Tyrosine-based rivastigmine-loaded organogels in the treatmant of Alzheimer's disease

Faculté de PharmacieOrganogels can be prepared by immobilizing an organic phase into a threedimensional network coming from the self-assembly of a low molecular weight gelator molecule. In this work, an injectable subcutaneous organogel system based on safflower oil and a modified-tyrosine organogelator was evaluated in vivo for the delivery of rivastigmine, an acetylcholinesterase (AChE) inhibitor used in the treatment of Alzheimer’s disease. Different implant formulations were injected and the plasmatic drug concentration was assayed for up to 35 days. In parallel, the inhibition of AChE in different brain sections and the biocompatibility of the implants were monitored. The pharmacokinetic profiles were found to be influenced by the gel composition, injected dose and volume of the implant. The sustained delivery of rivastigmine was accompanied by a significant prolonged inhibition of AChE in the hippocampus, a brain structure involved in memory. The implant induced only a minimal to mild chronic inflammation and fibrosis, which was comparable to poly(D,L-lactide-co-glycolide) in situ-forming implants. These findings suggest that tyrosine-based organogels could represent an alternative approach to current formulations for the sustained delivery of cholinesterase inhibitors.IRS

Nanonization of megestrol acetate by laser fragmentation in aqueous milieu

Faculté de PharmacieNanonization is a simple and effective method to improve dissolution rate and oral bioavailability of drugs with poor water solubility. There is growing interest to downscale the nanocrystal production to enable early preclinical evaluation of new drug candidates when compound availability is scarce. The purpose of the present study was to investigate laser fragmentation to form nanosuspensions in aqueous solution of the insoluble model drug megestrol acetate (MA) using very little quantities of the drug. Laser fragmentation was obtained by focusing a femtosecond (fs) or nanosecond (ns) laser radiation on a magnetically stirred MA suspension in water or aqueous solution of a stabilizing agent. The size distribution and physicochemical properties of the drug nanoparticles were characterized, and the in vitro dissolution and in vivo oral pharmacokinetics of a laser fragmented formulation were evaluated. A MA nanosuspension was also prepared by media milling for comparison purpose. For both laser radiations, smaller particles were obtained as the laser power was increased, but at a cost of higher degradation. Significant nanonization was achieved after a 30-min fs laser treatment at 250 mW and a 1-h ns laser treatment at 2500 mW. The degradation induced by the laser process of the drug was primarily oxidative in nature. The crystal phase of the drug was maintained, although partial loss of crystallinity was observed. The in vitro dissolution rate and in vivo bioavailability of the laser fragmented formulation were similar to those obtained with the nanosuspension prepared by media milling, and significantly improved compared to the coarse drug powder. It follows that this laser nanonization method has potential to be used for the preclinical evaluation of new drug candidates.IRSC - CRNS

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer’s Disease

SummaryLipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer’s disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer’s disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs

Trace-level quantification of N-nitrosopiperazine in treated wastewater using supported liquid extraction and hydrophilic interaction chromatography mass spectrometry

Regenerable amine-based solvents used for post-combustion CO2 capture, primarily monoethanolamine and piperazine, are known to undergo degradation and secondary reactions over time forming, amongst other species, N-nitrosamines. These carcinogenic species can eventually make their way from treated wastewater into environmental waters. The United States Environmental Protection Agency (US EPA) recommends that the concentration of N-nitrosamines in surface water not exceed 1.24 μg/L. We have developed a straightforward method to quantify N-nitrosopiperazine in treated wastewater by hydrophilic interaction liquid chromatography – mass spectrometry (HILIC–MS) after sample preparation by supported liquid extraction (SLE). To achieve the best extraction recovery and method limits of quantification (MLOQ), standards were prepared in a high-salt synthetic matrix to mimic the treated wastewater effluent. To further improve the MLOQ, the drying steps after extraction were optimized. HILIC separation of the highly polar analytes was achieved using an ethylene-bridged hybrid amide stationary phase. Detection was achieved using a triple quadrupole mass spectrometer operated in positive electrospray ionisation and multiple reaction monitoring mode, providing a final MLOQ of 0.25 μg/L for N-nitrosopiperazine. Validation of the method was carried out to ensure good confidence in the data obtained for a treated wastewater sample from a post-combustion CO2 capture facility. In addition, N-nitrosopiperazine was quantified with the developed SLE-HILIC–MS method in eight degraded carbon capture samples that had not yet undergone wastewater treatment.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

