Potential neuroprotective drups in cerebral ischemia : design, synthesis and biological evaluation of the new derivatives against stroke

Accidents Vasculaire Cérébraux (parfois appelés AVC ou attaques cérébrales) sont les 3èmes causes principales de mortalité et les causes de handicap dans les pays industrialisés. Ils représentent un problème de santé publique en raison de leurs fréquences, de leurs mortalités et des handicaps physiques et cognitifs qu'ils entraînent. Malgré d’importants progrès réalisés dans le domaine de la physiopathogénie de l’ischémie cérébrale, on ne dispose pas encore, aujourd’hui, de thérapeutiques efficaces pour traiter un accident vasculaire cérébral lors de sa phase aiguë. Les gangliosides GM1 sont des composants majeurs du feuillet externe de la membrane cellulaire au niveau du système nerveux central. Ces gangliosides ont des effets antineurotoxiques, neuroprotecteurs et les propriétés neurorestoratrices sur les divers neurotransmetteurs du SNC mais pour le moment ils n’ont pas des valeurs thérapeutiques en raison de leurs manques de biodisponibilités et de leurs manques de perméabilité de la barrière hématoencéphalique (BHE). Nous avons synthétisé les structures simplifiées de ces gangliosides GM1, L’idée qui a prévalu pour la conception, des nouvelles structures a été : d’introduire des chaînes grasses saturées ou insaturées sur un motif sérine, tyrosine ou cystéine, de remplacer la fonction carboxylique par des groupements reconnus comme bioisostères classiques ou non classiques de cette fonction ; comme par exemple les fonctions phosphonique, tétrazolique, 2,4-oxadiazolidine-3,5-dione. Nous avons élaboré un nouveau modèle de composé neuroprotecteur dans lequel une chaîne grasse est couplée à une entité acide ascorbique pour améliorer le passage de la BHE. Pour étudier l’activité neuroprotectrice des composés synthétisés nous avons utilisé deux modèles biologiques in vitro : un modèle cellulaire (cellules HT22) et un modèle tissulaire (tranches de cerveaux).Stroke is the third leading cause of mortality and the primary cause of disability in adults. Therefore, it is critical to identify new, efficacious pharmacological treatments. One pharmacological approach for treatment of stroke is called neuroprotective therapy. It has been reported that the amphiphilic, monosialotetrahexosylganglioside (GM1) (II3 NeuAc-GgOsc4Cer) has antineurotoxic, neuroprotective, and neurorestorative effects on various central neurotransmitter systems. Since GM1 is not of therapeutic value because of its lack of bioavailability and its low blood-brain barrier (BBB) permeation. Thus, molecules that mimic GM1 represent a novel approach to neuroprotection. We have synthesized the smalls GM1-like analogues whose simplified structure includes various lipophilic saturated, unsaturated, or cyclic polyunsaturated moieties have been introduced, while in the second series, thecarboxylic acid function was replaced by different hydrophilic groups including bioisosters of the carboxylate, such as a phosphonic acid, a tetrazole, the 1,2,4-oxadiazolidine-3,5-dione or an ascorbic acid moiety. Introduction of ascorbic acid was supported by several reports that showed that ascorbic acid conjugates can improve BBB permeation properties. We report their neuroprotective effects in two distinct models of nerve cell death using hippocampus-derived HT22 cells and an additional neuroprotective assays using cortical slices injured by glutamate confirmed these results

Innovation moléculaire à visée thérapeutique (conception, synthèse et évaluation biologique des nouveaux dérivés contre l'ischemie cérébrale)

Accidents Vasculaire Cérébraux (parfois appelés AVC ou attaques cérébrales) sont les 3èmes causes principales de mortalité et les causes de handicap dans les pays industrialisés. Ils représentent un problème de santé publique en raison de leurs fréquences, de leurs mortalités et des handicaps physiques et cognitifs qu'ils entraînent. Malgré d importants progrès réalisés dans le domaine de la physiopathogénie de l ischémie cérébrale, on ne dispose pas encore, aujourd hui, de thérapeutiques efficaces pour traiter un accident vasculaire cérébral lors de sa phase aiguë. Les gangliosides GM1 sont des composants majeurs du feuillet externe de la membrane cellulaire au niveau du système nerveux central. Ces gangliosides ont des effets antineurotoxiques, neuroprotecteurs et les propriétés neurorestoratrices sur les divers neurotransmetteurs du SNC mais pour le moment ils n ont pas des valeurs thérapeutiques en raison de leurs manques de biodisponibilités et de leurs manques de perméabilité de la barrière hématoencéphalique (BHE). Nous avons synthétisé les structures simplifiées de ces gangliosides GM1, L idée qui a prévalu pour la conception, des nouvelles structures a été : d introduire des chaînes grasses saturées ou insaturées sur un motif sérine, tyrosine ou cystéine, de remplacer la fonction carboxylique par des groupements reconnus comme bioisostères classiques ou non classiques de cette fonction ; comme par exemple les fonctions phosphonique, tétrazolique, 2,4-oxadiazolidine-3,5-dione. Nous avons élaboré un nouveau modèle de composé neuroprotecteur dans lequel une chaîne grasse est couplée à une entité acide ascorbique pour améliorer le passage de la BHE. Pour étudier l activité neuroprotectrice des composés synthétisés nous avons utilisé deux modèles biologiques in vitro : un modèle cellulaire (cellules HT22) et un modèle tissulaire (tranches de cerveaux).Stroke is the third leading cause of mortality and the primary cause of disability in adults. Therefore, it is critical to identify new, efficacious pharmacological treatments. One pharmacological approach for treatment of stroke is called neuroprotective therapy. It has been reported that the amphiphilic, monosialotetrahexosylganglioside (GM1) (II3 NeuAc-GgOsc4Cer) has antineurotoxic, neuroprotective, and neurorestorative effects on various central neurotransmitter systems. Since GM1 is not of therapeutic value because of its lack of bioavailability and its low blood-brain barrier (BBB) permeation. Thus, molecules that mimic GM1 represent a novel approach to neuroprotection. We have synthesized the smalls GM1-like analogues whose simplified structure includes various lipophilic saturated, unsaturated, or cyclic polyunsaturated moieties have been introduced, while in the second series, thecarboxylic acid function was replaced by different hydrophilic groups including bioisosters of the carboxylate, such as a phosphonic acid, a tetrazole, the 1,2,4-oxadiazolidine-3,5-dione or an ascorbic acid moiety. Introduction of ascorbic acid was supported by several reports that showed that ascorbic acid conjugates can improve BBB permeation properties. We report their neuroprotective effects in two distinct models of nerve cell death using hippocampus-derived HT22 cells and an additional neuroprotective assays using cortical slices injured by glutamate confirmed these results.AIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

