Distribution des récepteurs dopaminergiques dans le cerveau antérieur de la souris mutante Dystonia musculorum

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Distribution et altération des récepteurs centraux des kinines en physiopathologie

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

The time course of recognition memory impairment and glial pathology in the hAPP-J20 mouse model of Alzheimer’s disease

The role of cellular changes in the neurovascular unit is increasingly being investigated to understand the pathogenesis of Alzheimer’s disease (AD). The aim of the current study was to determine the time course of recognition memory impairment in the J20 mouse model of AD, in relation to neuroinflammatory responses and the pathology of amyloid-β (Aβ). Male hAPP-J20 and wild-type mice were assessed at 3, 6, 9, and 12 months of age. The spontaneous object recognition (SOR) task provided a measure of memory, with assessment of both a short delay (1 min) and a long delay (4 h). Immunohistochemistry was used to characterize Aβ deposition, and quantify astrocyte and microglial responses. At all ages tested, J20 mice had impaired long-term, but preserved short-term, recognition memory. Wild-types demonstrated preserved long-term memory up to 9 months of age, and preserved short-term memory at all ages tested. Plaque pathology in the J20 mice was present from 6 months onwards, with co-localization of reactive microglia and activated astrocytes. Reactive microglia and astrocyte activation in the hippocampus were significantly greater in the J20 mice at 9 months, compared to wild-types. This study contributes to our understanding of the pathological and cognitive mechanisms at play in AD. J20 mice showed impairment in retaining information over longer periods from an early age, preceding the deposition of Aβ and glial activation. Defining early physiological changes in relation to cognitive decline could provide insight into new therapeutic targets early in the disease process, when intervention is most likely to effectively slow disease progression

Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease.

Our understanding of the underlying biology of Alzheimer's disease (AD) has been steadily progressing; however, this is yet to translate into a successful treatment in humans. The use of transgenic mouse models has helped to develop our understanding of AD, not only in terms of disease pathology, but also with the associated cognitive impairments typical of AD. Plaques and neurofibrillary tangles are often amongst the last pathological changes in AD mouse models, after neuronal loss and gliosis. There is a general consensus that successful treatments need to be applied before the onset of these pathologies and associated cognitive symptoms. This review discusses the different types of AD mouse models in terms of the temporal progression of the disease, how well they replicate the pathological changes seen in human AD and their cognitive defects. We provide a critical assessment of the behavioural tests used with AD mice to assess cognitive changes and decline, and discuss how successfully they correlate with cognitive impairments in humans with AD. This information is an important tool for AD researchers, when deciding on appropriate mouse models, and when selecting measures to assess behavioural and cognitive change. This article is protected by copyright. All rights reserved

Impact de la réforme fiscale sur la pauvreté au Népal comparaison de CD Curves et de la micro simulation en EGC

L'objectif de ce travail est d'étudier les effets redistributifs d'une réforme fiscale marginale sur la pauvreté au Népal à travers un indice de pauvreté additif. Nous utiliserons à cet effet deux outils: la technique des CD-Curves et la micro simulation en équilibre général calculable. La technique des CD-Curves, introduite par Makdissi et Wodon (2002) nous permettra de tester l'impact simultané d'une augmentation marginale de la taxe sur le revenu pour financer la décroissance de la taxe sur l'ensemble de biens disponibles dans l'enquête budget-consommation (National Living Standard Survey) de 1995. Cette enquête avait été effectuée sur 3373 ménages. La technique des CD-Curves donne au planificateur économique la direction à suivre s'il souhaite effectuer une réforme fiscale. En effet, ce test nous permettra de déterminer, parmi tous les biens disponibles, quels sont ceux qui, une fois subventionnés par une taxe sur le revenu, tendraient à réduire la pauvreté. Comme ce test n'est que directionnel, nous allons le vérifier par une subvention sur chaque bien financé par une augmentation marginale de la taxe sur le revenu des ménages dans un modèle d'équilibre général calculable (MEGC). La micro simulation (l'introduction des ménages pris de façon individuelle dans un MEGC) est l'outil privilégié pour les questions de distribution de revenu en équilibre général calculable. Ce qui nous permettra d'affirmer ou d'infirmer les conclusions de test, obtenues à partir des CD-Curves

