Influence of constraining and confinement in the molecular mobility of low molecular weight materials

Dissertation presented to obtain a Ph.D. Degree in Chemical PhysicsDespite the importance that the glassy state has nowadays, the transition from liquid to the glass, glass transition, still remains a matter of debate which constitutes one of the great condensed matter physics challenges. Since this fact is closely related to the cooperativity dynamics, the study of this phenomenon in glass-forming liquids under confinement in the nanometer scale, has recently emerged as a strategy to clarify factors such as the existence of an inherent length scale of the cooperative dynamics that determines the glass transition temperature. In this context, this thesis represents an additional contribution to the study of molecular dynamics of glass-forming liquids under confinement in nanoporous inorganic materials. As target compounds the liquid crystal E7 and the drug Ibuprofen were selected. Since the first exhibit various transitions makes it more sensitive to perturbations and thus appears as the ideal candidate to evaluate confinement effects. The study of ibuprofen is of particular interest because confinement emerges as a method of stabilizing the amorphous phase that is mostly important in pharmaceutical applications. Dielectric Relaxation Spectroscopy(DRS) is the main technique used to obtain detailed information about the molecular mobility in a wide range of frequencies (10-2-109Hz) (Chapter I and II). The first part of the thesis is devoted to the characterization of the two target compounds in the bulk state. The combination of DRS with the specific heat spectroscopy allowed to determine which of the E7 observed relaxation processes (a process in the isotropic phase and two processes in the nematic phase: δ and tumbling) is responsible for the glass transition temperature Tg (tumbling process). Detailed studies of ibuprofen molecular mobility in the liquid, supercooled liquid and glassy states are also presented in this chapter, where four relaxation processes are detected: two secondary processes (γ and β), the cooperative process related to Tg (α ) and the Debye process (D), probably related to the hydrogen bonding dynamics. This study was preceded by an optimization of the conditions to obtain amorphous Ibuprofen which is a crystal in its natural state (Chapter III). In the next chapter (Chapter IV), the molecular dynamics of E7 confined to untreated and phospholipid lecithin treated rigid inorganic membranes with 20 nm pore diameter was evaluated. It was found that both the liquid crystal alignment, as well as the dynamics is influenced by confinement and treatment of the surface pores. Additionally, E7 was further studied confined to the mesoporous materials MCM-41 and SBA-15 type, 100% silica composition and pore size between the 2.8 and 6.8 nm. A multiplicity of relaxation processes was revealed by DRS, including the modes already observed in the bulk E7. In addition, twoFundação para a Ciência e Tecnologia (FCT),financial support by means of the PhD grant SFRH/BD/23829/200

