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Expression von Rezeptoren und Abbauenzymen des Endocannabinoidsystems in primären Zellen des ZNS als mögliche pharmakologische Zielproteine zur Behandlung neurodegenerativer Erkrankungen
No full textNeurodegenerative Erkrankungen wie Morbus Alzheimer, Morbus Parkinson, Multiple Sklerose, Amyotrophe Lateralsklerose oder Chorea Huntington stellen weltweit eine Herausforderung für die Gesundheitssysteme dar. Kausale Therapiemöglichkeiten, den Krankheitsprogress zu verhindern oder zu verlangsamen, fehlen weitgehend und den Patienten bleiben oftmals nur symptomatische Behandlungsmöglichkeiten. Es besteht somit die dringende Notwendigkeit, Therapiemöglichkeiten zu entwickeln, welche gezielt ins Krankheitsgeschehen eingreifen und den Verlauf der Erkrankungen mildern können.
Das Endocannabinoidsystem (ECS) stellt in dieser Hinsicht einen besonders interessanten Ansatzpunkt dar, da es maßgeblich entscheidende pathologischen Prozesse neurodegenerativer Erkrankungen wie Exzitotoxizität und Neuroinflammation beeinflussen kann. Das ECS besteht aus den Endocannabinoiden, den zugehörigen Rezeptoren und den für Auf- und Abbau verantwortlichen Enzymen. Vielversprechende pharmakologische Zielstrukturen sind die Cannabinoid-Rezeptoren 1 (CB1) und 2 (CB2) und die Abbauenzyme Monoacylglycerol Lipase (MAGL) und Fettsäureamid Hydrolase (FAAH).
In dieser Studie wurden diese vier Proteine in primären Neuronen, Astrozyten, Oligodendrozyten und Mikroglia untersucht, um so Rückschlüsse auf die Funktion und die Effekte möglicher pharmakologischer Interventionen an diesen Zielstrukturen zu ziehen. Dabei konnte bestätigt werden, dass CB2 primär von Mikroglia exprimiert wird und somit CB2-Agonisten vermutlich vorwiegend antiinflammatorisch wirken. Zudem konnte gezeigt werden, dass die Abbauenzyme MAGL und FAAH vor allem in Astrozyten exprimiert werden und diese anscheinend eine ganz wesentliche Rolle in der Regulierung der Endocannabinoid-Spiegel spielen
Investigation of monoacyglycerol lipase inhibition for disease modification in animal models of Parkinson’s disease: behavioural, neurochemical and histological investigations as well as biomarker evaluation
No full textParkinson’s disease (PD) is characterized by the selective and progressive loss of dopaminergic neurons. Neuroinflammatory processes including activated microglia might be involved in the pathogenesis. Indeed, the presence of an active inflammatory state in PD is established in patients as well as in animal models of the disease. Targeting the endocannabinoid (eCB) system, including cannabinoid receptors, endocannabinoids and its metabolising enzymes, may have beneficial and neuroprotective effects in various neurological diseases. Alterations in the endocannabinoid system have been observed in neurodegenerative diseases, including PD, and it is assumed that these changes represent an endogenous defence mechanism. One strategy might be to amplify these disease-related, compensatory changes in the endocannabinoid system through the inhibition of MAGL. Monoacylglycerol lipase (MAGL) is the principal enzyme hydrolysing the neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoyglycerol (2 AG) into arachidonic acid (AA) and glycerol, thereby terminating 2 AG signalling. The MAGL produced AA is the precursor for pro-inflammatory, cyclooxygenase (COX)-derived prostaglandins in the brain. Inhibition of MAGL might therefore be a promising therapeutic tool to achieve neuroprotection at sites where endocannabinoid production is present.
In this study, the concept of MAGL inhibition as a therapeutic option for neurodegenerative diseases was investigated in a pre-clinical animal model of PD. To select a suitable compound for the treatment study, several in vivo experiments for the profiling of available tool compounds with regards to the pharmacodynamic/pharmacokinetic (PD/PK)-relationship and tolerability were performed, including the development of an analytical method to assess biomarker changes. The anti-inflammatory and neuroprotective properties of MAGL inhibition were then investigated in a peripheral LPS and an intrastriatal 6 hydroxydopamine (OHDA) mouse model of PD. Additionally, the underlying mechanism of KML29 was investigated and compared with the effects of selective COX inhibition.
A sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of essential biomarkers (endocannabinoids, prostaglandins and arachidonic acid) and drug exposure in biological matrices was developed and validated. The method was shown to be linear, accurate and precise.
The value and applicability of the assay for the simultaneous profiling and quantification of this broad range of analytes was proven in several experiments supporting the early pre-clinical stages in drug development. Although differing in their compound-specific characteristics, the analyzed MAGL inhibitors showed a good exposure to the central nervous systems (CNS) in mice. The expected elevation of mouse brain 2-AG and subsequent decrease of arachidonic acid and prostaglandins were observed upon treatment with the tool compounds, demonstrating a successful target engagement in vivo. Especially KML29 showed a sufficient combination of selectivity, potency and suitable PK/PD profile for the use as a tool to explore the efficacy in vivo. Overall, the highly selective MAGL inhibitors KML29, MJN110 and RMI1 displayed a good tolerability with no or only mild cannabinoid behavioural effects. The potential of MAGL inhibition as an anti-inflammatory strategy was shown by the reduction of pro-inflammatory mediators in the brain following a systemic lipopolysaccharide (LPS) challenge.
