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Analyse de la neurotoxine β-méthylamino-L-alanine (BMAA) et ses isomères dans les lacs et les réservoirs pollués par chromatographie liquide couplée à la spectrométrie de masse haute résolution.Abbes, Safa 07 1900 (has links)
La neurotoxine β-N-méthyl-amino-l-alanine (BMAA) et ses isomères, notamment la N-(2- aminoéthyl glycine) (AEG), la β-amino-N-méthyl alanine (BAMA) et l'acide 2,4- diaminobutyrique (DAB), ont été détectés précédemment dans des échantillons de cyanobactéries. Cependant, il existe des rapports contradictoires concernant leur présence dans les eaux de surface. Dans cette étude, nous avons évalué l'impact de l'acide trichloracétique (TCA 0,1M) sur la détection des isomères de BMAA, par rapport aux protocoles préexistants. Une méthode instrumentale sensible a été utilisée pour l'étude, avec des limites de détection de l'ordre de 5-10 ng L-1. Des meilleures limites de détection plus élevés et des niveaux significativement plus importants (test des rangs signés de Wilcoxon appariés, p < 0,001) d'isomères de BMAA ont été observés dans les échantillons traités par le TCA, avec des augmentations relatives allant jusqu'à +725 % pour l'AEG et +1450 % pour le DAB, et des augmentations de concentration absolue allant jusqu'à +15 000 ng L-1 pour l'AEG et +650 ng L-1 pour le DAB. Nous avons également documenté les tendances de la présence des isomères de BMAA dans plusieurs lacs de différents pays tels que le Brésil, le Canada, la France, le Mexique et le Royaume-Uni. Les données obtenues au cours de cette étude (n = 390 provenant de 45 sites d'échantillonnage) indiquent des détections fréquentes des isomères AEG et DAB, avec des taux de détection de 30 % et 43 % et des niveaux maximums de 19 000 ng L-1 et 1 100 ng L-1, respectivement. En revanche, le BAMA a été trouvé dans moins de 8 % des échantillons d'eau, et la BMAA n'a été trouvée dans aucun échantillon. Ces résultats appuient les analyses des cyanobactéries libres, dans lesquelles la BMAA a souvent été détectée avec des concentrations inférieures de 2 à 4 ordres de grandeur à celles de l'AEG et du DAB. Les mesures saisonnières effectuées dans deux lacs impactés par des efflorescences ont indiqué des corrélations limitées entre les isomères de la BMAA et les microcystines totales ou la chlorophylle-a, ce qui mériterait une étude plus approfondie. / The neurotoxic alkaloid β-N-methyl-amino-l-alanine (BMAA) and related isomers, including N-(2-aminoethyl glycine) (AEG), β-amino-N-methyl alanine (BAMA) and 2,4-diaminobutyric acid (DAB), have been reported previously in cyanobacterial samples. However, there are conflicting reports regarding their occurrence in surface waters. In this study, we evaluated the impact of amending lake water samples with trichloroacetic acid (0.1M TCA) on the detection of BMAA isomers, compared with pre-existing protocols. A sensitive instrumental method was enlisted for the survey, with limits of detection in the range of 5-10 ng L-1. Higher detection limits ans significantly greater levels (paired Wilcoxon’s signed-rank tests, p < 0.001) of BMAA isomers were observed TCA-amended samples (method B) compared to samples without TCA (method A). The overall range of B/A ratios was 0.67-8.25 for AEG (up to +725 %) and 0.69-15.5 for DAB (up to +1450 %), with absolute concentration increases TCA-amended samples up to +15,000 ng L-1 for AEG and +650 ng L-1 for DAB. We also documented the trends in the occurrence of BMAA isomers for a large breadth of field-collected lakes from Brazil, Canada, France, Mexico, and the United Kingdom. Data gathered during this overarching campaign (overall n = 390 within 45 lake sampling sites) indicate frequent detections of AEG and DAB isomers, with detection rates of 30 % and 43 % and maximum levels of 19,000 ng L-1 and 1,100 ng L- 1, respectively. In contrast, BAMA was found in less than 8 % of the water samples, and BMAA not found in any sample. These results support analyses of free-living cyanobacteria, wherein BMAA was often reported at concentrations 2-4 orders of magnitude lower than AEG and DAB. Seasonal measurements conducted at two bloom-impacted lakes indicated limited correlations of BMAA isomers with total microcystins or chlorophyll-a, which deserves further investigation.