Impacto técnico-económico de medidas de gestão do consumo

Tese de mestrado integrado em Engenharia da Energia e do Ambiente, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2016O desafio principal de um sistema eletroprodutor é o de assegurar o equilíbrio entre a energia solicitada pelos consumidores e a que é entregue pelas fontes produtoras de energia, sendo esta a chave para a manutenção de um sistema estável. Tradicionalmente o consumo variava livremente, cabendo aos centros de produção de energia elétrica ajustarem-se a essa variação. No entanto, a atual e elevada penetração renovável variável no tempo – cuja produção é caracterizada pela não controlabilidade – dificulta a gestão do sistema electroprodutor e, em casos de penetração renovável extrema, exige capacidade de controlo adicional do binómio produção/consumo, a qual se situava do lado da produção e, recentemente, se tem vindo a explorar do lado do consumo, de modo a permitir o crescimento do sector renovável. A restruturação das atuais redes de energia em redes inteligentes apresenta diversos benefícios tanto para os consumidores como para os produtores e gestores da rede de transporte e distribuição. Este novo conceito de sistema electroprodutor promove a interação entre o lado do consumo e o lado da produção através da implementação de novas tecnologias. O envio de sinais de preço aos consumidores domésticos, por exemplo, contribui para a sua consciencialização para o preço da eletricidade em tempo real. Desta forma, a manutenção do equilíbrio entre produção e consumo deixa de ser um encargo somente do lado da produção. Por forma a caracterizar o potencial de controlo do consumo e alcançar o objetivo desta dissertação é necessária a modelação do comportamento dos consumidores. Neste trabalho pretende-se modelar a variação da procura de eletricidade em função do preço da energia sob a forma de funções de elasticidade. A composição dos fatores de elasticidade para os consumidores resultará numa matriz de elasticidade, que poderá conduzir à previsão e conceção de cenários para o sistema eletroprodutor português.The main operational challenge of an electric power system is to insure the balance between the power demanded by the consumers and the one that is delivered by the operating power plants, being this the key to the maintenance of a stable system. Traditionally, the electric consumption varies freely in time and it was the responsibility of the production centers to adjust themselves to these variations. Nonetheless, the current high penetration of renewable power generation – which production is characterized by its non-controllability – difficult the power system management and, in cases of extremely high renewable penetration, requires additional control capability on existing conventional generation and that, recently, has also been explored on the consumption side in order to allow the growth of variable renewable sector. The restructuring of the current power grid into smart grids has many benefits for both consumers and producers. This new concept of power generation system allows and promotes an interaction between these two main players through the implementation of innovating technologies. Given the awareness of consumers to the price of electricity in real time – strongly correlated with the amount of energy being consumed -, the maintenance of the balance between production and consumption becomes not only a producers’ responsibility but also a consumers’ one. In order to characterize the potential regarding consumption management and attain the goal of this thesis it is necessary to model consumer’s profile behavior. Thus, it is intend of this work to model the electricity demand variation due to electricity’s price fluctuations in the form of elasticity functions. The composition of elasticity factors for consumers and different price signals result in an elasticity matrix, which leads to the prediction and generation of scenarios for the Portuguese power system

