Chronic administration of atypical antipsychotics improves behavioral and synaptic defects of STOP null mice.

International audienceINTRODUCTION: Recent studies have suggested that schizophrenia is associated with alterations in the synaptic connectivity involving cytoskeletal proteins. The microtubule-associated protein stable tubule only polypeptide (STOP) plays a key role in neuronal architecture and synaptic plasticity, and it has been demonstrated that STOP gene deletion in mice leads to a phenotype mimicking aspects of positive and negative symptoms and cognitive deficits classically observed in schizophrenic patients. In STOP null mice, behavioral defects are associated with synaptic plasticity abnormalities including defects in long-term potentiation. In these mice, long-term administration of typical antipsychotics has been shown to partially alleviate behavioral defects but, as in humans, such a treatment was poorly active on deficits related to negative symptoms and cognitive impairments. Here, we assessed the effects of risperidone and clozapine, two atypical antipsychotics, on STOP null mice behavior and synaptic plasticity. RESULTS: Long-term administration of either drug results in alleviation of behavioral alterations mimicking some negative symptoms and partial amelioration of some cognitive defects in STOP null mice. Interestingly, clozapine treatment also improves synaptic plasticity of the STOP null animals by restoring long-term potentiation in the hippocampus. DISCUSSION: All together, the pharmacological reactivity of STOP null mice to antipsychotics evokes the pharmacological response of humans to such drugs. Totally, our study suggests that STOP null mice may provide a useful preclinical model to evaluate pharmacological properties of antipsychotic drugs

Systemically Administered Brain-Targeted Nanoparticles Transport Peptides across the Blood—Brain Barrier and Provide Neuroprotection

Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood—brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against strokeTurgay Dalkara’s work is supported by the Turkish Academy of Sciences. This study is supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project Number: 109S017)S

In vitro and in vivo intracellular delivery of quantum dots by maurocalcine

International audienceMaurocalcine is a new member of the increasing family of cell penetrating peptides. We report for the first time that this peptide is able to deliver quantum dots inside a variety of cells, both in vitro and in vivo. In vivo, maurocalcine produces intracellular delivery of the nanoparticles without affecting the relative distribution of quantum dots within organs. The data stress out that maurocalcine can be used for intracellular delivery of functionalised nanoparticles in vivo

Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

International audienceThe genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD

INTERACTIONS DES SELS BILIAIRES ET DES PHOSPHOLIPIDES (APPLICATION A LA TRANSITION VESICULE-MICELLE (DOCTORAT : PHARMACOTECHNIE ET BIOPHARMACIE))

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Nanoparticules pour la délivrance cérébrale de principes actifs ou d’agents de contraste. Application à la maladie d’Alzheimer

Le traitement et le diagnostic des maladies cérébrales comme la maladie d’Alzheimer sont à l’heure actuelle un challenge. En effet la délivrance de molécules actives ou d’agents de contraste au niveau cérébral est rendue très difficile à cause de la perméabilité très faible de la Barrière Hémato-Encéphalique (BHE) qui entoure et protège le cerveau. Une nouvelle stratégie pour améliorer le passage des molécules thérapeutiques à travers cette barrière est l’utilisation de vecteurs colloïdaux appelés nanoparticules. Ces objets choisis pour leur biocompatibilité et leur biodégradation présentent un devenir différent dans l’organisme en fonction de leur composition et de leur structure. L’application de ces nanoparticules au traitement et au diagnostic de la maladie d’Alzheimer est actuellement proposée par un projet européen. Les stratégies développées dans ce projet consistent à mettre au point des vecteurs capables de franchir la BHE et d’interagir avec le peptide β-amyloïde pour (1) détecter les plaques cérébrales formées, en vue d’un diagnostic de la maladie et (2) empêcher son agrégation toxique pour les neurones, en vue de proposer une nouvelle approche thérapeutique de la maladie d’Alzheimer

Optimisation, purification et caractérisation de nanoparticules de copolymère encapsulant deux agents de contraste (nanoparticules d'oxyde de fer et gadolinium. Application à la maladie d'alzheimer)

