Effects of antidepressants on the conformation of phospholipid headgroups studied by solid‐state NMR

Abstract

The effect of tricyclic antidepressants (TCA) on phospholipid bilayer structure and dynamics was studied to provide insight into the mechanism of TCA-induced intracellular accumulation of lipids (known as lipidosis). Specifically we asked if the lipid-TCA interaction was TCA or lipid specific and if such physical interactions could contribute to lipidosis. These interactions were probed in multilamellar vesicles and mechanically oriented bilayers of mixed phosphatidylcholine-phosphatidylglycerol (PC-PG) phospholipids using (31)P and (14)N solid-state NMR techniques. Changes in bilayer architecture in the presence of TCAs were observed to be dependent on the TCA's effective charge and steric constraints. The results further show that desipramine and imipramine evoke distinguishable changes on the membrane surface, particularly on the headgroup order, conformation and dynamics of phospholipids. Desipramine increases the disorder of the choline site at the phosphatidylcholine headgroup while leaving the conformation and dynamics of the phosphate region largely unchanged. Incorporation of imipramine changes both lipid headgroup conformation and dynamics. Our results suggest that a correlation between TCA-induced changes in bilayer architecture and the ability of these compounds to induce lipidosis is, however, not straightforward as imipramine was shown to induce more dramatic changes in bilayer conformation and dynamics than desipramine. The use of (14)N as a probe was instrumental in arriving at the presented conclusions.

Desipramine Modulation of α-, γ-Synuclein, and the Norepinephrine Transporter in an Animal Model of Depression

“…Although it is unknown how g-Syn participates in chaperoning events and membrane interactions, g-Syn has been shown to enhance estrogen receptor trafficking to the cell surface (Liu et al, 2007). DMI is also known to disrupt membranes (Fisar et al, 2005;Santos et al, 2004). Therefore, the upregulation of a-Syn in the WKY, which itself can Figure 9 Synuclein (Syn) modulation of norepinephrine transporter (NET) in depression and after treatment with desipramine (DMI).…”

Direct detection of nitrogen-14 in solid-state NMR spectroscopy

“…The above publications spurred an increase in the use of 14 N NMR as a probe of LCs, lipid bilayers and related systems, with a number of reports studying 14 N linewidths and relaxation [180][181][182][183][184][185][186][187][188][189][190][191], and others investigating quadrupolar splittings [192][193][194][195][196][197][198][199][200][201][202][203][204][205][206][207][208][209][210].…”

Confocal Raman microscopy for simultaneous monitoring of partitioning and disordering of tricyclic antidepressants in phospholipid vesicle membranes

“…[59] In general, the literature suggests that TCAs are located with the rings near the lipid acyl chains and the charged tail near the lipid headgroup, [60] although one report concludes that the drug conformation in DPPC is quite mobile but preferentially assumes a state where the charged tail is folded back on the rings. [49,51,61] Indeed, ring flexibility in TCA differs depending on specific drug structure. [42] The results in Figs 3-5 align well with the general picture from the literature; the fact that the drugs lower the lipid T m means that they must affect the acyl chain packing in the lipid.…”