Avaliação de duas medidas na mitigação da erosão do solo após incêndio

Wildfires contribute for soil degradation and acceleration of erosion processes. Emergency measures applied after wildfire can be decisive in mitigating soil loss and preserving fertility. In this study, which was held in Semide in a area burned in August 2015, two measures were evaluated: ploughing and mulching. Both selected by the stakeholders during a participatory process developed under the RECARE European project. Ploughing is a recurrent practice of forestland management following a wildfire in order to prepare soil for planting and / or seedling. Ploughing was implemented in July 2016 and consisted on the analysis of two contiguous areas, with ploughed plots and control, respectively. Soil and organic matter losses were monitored at two scales: MP (0.25m2) and SF plots (16m2). Soil losses in the SF plots were quite similar between the both treatments. In the MP soil losses were three times higher in the ploughed plots. At the level of the SF plots the efficiency of the treatment was positive, with a more relevance in the mitigation of organic matter loss (61%). In the MP ploughing was inefficient in losses mitigation. Losses decreased over the study time. The ploughed plots revealed, at both scales, a higher cover of the soil surface by stones and less vegetation, when compared to the control. However, results obtained from the ploughing experience are considered inconclusive given the short period of experimental monitoring (7 months) and the fact that soils were ploughed 11 months after the wildfire. The second year of data monitoring of the mulching experience aimed to evaluate the efficiency of the treatments on soil protection against the direct impact of the raindrops. The treatments consisted in the application of the mulch at two rates: the standardized rate in the literature as efficient in soil protection (8 Mg ha-1) and the innovative low rate (2.6 Mg ha-1). The treatments were applied in three replicate SF plots, one per block. It was also monitored 6 MP, 2 for each block, where in addition to soil and organic matter was also evaluated the surface runoff. The SF plots with the application of the high mulch rate revealed lower losses of soil than the plots treated with the low mulch rate. The highest losses were obtained in the control SF plots. The efficiency of the treatments in soil and organic matter loss mitigation was 94% and 90%, respectively, in the SF plots with the high rate mulch, and 68% and 62%, respectively, in the SF plots with the lowest rate application. In the three treatments the soils losses area considered in the literature as tolerable (1 Mg ha-1 year -1). The development of new vegetation was higher in the control SF plots than in the treated ones. The MP revealed intolerable soil losses.Os incêndios florestais contribuem para a degradação do solo e aceleração dos processos de erosão. As medidas de emergência aplicadas após incêndio podem ser determinantes na mitigação da perda de solo e na preservação da fertilidade. Neste estudo, que decorreu em Semide, numa área ardida em Agosto de 2015, foram avaliadas duas medidas: lavragem e a aplicação de mulching. Ambas as medidas foram selecionadas pelos atores sociais interessados no decorrer do processo participativo desenvolvido no âmbito do projeto europeu RECARE. Considera-se a lavragem uma prática recorrente de gestão de terrenos florestais depois de um incêndio na preparação dos mesmos para plantação e/ou sementeira. A lavragem, implementada em Julho 2016, consistiu na análise de duas áreas contíguas, com parcelas lavradas e controlo. Foi monitorizada a perda de solo e matéria orgânica a duas escalas: MP (0.25m2) e parcelas SF (16 m2). As perdas de solo nas parcelas SF foram similares entre tratamentos. Nas MP as perdas de solo foram três vezes mais altas nas parcelas lavradas. Ao nível das parcelas SF a eficiência foi positiva, com maior relevância na mitigação de perda de matéria orgânica (61%). Nas MP a lavragem revelou-se ineficiente na mitigação de perdas. A perda de solo e de matéria orgânica foi diminuindo ao longo do tempo de estudo. As parcelas lavradas revelaram, em ambas as escalas, maior cobertura de solo com pedras e menos vegetação, relativamente ao controlo. Contudo os resultados obtidos foram considerados inconclusivos dado o curto período de monitorização experimental (7 meses) e ao facto da lavragem ter sido implementada 11 meses após o incêndio. A monitorização do segundo ano da experiência de mulching visou avaliar a eficiência na proteção do solo à ação da precipitação, tendo os tratamentos derivado da aplicação do material a duas taxas: a taxa estandardizada na literatura como eficiente (8 Mg ha-1), e a inovadora baixa aplicação (2.6 Mg ha-1). Estas taxas foram aplicadas em três parcelas SF replicadas por três blocos. Foram ainda monitorizadas 6 MP, 2 por cada bloco, onde, para além da avaliação das perdas de solo e matéria orgânica, foi analisada a escorrência superficial. As parcelas SF com a aplicação da taxa de mulch mais alta revelaram perdas mais baixas de solo e de matéria orgânica que as parcelas com a aplicação da taxa mais baixa. As perdas mais elevadas foram obtidas no controlo. A eficiência na mitigação de perda de solo e matéria orgânica foi de 94% e 90%, respectivamente, nas parcelas com taxa de mulch mais alta, e 68% e 62%, respectivamente, nas parcelas com a taxa mais baixa. Nos três tratamentos as perdas de solo consideradas pela literatura como toleráveis (1 Mg ha-1 ano-1). O desenvolvimento de nova vegetação foi mais elevado no controlo do que nas parcelas SF tratadas. As MP revelaram perdas intoleráveis de solo.Tese desenvolvida no âmbito do projeto europeu RECARE – Preventing and Remediating degradation of soils in Europe through Land Care, financiado pelo 7º Programa-Quadro Europeu (FP7) direcionado para pesquisa e desenvolvimento tecnológico.Mestrado em Gestão e Políticas Ambientai