La maladie d Alzheimer (MA) est une maladie neurodégénérative qui représente aujourd hui la première cause de démence sénile au monde. L hypothèse amyloïde explique en partie la physiopathologie de la MA par l accumulation du peptide amyloïde b 1-42 (Ab42) au niveau extraneuronal. Dans un contexte de recherche d un diagnostic précoce, la technique d imagerie par résonnance magnétique (IRM) est l une des voies possibles permettant ainsi un diagnostic non invasif, non irradiant, sensible et précoce de la MA. L intensité du signal IRM peut être augmentée par l administration d agent de contraste comme les particules d oxyde de fer (USPIO) et le gadolinium (Gd). Pour mieux observer les lésions cérébrales provoquées par la MA, le passage de la barrière hémato-encéphalique (BHE) par ces agents de contraste est essentiel. Pour résoudre cet obstacle majeur, leur encapsulation au sein de nanoparticules (NPs) de poly (éthylène glycol-cyanoacétate) - poly (hexadécyl-cyanoacrylate) (PEG-PHDCA) est une voie intéressante, car ces NPs ont montré précédemment leur double capacité : à traverser la BHE in vivo et à interagir avec le peptide Ab42. Les USPIO et le Gd ont été encapsulés en parallèle par une méthode d émulsion/évaporation au sein de NPs de PEG-PHDCA fluorescent ou non. Les USPIO ont été modifiés par adsorption d une couche d acide oléique (USPIO-AO). Le Gd est chélaté par le DTPA avec deux chaînes d acide stéarique greffées. La préparation et la purification des NPs ont été optimisées avant leur caractérisation et évaluation par diffusion de la lumière, microscopie électronique en transmission (TEM), IRM et analyse élémentaire par ICP-AES. La préparation des USPIO-AO a été optimisée pour obtenir des particules non agrégées d une taille de 22 nm, stables dans le dichlorométhane pendant 15 jours. La formulation des NPs associant chaque agent de contraste a été mise au point. L observation en TEM montre l association des USPIO-AO ou du Gd aux NPs de taille moyenne respectivement inférieure à 300 nm. Une méthode de purification par gradient de densité de saccharose suivi d une ultracentrifugation a permis d éliminer dans chaque préparation les deux agents de contraste libres. Le dosage des agents de contraste réalisé par ICP-AES a montré une encapsulation plus importante du Gd. L analyse qualitative du pouvoir contrastant des NPs effectuée par IRM a confirmé ce résultat. En conclusion, des NPs de PEG-PHDCA encapsulant les USPIO ou le Gd ont été obtenues. Leur évaluation montre un plus grand potentiel des NPs chargées en Gd comme nouvel agent de contraste.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Dermatillomania: Strategies for Developing Protective Biomaterials/Cloth

Dermatillomania or skin picking disorder (SPD) is a chronic, recurrent, and treatment resistant neuropsychiatric disorder with an underestimated prevalence that has a concerning negative impact on an individual’s health and quality of life. The current treatment strategies focus on behavioral and pharmacological therapies that are not very effective. Thus, the primary objective of this review is to provide an introduction to SPD and discuss its current treatment strategies as well as to propose biomaterial-based physical barrier strategies as a supporting or alternative treatment. To this end, searches were conducted within the PubMed database and Google Scholar, and the results obtained were organized and presented as per the following categories: prevalence, etiology, consequences, diagnostic criteria, and treatment strategies. Furthermore, special attention was provided to alternative treatment strategies and biomaterial-based physical treatment strategies. A total of six products with the potential to be applied as physical barrier strategies in supporting SPD treatment were shortlisted and discussed. The results indicated that SPD is a complex, underestimated, and underemphasized neuropsychiatric disorder that needs heightened attention, especially with regard to its treatment and care. Moreover, the high synergistic potential of biomaterials and nanosystems in this area remains to be explored. Certain strategies that are already being utilized for wound healing can also be further exploited, particularly as far as the prevention of infections is concerned

Placental Models for Evaluation of Nanocarriers as Drug Delivery Systems for Pregnancy Associated Disorders

International audiencePregnancy-associated disorders affect around 20% of pregnancies each year around the world. The risk associated with pregnancy therapeutic management categorizes pregnant women as “drug orphan” patients. In the last few decades, nanocarriers have demonstrated relevant properties for controlled drug delivery, which have been studied for pregnancy-associated disorders. To develop new drug dosage forms it is mandatory to have access to the right evaluation models to ensure their usage safety and efficacy. This review exposes the various placental-based models suitable for nanocarrier evaluation for pregnancy-associated therapies. We first review the current knowledge about nanocarriers as drug delivery systems and how placenta can be used as an evaluation model. Models are divided into three categories: in vivo, in vitro, and ex vivo placental models. We then examine the recent studies using those models to evaluate nanocarriers behavior towards the placental barrier and which information can be gathered from these results. Finally, we propose a flow chart on the usage and the combination of models regarding the nanocarriers and nanoparticles studied and the intended therapeutic strateg

Co–encapsulation of flavonoids with anti–cancer drugs: A challenge ahead

International audienc