Targeting kinin receptors for the treatment of neurological diseases

Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and nociception. They are believed to play a role in disease states like asthma, allergies, rheumatoid arthritis, cancer, diabetes, endotoxic and pancreatic shock, and to contribute to the therapeutic effects of ACE inhibitors in cardiovascular diseases. Although kinins are also neuromediators in the central nervous system, their involvement in neurological diseases has not been intensively investigated thus far. This review analyzes the potential of central kinin receptors as therapeutic targets for neurological disorders. Initial data highlight potential roles for B1 receptor antagonists as antiepileptic agents, and for B2 receptor antagonists (and/or B1 agonists) in the treatment of stroke. Functional B1 receptors located on T-lymphocytes and on the blood brain-barrier are also putative targets for the management of multiple sclerosis. However, successful elucidation of the therapeutic value of these new pharmacological approaches will require refinement of our knowledge on the physiology and cellular localization of central kinin receptors

Inhibition of human immunodeficiency virus type-1 (HIV-1) glycoprotein-mediated cell-cell fusion by immunor (IM28)

Abstract Background Immunor (IM28), an analog of dehydroepiandrosterone (DHEA), inhibits human immunodeficiency virus type-1 (HIV-1) by inhibiting reverse transcriptase. We assessed the ability of IM28 to inhibit the cell-cell fusion mediated by HIV envelope glycoprotein in an in vitro system. For this purpose, we co-cultured TF228.1.16, a T-cell line expressing stably HIV-1 glycoprotein envelopes, with an equal number of 293/CD4+, another T cell line expressing CD4, and with the SupT1 cell line with or without IM28. Results In the absence of IM28, TF228.1.16 fused with 293/CD4+, inducing numerous large syncytia. Syncytia appeared more rapidly when TF228.1.16 was co-cultured with SupT1 cells than when it was co-cultured with the 293/CD4+ cell line. IM28 (1.6 – 45 μg/ml) completely inhibits cell-cell fusion. IM28 also prevented the development of new syncytia in infected cells and protected naive SupT1 cells from HIV-1 infection. Evaluation of 50% inhibitory dose (IC50) of IM28 revealed a decrease in HIV-1 replication with an IC50 of 22 mM and 50% cytotoxicity dose (CC50) as determined on MT2 cells was 75 mM giving a selectivity index of 3.4 Conclusions These findings suggest that IM28 exerts an inhibitory action on the env proteins that mediate cell-cell fusion between infected and healthy cells. They also suggest that IM28 interferes with biochemical processes to stop the progression of existing syncytia. This property may lead to the development of a new class of therapeutic drug.</p

Autoradiographic detection of kinin receptors in the human medulla of control, hypertensive, and diabetic donors

Kinins have been elected to the status of central neuromediators. Their effects are mediated through the activation of two G-protein-coupled receptors, denoted B-1 and B-2. Functional and binding studies suggested that B-1 and B-2 receptors are upregulated in the medulla and spinal cord of hypertensive and diabetic rats. the aim of this study was to localize and quantify kinin receptors in post-mortem human medulla obtained from normotensive, hypertensive, and diabetic subjects, using in vitro receptor autoradiography with the radioligands [I-125]HPP-HOE140 (B-2 receptor) and [I-125]HPP[des-Arg(10)]-HOE140 (B-1 receptor). Data showed specific binding sites for B-2 receptor (0.4-1.5 fmol/mg tissue) in 11 medullary nuclei from 4 control specimens (paratrigeminal > ambiguus > cuneate, gelatinous layer of the caudal spinal trigeminal nucleus > caudal and interpolar spinal trigeminal, external cuneate, solitary tract > hypoglossal > gracile > inferior olivary nuclei). Increased density of B-2 receptor binding sites was observed in seven medullary nuclei of four hypertensive specimens (paratrigeminal > external cuneate > interpolar and caudal spinal trigeminal, gracile, inferior olivary > hypoglossal nuclei). B-2 receptor binding sites were seemingly increased in the same medullary nuclei of two diabetic specimens. Specific binding sites for B-1 receptor (1.05 and 1.36 fmol/mg tissue) were seen only in the inferior olivary nucleus in two out of the ten studied specimens. the present results support a putative role for kinins in the regulation of autonomic, nociceptive, and motor functions at the level of the human medulla. Evidence is also provided that B-2 receptors are upregulated in medullary cardiovascular centers of subjects afflicted of cardiovascular diseases.Univ Montreal, Fac Med, Dept Physiol, Montreal, PQ H3T 1J4, CanadaUniv Montreal, Clin Res Inst, Montreal, PQ H3T 1J4, CanadaUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilWeb of Scienc