Development of an injectable grout for concrete repair and strengthening

This paper deals with the coupled effect of temperature and silica fume addition on rheological, mechanical behaviour and porosity of grouts based on CEMI 42.5R, proportioned with a polycarboxylate-based high range water reducer. Preliminary tests were conducted to focus on the grout best able to fill a fibrous network since the goal of this study was to develop an optimized grout able to be injected in a mat of steel fibers for concrete strengthening. The grout composition was developed based on criteria for fresh state and hardened state properties. For a CEMI 42.5R based grout different high range water reducer dosages (0%, 0.2%, 0.4%, 0.5%, 0.7%) and silica fume (SF) dosages (0%, 2%, 4%) were tested (as replacement of cement by mass). Rheological measurements were used to investigate the effect of polycarboxylates (PCEs) and SF dosage on grout properties, particularly its workability loss, as the mix was to be injected in a matrix of steel fibers for concrete jacketing. The workability behaviour was characterized by the rheological parameters yield stress and plastic viscosity (for different grout temperatures and resting times), as well as the procedures of mini slump cone and funnel flow time. Then, further development focused only on the best grout compositions. The cement substitution by 2% of SF exhibited the best overall behaviour and was considered as the most promising compared to the others compositions tested. Concerning the fresh state analysis, a significant workability loss was detected if grout temperature increased above 35 degrees C. Below this temperature the grout presented a self-levelling behaviour and a life time equal to 45 min. In the hardened state, silica fumes increased not only the grout's porosity but also the grout's compressive strength at later ages, since the pozzolanic contribution to the compressive strength does not occur until 28 d and beyond. (C) 2012 Elsevier Ltd. All rights reserved

O lugar “desconseguido” da educação artística no Sul

This article introduces the Ph.D. studies of its authors, who put into question the bridge between utopia and the reality experienced at the Mindelo_International School of Art (Mindelo_Escola Internacional de Arte – M_EIA), legally known as the University Institute of Art, Technology, and Culture [Instituto Universitário de Arte, Tecnologia e Cultura], the first Higher Education space in the areas of arts and design in Cape Verde, constituting a singular, irreverent, project  in the struggle for art education practices informed by decolonized policies. Created in 2004, this utopian project sent its anchors out to the practices, promoting the country’s culture and development, by means of a relationship with the Atelier Mar’s local development projects, consolidating a long experience in the art education area. Tensions arise between expectations about the experimental and local nature of the M_EIA and its regulation and (non-)conformity with hegemonic knowledge in art education or development models foreign to  the Cape Verdean reality.Este artículo presenta las investigaciones de doctorado de sus autoras, que cuestionan el puente entre la utopía y la realidad vivenciada en la Mindelo_Escuela Internacional de Arte (Mindelo_Escola Internacional de Arte – M_EIA), legalmente reconocida como Instituto Universitario de Arte, Tecnología y Cultura [Instituto Universitário de Arte, Tecnologia e Cultura], el primer espacio de Educación Superior en las áreas de arte y design en Cabo Verde, constituyendo un proyecto singular, irreverente, en la lucha por prácticas de educación artística informadas por políticas descolonizadas. Creado en 2004, este proyecto utópico lanza sus anclas a las prácticas, promoviendo la cultura y el desarrollo del país, a través de una relación con los proyectos de desarrollo local del Atelier Mar, consolidando una larga experiencia en el área de educación artística. Las tensiones surgen entre las expectativas sobre el carácter experimental y local de la M_EIA y su reglamentación y (no) conformidad con el conocimiento hegemónico en educación artística o los modelos de desarrollo ajenos a la realidad caboverdiana.Cet article présente les recherches doctorales de ses auteurs, qui questionnent le pont entre l’utopie et la réalité vécue à la Mindelo_École Internationale d’Art (Mindelo_Escola Internacional de Arte – M_EIA), légalement reconnu comme Institut Universitaire d’Art, de Technologie et de Culture [Instituto Universitário de Arte, Tecnologia e Cultura], le premier espace de l’Enseignement Supérieur dans les domaines des arts et du design au Cap-Vert, constituant un projet singulier, irrévérencieux, dans la lutte pour des pratiques d’éducation artistique inspirées par des politiques décolonisées. Créé en 2004, ce projet utopique lance ses ancres dans les pratiques, promouvant la culture et le développement du pays, à travers une relation avec les projets de développement local de l’Atelier Mar, consolidant sa longue expérience dans le domaine de l’éducation artistique. Des tensions apparaissent entre les attentes concernant le caractère expérimental et local de la M_EIA et sa réglementation et le (non-)conformité avec les connaissances hégémoniques en éducation artistique ou avec des modèles de développement étrangers à la réalité cap-verdienne.Este artigo apresenta as pesquisas de doutoramento de suas autoras, que questionam a ponte entre a utopia e a realidade vivenciada na Mindelo_Escola Internacional de Arte (M_EIA), reconhecida juridicamente como Instituto Universitário de Arte, Tecnologia e Cultura, o primeiro espaço de Ensino Superior nas áreas das artes e do design em Cabo Verde, constituindo um projeto singular, irreverente, na luta por práticas de educação artística informadas por políticas descolonizadas. Criado em 2004, esse projeto utópico lança suas âncoras às práticas, promovendo a cultura e o desenvolvimento do país, por meio de uma relação com os projetos de desenvolvimento local do Atelier Mar, consolidando a longa experiência na área da educação artística. As tensões surgem entre as expectativas sobre o carácter experimental e local da M_EIA e sua regulamentação e (não) conformidade com o conhecimento hegemónico em educação artística ou os modelos de desenvolvimento estranhos à realidade cabo-verdiana

