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- W2737112011 abstract "Major depression is a debilitating and highly prevalent disease that up to now has been treated predominantly with antidepressants that increase the availability of serotonin and/or noradrenaline in the synaptic cleft. High rates of non-responders to first line therapy and high levels of chronicity within patients, however, demonstrate the limits of the monoamine hypothesis of depression. Thus the search for novel, more-rapidly acting and more effective antidepressants has become the focus of much research during the past years. Autophagy, a process whereby cells salvage and recycle cellular macromole-cules or organelles involving dynamic reorganization and fusion of membranous structures in response to stress, has been implicated as playing a role in several diseases, namedly different cancers and neurodegenerative diseases such as Parkinson’s, Huntington’s and Alzheimer’s. It has recently been observed that autophagic markers such as Beclin1 were increased following treatment with serotonin reuptake inhibitors and conversely, a stabilisation of Beclin1 (and therefore autophagic pathways) might lead to an antidepressant-like effect. 24 substances that were found to be inhibitors of the SKP2 E3 ligase via a high throughput screen were tested as potential autophagy inducers and thus novel antidepressants and primary rat astrocytes were treated with them in non-toxic concentrations. Effects on autophagic markers or molecules involved in autophagy such as Beclin1, LC3, and Vps34, as well as the cyclin dependent kinase p27, were investigated via Western Blot. In addition, effects on autophagic flux were determined with Bafilomycin A1 and p62 degradation assays. As a result, I could show that drugs such as Salinomycin, Celecoxibe, Etoposide, Xanthohumol and Perphenazine increased autophagic markers, making them promising candidates for the treatment of major depression. The effects of Salinomycin were further tested on mice subjected to a forced swim test. Here, Salinomycin was found to increase struggling and to decrease the time spent floating, thus exhibiting an antidepressant-like effect. An increase in autophagy seems to harbor a large psychopharmacological potential. Yet it still needs to be seen whether autophagy, the recycling of proteins per se, or the membrane processes kicked off by the initiator complexes underly the antidepressant action. Hence, before proceeding to test the respective substances in clinical trials, further research is needed to expand the range of autophagic markers examined, check the drugs’ blood-brain-barrier crossing potentials, and test the substances in further animal experiments." @default.
- W2737112011 created "2017-07-31" @default.
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- W2737112011 date "2017-03-30" @default.
- W2737112011 modified "2023-09-26" @default.
- W2737112011 title "24 drugs as potential SKP2 Inhibitors" @default.
- W2737112011 hasPublicationYear "2017" @default.
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