Potential neuroprotective drugs in cerebral ischemia: new saturated and polyunsaturated lipids coupled to hydrophilic moieties: synthesis and biological activity

International audienc

Neuroprotective Effects against in vitro Cerebral Ischemia of N-alkyl-1,2,4-oxadiazolidine-3,5-diones and Their Corresponding Synthetic Intermediates N-Alkylhydroxylamines and N-1-Alkyl-3-carbonyl-1-hydroxyureas"

International audienc

Additional file 1: of Trial of labour or elective repeat caesarean delivery:are women making an informed decision at Kenyatta national hospital?

Questionnaire. (DOCX 31 kb

Bis-8-hydroxy-quinoline and Bis-8-hydroxy-quinaldine N-substituted amines: a single methyl group structural difference between the two heterocycles, wich modulates the antiproliferative effects

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Synthesis and biological activity of amino acid conjugates of abscisic acid.

We prepared 19 amino acid conjugates of the plant hormone abscisic acid (ABA) and investigated their biological activity, enzymatic hydrolysis by a recombinant Arabidopsis amidohydrolases GST-ILR1 and GST-IAR3, and metabolic fate in rice seedlings. Different sets of ABA-amino acids induced ABA-like responses in different plants. Some ABA-amino acids, including some that were active in bioassays, were hydrolyzed by recombinant Arabidopsis GST-IAR3, although GST-ILR1 did not show hydrolysis activity for any of the ABA-amino acids. ABA-L-Ala, which was active in all the bioassays, an Arabidopsis seed germination, spinach seed germination, and rice seedling elongation assays, except in a lettuce seed germination assay and was hydrolyzed by GST-IAR3, was hydrolyzed to free ABA in rice seedlings. These findings suggest that some plant amidohydrolases hydrolyze some ABA-amino acid conjugates. Because our study indicates the possibility that different plants have hydrolyzing activity toward different ABA-amino acids, an ABA-amino acid may function as a species-selective pro-hormone of ABA.autho

Trial of labour or elective repeat caesarean delivery:are women making an informed decision at Kenyatta national hospital?

Abstract Background Trial of labour is a safe option for most women after one previous caesarean delivery. However, the proportion of women attempting trial of labour after previous caesarean delivery (TOLAC) has been declining in many countries. In addition, women with prior caesarean delivery appear to know little regarding their mode of delivery and healthcare providers’ recommendations. The doctors’ preferences exert a strong influence on patient’s decision whether or not to pursue TOLAC. In Kenya, it is unclear whether women who opt for trial of labour after caesarean delivery (TOLAC) or elective repeat caesarean delivery (ERCD) do that based on clear understanding of risks and benefits of both modes of delivery. This study aimed at determining whether patients with one previous caesarean delivery make an informed decision on preferred mode of delivery following their interactions with doctors. Methods A cross-sectional descriptive study was carried out on 202 pregnant women with one previous caesarean delivery at Kenyatta National Hospital (KNH) antenatal clinic. Data was collected from both the patients’ records and women were interviewed using a structured questionnaire. Results Out of 202 women with mean age of 30.2 years 136 (67.2%) chose Elective Repeat Caesarean Delivery (ERCD), while 66 (32.8%) opted for TOLAC. Only 61/202 (30.6%; 95% C.I: 24.4 to 37.6%) made informed decisions. Few women (65: 32.2%) knew that the chance of successful TOLAC was high (60-80%) and 97 (48%) were not aware of the chances for a successful TOLAC. More than half of the women (109: 53.9%) were unaware of the risk of uterine rupture after one previous delivery and only few patients (64: 31.7%) knew that the risk of uterine rupture in TOLAC is low (< 1%). The majority of the women (112: 55.4%) did not know that the indications for previous caesarean delivery are an important factor in determining the chance of a successful Vaginal Birth after Caesarean Delivery (VBAC). For 47(23.3%) of the women, there was no documented indication for the previous caesarean delivery. The women’s mode of delivery was significantly associated with the preference of the counseling doctor (p < 0.001) and their qualification (p = 0.020). Only 23 (11.4%) women signed the consent form for ERCD while none of the women for TOLAC signed any consent form. Conclusions There was an overall lack of information on both modes of delivery while doctor’s preferences affected women’s decisions. Only just under one third of the women made an informed decision. There is a need to develop clear standard protocols and checklists for information to be disseminated to doctors and all patients with previous caesarean deliveries in subsequent pregnancies in Kenya