Ruthenium(II)–cyclopentadienyl-derived complexes as new emerging anti-colorectal cancer drugs

Colorectal cancer (CRC) is one of the most common malignancies and one of the leading causes of cancer-related death worldwide, urging the need for new and more efficient therapeutic approaches. Ruthenium complexes have emerged as attractive alternatives to traditional platinum-based compounds in the treatment of CRC. This work aims to evaluate anti-CRC properties, as well as to identify the mechanisms of action of ruthenium complexes with the general formula [Ru(η5-C5H4R)(PPh3)(4,4'-R'-2,2'-bipyridine)][CF3SO3], where R = CH3, CHO or CH2OH and R' = H, CH3, CH2OH, or dibiotin ester. The complexes (Ru 1-7) displayed high bioactivity, as shown by low IC50 concentrations against CRC cells, namely, RKO and SW480. Four of the most promising ruthenium complexes (Ru 2, 5-7) were phenotypically characterized and were shown to inhibit cell viability by decreasing cell proliferation, inducing cell cycle arrest, and increasing apoptosis. These findings were in accordance with the inhibition of MEK/ERK and PI3K/AKT signaling pathways. Ruthenium complexes also led to a decrease in cellular clonogenic ability and cell migration, which was associated with the disruption of F-actin cytoskeleton integrity. Here, we demonstrated that ruthenium complexes, especially Ru7, have a high anticancer effect against CRC cells and are promising drugs to be used as a new therapeutical strategy for CRC treatment.Fundação para a Ciência e Tecnologia (FCT), I.P./MCTES through national funds (PIDDAC)—UIDB/00100/2020, UIDB/04050/2020 and through PTDC/QUI-QIN/28662/2017. A.V. acknowledges the CEECIND 2017 Initiative (CEECCIND/01974/2017). A.R.B. and R.G.T. thank FCT for their Ph.D. Grants (SFRH/BD/139271/2018 and SFRH/BD/135830/2018, respectively

A new family of iron(II)-cyclopentadienyl compounds shows strong activity against colorectal and triple negative breast cancer cells

