Polycyclic propargylamine derivatives as multifunctional neuroprotective agents

Philosophiae Doctor - PhDThe abnormal death of neurons in the central nervous system of individuals suffering from neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, takes place by an intrinsic cell suicide programme known as apoptosis. This process is triggered by several stimuli, and consists of numerous pathways and cascades which lead to the death of neuronal cells. It is this multifactorial nature of neurodegenerative diseases that has over the years seen many researchers develop compounds that may serve as multi-target directed ligands (MTDLs) which could potentially confer neuroprotection by acting simultaneously on different receptors and target sites implicated in neurodegeneration. This study was aimed at developing MTDLs that may serve as neuroprotective agents by simultaneously (a) inhibiting N-methyl D-aspartate receptors (NMDAR) and blocking L-type voltage gated calcium channels (VGCC) thus regulating the Ca2+ influx mediated excitotoxic process; (b) inhibiting the monoamine oxidase enzymes A and -B (MAO-A/B) thus allowing increase in dopamine levels in the central nervous system and reducing the levels of the highly oxidative products produced by the activity of these enzymes; (c) possessing anti-apoptotic activity to halt the neuronal cell death process. In designing the compounds we focused on the structures of rasagiline and selegiline, two well-known MAO-B inhibitors and proposed neuroprotective agents, and of NGP1-01, a known VGCC blocker and NMDAR antagonist. The first series of compounds (reported in research article 1, Chapter 3), comprised polycyclic propargylamine and acetylene derivatives. Compounds 12, 15 and 16 from this series showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18 % to 59 % in micromolar concentrations, and compared favourably to the reference compounds. In the MAO-B assay, compound 10 exhibited weak MAO-B inhibition of 73.32 % at 300 μM. The rest of the series showed little to no activity on these target sites, despite showing significant anti-apoptotic activity. This suggested the compounds in this series to be exhibiting their neuroprotective action through some other mechanism(s) unexplored in this study

Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial.

BACKGROUND: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe. METHODS: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940. FINDINGS: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08-0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28-2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported. INTERPRETATION: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone. FUNDING: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health.The SHINE trial is funded by the Bill & Melinda Gates Foundation (OPP1021542 and OPP113707); UK Department for International Development; Wellcome Trust, UK (093768/Z/10/Z, 108065/Z/15/Z and 203905/Z/16/Z); Swiss Agency for Development and Cooperation; US National Institutes of Health (2R01HD060338-06); and UNICEF (PCA-2017-0002)

不飽和脂酸の微量定量法の吟味

京都大学0048新制・課程博士医学博士医博第39号新制||医||9(附属図書館)108京都大学大学院医学研究科外科系専攻(主査)教授 青柳 安誠, 教授 荒木 千里, 教授 近藤 鋭矢学位規則第5条第1項該当Kyoto UniversityDA

Versatility of 7-substituted coumarin molecules as antimycobacterial agents, neuronal enzyme inhibitors and neuroprotective agents

Kapp, E., et al. 2017. Versatility of 7-substituted coumarin molecules as antimycobacterial agents, neuronal enzyme inhibitors and neuroprotective agents. Molecules, 22(10):1644, doi:10.3390/molecules22101644The original publication is available at http://www.mdpi.comENGLISH ABSTRACT: A medium-throughput screen using Mycobacterium tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. In this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at 50 µM. This prompted further exploration of all the 7-substituted coumarins in our library. Four compounds showed promising MIC99 values of 8.31–29.70 µM and 44.15–57.17 µM on M. tuberculosis H37Rv in independent assays using GAST-Fe and 7H9+OADC media, respectively. These compounds were found to bind to albumin, which may explain the variations in MIC between the two assays. Preliminary data showed that they were able to maintain their activity in fluoroquinolone resistant mycobacteria. Structure-activity relationships indicated that structural modification on position 4 and/or 7 of the coumarin scaffold could direct the selectivity towards either the inhibition of neuronal enzymes or the antimycobacterial effect. Moderate cytotoxicities were observed for these compounds and slight selectivity towards mycobacteria was indicated. Further neuroprotective assays showed significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and neuroprotective agents.http://www.mdpi.com/1420-3049/22/10/1644Publisher's versio