A light-harvesting polyoxometalate-polypyridine hybrid induces electron transfer as its Re(I) complex

A derivative of the Dawson polyoxometalate [P2V3W15O62]9− functionalized with one remote bipyridine coordination site (2) has been synthesized and combined with the neutral {Re(CO)3Br} moiety. The new ReI-hybrid (3) was characterized by various analytical techniques. Hybrid 3 exhibits several redox processes on a wide range of potentials with reductions centered on V(V), W(VI) and the organic ligand in order of decreasing potential. Both units, the polyoxometalate and the transition metal complex, retain their intrinsic properties in the hybrid 3, which displays photosensitization in the UV region with tailing into high-energy visible region

A light-harvesting polyoxometalate-polypyridine hybrid induces electron transfer as its Re(I) complex

A derivative of the Dawson polyoxometalate [P2V3W15O62]9− functionalized with one remote bipyridine coordination site (2) has been synthesized and combined with the neutral {Re(CO)3Br} moiety. The new ReI-hybrid (3) was characterized by various analytical techniques. Hybrid 3 exhibits several redox processes on a wide range of potentials with reductions centered on V(V), W(VI) and the organic ligand in order of decreasing potential. Both units, the polyoxometalate and the transition metal complex, retain their intrinsic properties in the hybrid 3, which displays photosensitization in the UV region with tailing into high-energy visible region

Data from: Does divergent selection predict the evolution of mate preference and reproductive isolation in the tropical butterfly genus Melinaea (Nymphalidae: Ithomiini)?

Many studies have shown that speciation can be facilitated when a trait under divergent selection also causes assortative mating. In Müllerian mimetic butterflies, a change in wing colour pattern can cause reproductive isolation. However, colour pattern divergence does not always lead to reproductive isolation. Understanding how divergent selection affects speciation requires identifying the mechanisms that promote mate preference and/or choosiness. This study addresses whether shifts in wing colour pattern drives mate preference and reproductive isolation in the tropical butterfly genus Melinaea (Nymphalidae: Ithomiini), and focuses on five taxa that form a speciation continuum, from subspecies to fully recognized species. Using genetic markers, wing colour pattern quantification, male pheromone characterization and behavioural assays of mating preference, we characterize the extent of genetic and phenotypic differentiation between taxa and compare it to the level of reproductive isolation. We show strong premating isolation between the closely related species M. satevis and M. marsaeus, in addition to genetic and phenotypic (colour pattern and pheromones) differentiation. By contrast, M. menophilus and M. marsaeus consist of pairs of subspecies that differ for colour pattern but that cannot be differentiated genetically. Pheromonal differentiation of subspecies was significant only for M. marsaeus, although most individuals were indistinguishable. Melinaea menophilus and M. marsaeus also differ in the strength of assortative mating, suggesting that mate preference has evolved only in M. marsaeus, consistent with selection against maladaptive offspring, as subspecific “hybrids” of M. marsaeus have intermediate, non‐mimetic colour patterns, unlike those of M. menophilus which display either parental phenotypes. We conclude that a shift in colour pattern per se is not sufficient for reproductive isolation, but rather, the evolution of assortative mating may be caused by selection against maladaptive intermediate phenotypes. This study suggests that mate preference and assortative mating evolve when adaptive, and that even in the early stages of divergence, reproductive isolation can be nearly complete due to mating preferences