The following is available online, Figure S1—1H NMR spectrum of complexes 6, in acetone-d6, Table S1. Bond lengths [Å] and angles [°] for [Fe(η5-Cp)(CO)(PhCN)(PPh3)][CF3SO3] 1, [Fe(η5-Cp)(CO)(p-NCPhNH2)(PPh3)][CF3SO3] 4 and [Fe(η5-Cp)(CO)(p-NCPhBr)(PPh3)][CF3SO3] 5, Table S2. Relevant TD-DFT (PBE0) excitation energies (λ), oscillator strengths (f) and compositions (only those > 5% are shown), for complexes 1–6, compared with experimental data (λexp). Both calculated and experimental values were obtained in dichloromethane, Figure S2—UV-Vis spectra of complexes 1–6 in DMSO along the 24 h study, Figure S3—UV-Vis spectra of complexes 1–6 in DMSO/DMEM mixture along the 24 h study and its variation plot (%) (bottom), Figure S4. ‘FeCp’ compounds affect the colony formation ability of SW480 cell line. Analysis of the colony formation ability, after 48 h of incubation with 1/4 IC50 and IC50, in SW480 cell line. Representative images of colony formation assay in SW480 cell line, Figure S5. ‘FeCp’ compounds induce apoptosis colorectal cancer-derived cell line. Apoptotic cell death was analyzed by Annexin V fluorescein isothiocyanate (AV-FITC) and propidium iodide (PI) assay in SW480 cells, after incubation with IC50 and 2×IC50 concentrations for 48 h. Representative histograms of SW480 cell line double stained with AV and PI, Table S4. Crystal data and structure refinement for [Fe(η5-Cp)(CO)(PhCN)(PPh3)][CF3SO3] 1, [Fe(η5-Cp)(CO)(p-NCPhNH2)(PPh3)][CF3SO3] 4 and [Fe(η5-Cp)(CO)(p-NCPhBr)(PPh3)][CF3SO3] 5.A family of compounds with the general formula [Fe(η5-C5H5)(CO)(PPh3)(NCR)]+ has been synthesized (NCR = benzonitrile (1); 4-hydroxybenzonitrile (2); 4-hydroxymethylbenzonitrile (3); 4-aminobenzonitrile (4); 4-bromobenzonitrile (5); and, 4-chlorocinnamonitrile (6)). All of the compounds were obtained in good yields and were completely characterized by standard spectroscopic and analytical techniques. Compounds 1, 4, and 5 crystallize in the monoclinc P21/c space group and packing is determined by short contacts between the phosphane phenyl rings and cyclopentadienyl (compounds 1 and 4) or π-π lateral interactions between the benzonitrile molecules (complex 5). DFT and TD-DFT calculations were performed to help in the interpretation of the experimental UV-Vis. data and assign the electronic transitions. Cytotoxicity studies in MDA-MB-231 breast and SW480 colorectal cancer-derived cell lines showed IC50 values at a low micromolar range for all of the compounds in both cell lines. The determination of the selectivity index for colorectal cells (SW480 vs. NCM460, a normal colon-derived cell line) indicates that the compounds have some inherent selectivity. Further studies on the SW480 cell line demonstrated that the compounds induce cell death by apoptosis, inhibit proliferation by inhibiting the formation of colonies, and affect the actin-cytoskeleton of the cells. These results are not observed for the hydroxylated compounds 2 and 3, where an alternative mode of action might be present. Overall, the results indicate that the substituent at the nitrile-based ligand is associated to the biological activity of the compounds.Centro de Química Estrutural acknowledges Fundação para a Ciência e Tecnologia (FCT) for the Project UIDB/00100/2020. This work was also funded in the scope of the project PTDC/QUI-QIN/28662/2017 (FCT) and by the strategic program UID/BIA/04050/2019 (FCT). A. Pilon and Ana Rita Brás thank FCT for their Ph.D. Grants (SFRH/BD/139412/2018 and SFRH/BD/139271/2018, respectively). A. Valente acknowledges the CEECIND 2017 Initiative (CEECIND/01974/2017). P. J Costa thank FCT for Investigador FCT Program IF/00069/2014, exploratory project IF/00069/2014/CP1216/CT0006, and strategic project UID/MULTI/04046/2019. P. J. Costa also acknowledges FCT, Programa Operacional Regional de Lisboa (Lisboa 2020), Portugal 2020, FEDER/FN, and the European Union for project LISBOA-01-0145-FEDER-028455 / PTDC/QUI-QFI/28455/2017

