotherm infers the partitioning of a drug molecule into the lipid monolayer at the air water interface, providing a higher surface area per molecule and reducing the in-plane elasticity. Further, the surface electrostatic potential of the lipid monolayer is found to increase due to the insertion of drug molecule. The interfacial rheology revealed a reduction of the in-plane viscoelasticity of the lipid film, which, depends on the adsorption of the drug molecule onto the film. Small-angle X-ray scattering (SAXS) measurements on multilamellar vesicles (MLVs) have revealed that the AMT molecules partition into the hydrophobic core of the lipid membrane, modifying the organization of lipids in the membrane. The modified physical state of less rigid membrane and the transformed electrostatics of the membrane could influence its interaction with synaptic vesicles and neurotransmitters making higher availability of the neurotransmitters in the synaptic cleft. [Display omitted] •Understanding interaction of tricyclic drug with membrane helps developing new drug.•Amitriptyline provides high area to lipid to reduce compressional modulus of membrane.•Amitriptyline has positively charged surface, hence modifies membrane electrostatics.•Amitriptyline helps fusion of synaptic vesicle by reducing bulk modulus of membrane.•Amitriptyline helps repelling neurotransmitters to make available in synaptic cleft.