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NeurotoxinsKostrzewa, Richard M. 01 January 2016 (has links)
The era of selective neurotoxins arose predominately in the 1960s with the discovery of the norepinephrine (NE) isomer 6-hydroxydopamine (6-OHDA), which selectively destroyed noradrenergic sympathetic nerves in rats. A series of similarly selective neurotoxins were later discovered, having high affinity for the transporter site on nerves and thus being accumulated and able to disrupt vital intraneuronal processes, to lead to cell death. The Trojan Horse botulinum neurotoxins (BoNT) and tetanus toxin bind to glycoproteins on the neuronal plasma membrane, then these stealth neurotoxins are taken inside respective cholinergic or glycinergic nerves, producing months-long functional inactivation but without overtly destroying those nerves. The mitochondrial complex I inhibitor rotenone, while lacking total specificity, still destroys dopaminergic nerves with some selectivity; and importantly, results in the neural accumulation of synuclein-to model Parkinson’s disease (PD) in animals. Other neurotoxins target specific subtypes of glutamate receptors and produce excitotoxicity in nerves with that receptor population. The dopamine D2 receptor agonist quinpirole, termed a selective neurotoxin, produces a behavioral state replicating some of the notable features of schizophrenia, but without overtly destroying nerves. These processes, mechanisms or treatment-outcomes account for the means by which neurotoxins are classified as such, and represent some of the means by which neurotoxins as a group are able to destroy or functionally inactivate nerves; or replicate an altered neurological state. Selective neurotoxins have proven to be important in gaining insight into biochemical processes and mechanisms responsible for survival or demise of a nerve. Selective neurotoxins are useful also for animal modeling of human neural disorders such as PD, Alzheimer disease, attention-deficit hyperactivity disorder (ADHD), Lesch-Nyhan disease, tardive dyskinesia, schizophrenia and others. The importance of neurotoxins in neuroscience will continue to be ever more important as even newer neurotoxins are discovered.
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Survey of Selective NeurotoxinsKostrzewa, Richard M. 01 January 2014 (has links)
There has been an awareness of nerve poisons from ancient times. At the dawn of the twentieth century, the actions and mechanisms of these poisons were uncovered by modern physiological and biochemical experimentation. However, the era of selective neurotoxins began with the pioneering studies of R. Levi-Montalcini through her studies of the neurotrophin "nerve growth factor" (NGF), a protein promoting growth and development of sensory and sympathetic noradrenergic nerves. An antibody to NGF, namely, anti-NGF - developed in the 1950s in a collaboration with S. Cohen - was shown to produce an "immunosympathectomy" and virtual lifelong sympathetic denervation. These Nobel Laureates thus developed and characterized the first identifiable selective neurotoxin. Other selective neurotoxins were soon discovered, and the compendium of selective neurotoxins continues to grow, so that today there are numerous selective neurotoxins, with the potential to destroy or produce dysfunction of a variety of phenotypic nerves. Selective neurotoxins are of value because of their ability to selectively destroy or disable a common group of nerves possessing (1) a particular neural transporter, (2) a unique set of enzymes or vesicular transporter, (3) a specific type of receptor or (4) membranous protein, or (5) other uniqueness. The era of selective neurotoxins has developed to such an extent that the very definition of a "selective" neurotoxin has warped. For example, (1) N-methyl-D- aspartate receptor (NMDA-R) antagonists, considered to be neuroprotectants by virtue of their prevention of excitotoxicity from glutamate receptor agonists, actually lead to the demise of populations of neurons with NMDA receptors, when administered during ontogenetic development. The mere lack of natural excitation of this nerve population, consequent to NMDA-R block, sends a message that these nerves are redundant - and an apoptotic cascade is set in motion to eliminate these nerves. (2) The rodenticide rotenone, a global cytotoxin that acts mainly to inhibit complex I in the respiratory transport chain, is now used in low dose over a period of weeks to months to produce relatively selective destruction of substantia nigra dopaminergic nerves and promote alpha-synuclein deposition in brain to thus model Parkinson's disease. Similarly, (3) glial toxins, affecting oligodendrocytes or other satellite cells, can lead to the damage or dysfunction of identifiable groups of neurons. Consequently, these toxins might also be considered as "selective neurotoxins," despite the fact that the targeted cell is nonneuronal. Likewise, (4) the dopamine D2-receptor agonist quinpirole, administered daily for a week or more, leads to development of D2-receptor supersensitivity - exaggerated responses to the D2-receptor agonist, an effect persisting lifelong. Thus, neuroprotectants can become "selective" neurotoxins; nonspecific cytotoxins can become classified as "selective" neurotoxins; and receptor agonists, under defined dosing conditions, can supersensitize and thus be classified as "selective" neurotoxins. More examples will be uncovered as the area of selective neurotoxins expands. The description and characterization of selective neurotoxins, with unmasking of their mechanisms of action, have led to a level of understanding of neuronal activity and reactivity that could not be understood by conventional physiological observations. This chapter will be useful as an introduction to the scope of the field of selective neurotoxins and provide insight for in-depth analysis in later chapters with full descriptions of selective neurotoxins.
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