Devansh Kaushik , Prashant Hitaishi , Ashwani Kumar , Debasis Sen , Syed M. Kamil , Sajal K. Ghosh
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引用次数: 0
摘要
盐酸阿米替林(AMT)等三环类药物最初用于治疗抑郁症,现在也用于治疗神经性疼痛、焦虑症和偏头痛。这类药物的作用机制尚不明确。了解其机制对于设计药效更高的新药物分子非常重要。因此,本研究采用生物物理方法来揭示它们与单层和多层膜泡形式的脑鞘磷脂模型细胞膜之间的相互作用。表面压力-面积等温线推断出药物分子在空气-水界面上被分隔到脂质单层中,从而为每个分子提供了更大的表面积,并降低了平面内弹性。此外,由于药物分子的插入,脂质单层的表面静电势也会增加。界面流变学显示,脂质薄膜的面内粘弹性降低,这取决于药物分子在薄膜上的吸附情况。对多拉米尔囊泡进行的小角 X 射线散射(SAXS)测量显示,AMT 分子进入了脂膜的疏水核心,改变了膜中脂质的组织结构。改变后的膜物理状态刚性降低,膜的静电状态也发生了变化,这可能会影响膜与突触小泡和神经递质之间的相互作用,从而提高神经递质在突触裂隙中的可用性。
Modulating a model membrane of sphingomyelin by a tricyclic antidepressant drug
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.
期刊介绍:
Chemistry and Physics of Lipids publishes research papers and review articles on chemical and physical aspects of lipids with primary emphasis on the relationship of these properties to biological functions and to biomedical applications.
Accordingly, the journal covers: advances in synthetic and analytical lipid methodology; mass-spectrometry of lipids; chemical and physical characterisation of isolated structures; thermodynamics, phase behaviour, topology and dynamics of lipid assemblies; physicochemical studies into lipid-lipid and lipid-protein interactions in lipoproteins and in natural and model membranes; movement of lipids within, across and between membranes; intracellular lipid transfer; structure-function relationships and the nature of lipid-derived second messengers; chemical, physical and functional alterations of lipids induced by free radicals; enzymatic and non-enzymatic mechanisms of lipid peroxidation in cells, tissues, biofluids; oxidative lipidomics; and the role of lipids in the regulation of membrane-dependent biological processes.