The effect of neuroleptic drugs on DPPC/sphingomyelin/cholesterol membranes

Pérez-Isidoro, Rosendo; Costas, Miguel

doi:10.1016/j.chemphyslip.2020.104913

Cited by 14 publications

(17 citation statements)

References 55 publications

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“…Neuroleptics Trifluoperazine, Haloperidol decanoate, Clozapine, Quetiapine, Olanzapine, Aripiprazole, Amisulpride [323] Alzheimer disease Pregnanolone sulfate, Pregnanolone glutamate [324], Carbazoles [325] Anticonvulsant and muscle relaxant Carbamazepine [326][327][328], Nordazepam [199], Lamotrigine [199], Chlorzoxazone [132] Cardiac arrhythmias Dronedarone [312] P2Y1 antagonist BPTU [329] Urea cycle disorders 4-phenylbutyrate Immunosuppressant Cyclosporine A and E [330] Cardiac Ca 2+ pump inhibitors CDN1163, CP-154526, Ro 41-0960 [331] Eye drops components Cetalkonium chloride, Poloxamer 188 [332] Vaccine adjuvant Cobalt porphyrin phospholipid [333], Lipidated nicotine [334] Other potential drugs Baicalin [282], Emodin [282], Siramesine [335], HMI and HMI-1a3 [336], Peptide mimicking GM1 [337], AMG3 [338], 1,8-naphthyridine derivatives [339], Protein kinase inhibitors [340], Bile salt export pump inhibitors [341] Pulmonary surfactants form a complex structure on the inner lung surfaces, the alveoli, including the only monolayer in the human body at the boundary between the pulmonary liquids and air. For drugs designed to treat lung conditions that are delivered through pulmonary administration, e.g., corticosteroid and salbutamol inhalers for the treatment of asthma, this monolayer is the first barrier that they encounter.…”

Section: Application and Target Drugs And Pharmaceuticsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Application and Target Drugs And Pharmaceuticsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…Equally, the presence of substantial inhomogeneity is not unexpected. Although DPPC and SM have been reported to be miscible, the addition of Chol, particularly in ternary systems, is known to induce phase separation 14,15 , and previous DSC studies of DPPC/SM/Chol systems (albeit with lower concentrations of SM and Chol) have also reported evidence of microdomain formation 4 . In other ternary systems, phase coexistence below Tm in the range of Chol concentrations studied here is usually identified as lamellar gel (Lβ) plus liquid-ordered (Lo) coexistence 1 .…”

Section: Resultsmentioning

confidence: 99%

“…Electron density plots were obtained using the approach of Harper et al 4 , and refined according to the method proposed by Rappolt 5 and following Pabst et al 11 . Appropriate lipid structural parameters were taken from Greenwood et al 12 with reference to Nagle et al 13 .…”

Section: X-ray Electron Density Profilesmentioning

confidence: 99%

Phase Heterogeneity in Cholesterol-containing Ternary Phospholipid Lamellar Phases

Gater

Hughes

Stojanoff

et al. 2022

Preprint

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Pseudo-ternary mixtures of lamellar phase phospholipids (DPPC and brain sphingomyelin with cholesterol) were studied below Tm, while comparing the influence of cholesterol content, temperature and the presence of small quantities of Vitamin D binding protein (DBP) or Vitamin D receptor (VDR). The measurements, conducted by X-ray diffraction (XRD) and nuclear magnetic resonance (NMR), cover a range of cholesterol concentrations (20% mol. wt to 40% mol. wt.) and physiologically relevant temperature range (294 K – 314 K). In addition to rich intra-phase behaviour, data and modelling are used to approximate the lipids’ headgroup location variations under the above-mentioned experimental conditions.

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“…Antipsychotics act upon membrane lipids at different levels. Modelling studies have shown that the insertion of antipsychotics into the lipid bilayer increases fluidisation and disorganises lipids of the plasma membrane [36]. In schizophrenia patients, a 3-month treatment with antipsychotics (mostly phenothiazine) showed that PUFA composition and omega-3/omega-6 ratios in erythrocyte membranes became comparable to those in healthy controls [37].…”

Section: The Role Of Omega-3 In the Plasma Membrane Composition And Dynamicsmentioning

confidence: 99%

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

Frajerman

Scoriels

Kébir

et al. 2021

IJMS

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Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.

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The effect of neuroleptic drugs on DPPC/sphingomyelin/cholesterol membranes

Cited by 14 publications

References 55 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Phase Heterogeneity in Cholesterol-containing Ternary Phospholipid Lamellar Phases

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

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