Establishment and characterization of human pluripotent stem cells-derived brain organoids to model cerebellar diseases

Supplementary Information Te online version contains supplementary material available at https://doi.org/ 10.1038/s41598-022-16369-y.The establishment of robust human brain organoids to model cerebellar diseases is essential to study new therapeutic strategies for cerebellum-associated disorders. Machado-Joseph disease (MJD) is a cerebellar hereditary neurodegenerative disease, without therapeutic options able to prevent the disease progression. In the present work, control and MJD induced-pluripotent stem cells were used to establish human brain organoids. These organoids were characterized regarding brain development, cell type composition, and MJD-associated neuropathology markers, to evaluate their value for cerebellar diseases modeling. Our data indicate that the organoids recapitulated, to some extent, aspects of brain development, such as astroglia emerging after neurons and the presence of ventricular-like zones surrounded by glia and neurons that are found only in primate brains. Moreover, the brain organoids presented markers of neural progenitors proliferation, neuronal differentiation, inhibitory and excitatory synapses, and firing neurons. The established brain organoids also exhibited markers of cerebellar neurons progenitors and mature cerebellar neurons. Finally, MJD brain organoids showed higher ventricular-like zone numbers, an indication of lower maturation, and an increased number of ataxin-3-positive aggregates, compared with control organoids. Altogether, our data indicate that the established organoids recapitulate important characteristics of human brain development and exhibit cerebellar features, constituting a resourceful tool for testing therapeutic approaches for cerebellar diseases.This work was funded by the European Regional Development Fund (ERDF) through the Centro 2020 Regional Operational Programme under BrainHealth2020 projects (CENTRO-01-0145-FEDER-000008), through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization and Portuguese national funds via FCT—Fundação para a Ciência e a Tecnologia, under projects — UIDB/04539/2020 and UIDP/04539/2020, POCI-01-0145-FEDER-030737 (NeuroStemForMJD, PTDC/BTM-ORG/30737/2017), CEEC-IND/04242/2017, PhD Scholarships 2020.04751.BD and 2020.07385.BD. It was also funded by the National Ataxia Foundation, the French Muscular Dystrophy Association (AFM-Téléthon) Trampoline Grant #20126, EU Joint Programme—Neurodegenerative Disease Research (JPND) Project JPCO FUND/0005/2015-ModelPolyQ), and the Richard Chin and Lily Lock Machado-Joseph Disease Research Fund.info:eu-repo/semantics/publishedVersio

Lidocaine turns the surface charge of biological membranes more positive and changes the permeability of blood-brain barrier culture models

The surface charge of brain endothelial cells forming the blood-brain barrier (BBB) is highly negative due to phospholipids in the plasma membrane and the glycocalyx. This negative charge is an important element of the defense systems of the BBB. Lidocaine, a cationic and lipophilic molecule which has anaesthetic and antiarrhytmic properties, exerts its actions by interacting with lipid membranes. Lidocaine when administered intravenously acts on vascular endothelial cells, but its direct effect on brain endothelial cells has not yet been studied. Our aim was to measure the effect of lidocaine on the charge of biological membranes and the barrier function of brain endothelial cells. We used the simplified membrane model, the bacteriorhodopsin (bR) containing purple membrane of Halobacterium salinarum and culture models of the BBB. We found that lidocaine turns the negative surface charge of purple membrane more positive and restores the function of the proton pump bR. Lidocaine also changed the zeta potential of brain endothelial cells in the same way. Short-term lidocaine treatment at a 10 μM therapeutically relevant concentration did not cause major BBB barrier dysfunction, substantial change in cell morphology or P-glycoprotein efflux pump inhibition. Lidocaine treatment decreased the flux of a cationic lipophilic molecule across the cell layer, but had no effect on the penetration of hydrophilic neutral or negatively charged markers. Our observations help to understand the biophysical background of the effect of lidocaine on biological membranes and draws the attention to the interaction of cationic drug molecules at the level of the BBB