We demonstrated that the eCB system is dysregulated in the 6-OHDA mouse model of PD and that these changes are accompanied by pro-inflammatory processes. The results of this study supplement aspects of the neurodegenerative process in the 6-OHDA mouse model. Based on the results of the pre-studies, the treatment study to investigate the effect of MAGL inhibition in comparison to COX2 inhibition was designed. KML29 significantly reduced the nigral neuron loss by 50%. The effects of COX2 inhibition were less pronounced in comparison to MAGL inhibition. MAGL inhibition increased 2 AG levels and decreased AA, prostaglandins and pro-inflammatory cytokines in the brain. Additionally, MAGL inhibition attenuated the 6 OHDA-induced glial cell line-derived neurotrophic factor (GDNF) decrease and elevated the brain-derived neurotrophic factor (BDNF) expression. COX2 inhibition reduced pro-inflammatory cytokines without affecting BDNF
Investigation of motor and olfactory dysfunction in genetic and non-genetic animal models of Parkinson’s disease: implications for translational research in medicine
No full textParkinson’s disease (PD) is a progressive neurodegenerative disorder which manifests with a broad range of symptoms including motor and non-motor disturbances. The development of neuroprotective and disease-modifying drugs requires the presence of reliable biomarkers to monitor disease progression and to identify potential treatment effects. Furthermore, reliable animal models of PD recapitulating the human disease condition with high validity are urgently needed.
Based on pharmacokinetic, neurochemical and behavioural observations, the symptomatic PD models of haloperidol-induced catalepsy in rats and reserpine-induced akinesia in mice have been modified. Interventions such as changing the route of administration of haloperidol as well as decreasing the dose of reserpine, reducing the latency time after reserpine injection and lowering the portion of acetic acid in the reserpine vehicle solution resulted in animal models of high predictive and face validity as well as enhanced animal welfare.
The concept of continuous dopaminergic stimulation (CDS) was evaluated in the haloperidol-induced catalepsy as well as reserpine-induced akinesia model in rats. It has been shown that continuous dopamine (DA) receptor stimulation using pramipexole (PPX) offered a clear therapeutic benefit compared to acute PPX treatment regarding early morning akinesia. The behavioural effects corresponded to in vivo microdialysis measurements in the striatum of rats showing a continuous decrease of extracellular DA levels and a constant PPX exposure following continuous PPX release.
Amantadine is the most commonly used drug to alleviate L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in PD patients. Amantadine was investigated in the L-DOPA-induced dyskinesia as well as haloperidol-induced catalepsy model in rats. It has been demonstrated that high cerebrospinal fluid (CSF) levels of amantadine in a µmolar range were necessary to achieve antidyskinetic and anticataleptic efficacy in rats. This high CSF exposure in rats translated well into clinically effective CSF levels, highlighting the importance to combine CSF exposure measurements and behavioural observations to better bridge the gap between preclinical and clinical effects of amantadine.
Olfactory dysfunction, one of the first non-motor symptoms of PD, was evaluated as an early biomarker in a genetic adeno-associated virus (AAV)-based rat model of PD. It has been shown that AAV-mediated overexpression of human wild-type α-synuclein (α-syn) in the bulbus olfactorius (BO) of rats led to olfactory disturbances, measured by the buried food pellet test, which were detectable three weeks after viral vector injection and persisted at nine weeks. Moreover, α-syn was transported to deeper located brain regions resulting in striatal DA depletion 11 weeks after viral vector injection. These findings underpin the important role of olfactory dysfunction to be a premotor biomarker which reflects PD pathogenesis at early stages of the disease and can be used to follow PD progression.
γ-aminobutyric acid (GABA), glutamate as well as glycine are important amino acid neurotransmitters and their measurement in CSF and brain microdialysis samples is of great interest to neuropharmacological and biomarker studies, making an accurate, precise and fast quantification essential. A rapid and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of GABA and glutamate in brain microdialysates. The method provided high sensitivity and selectivity, no sample pre-treatment and a short running time of 3 min. A limit of quantitation (LOQ) of 1 nmol/l for GABA and 10 nmol/l for glutamate was achieved, which was sensitive to quantify extracellular levels of GABA and glutamate in microdialysis samples of the globus pallidus (GP). Another fast and reliable LC-MS/MS method was established for the quantification of glycine in CSF and brain microdialysis samples. This novel method showed similar advantages such as no sample pre-treatment and a short running time. The procedure achieved a LOQ of 100 nmol/l, which was sensitive for the quantification of glycine in CSF samples and brain microdialysates.
In conclusion, the present work demonstrates the face and predictive validity of PD animal models investigating symptoms such as catalepsy, akinesia or dyskinesia and evaluating PPX and amantadine as antiparkinsonian and antidyskinetic drugs. The AAV-α-syn-overexpression model recapitulating olfactory dysfunction as a premotor biomarker for progressive PD may provide a valuable tool for screening neuroprotective and disease-modifying therapies in the early premotor phase of PD. In order to support biomarker studies investigating GABA, glutamate and glycine, the rapid and sensitive LC-MS/MS methods can be used for the quantification of these compounds in brain microdialysis and CSF samples
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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