| dc.contributor.advisor | Lingor, Paul Prof. Dr. | |
| dc.contributor.author | Günther, René | |
| dc.date.accessioned | 2015-06-12T09:53:21Z | |
| dc.date.available | 2015-06-30T22:50:05Z | |
| dc.date.issued | 2015-06-12 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0022-601B-7 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5125 | |
| dc.language.iso | deu | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | de |
| dc.title | Pharmakologische Inhibition von Rho-Kinase im Mausmodell der Amyotrophen Lateralsklerose | de |
| dc.type | doctoralThesis | de |
| dc.title.translated | Pharmacological inhibition of Rho-kinase in the mouse model of amyotrophic lateral sclerosis | de |
| dc.contributor.referee | Lingor, Paul Prof. Dr. | |
| dc.date.examination | 2015-06-23 | |
| dc.description.abstracteng | Since the development of Riluzol no substance, which had been successfully tested in a preclinical setting before, has been able to be successful as a disease modifying drug in human ALS although there has been enormous growth of scientific knowledge in ALS pathogenesis (Aggarwal and Cudkowicz 2008). With a life-prolonging effect of only two to three months Riluzole is not a sufficient therapeutic option in this fatal neurodegenerative disease. Research and establishment of new therapeutic strategies based on the pathophysiological changes are urgently needed. A promising therapy strategy represents the inhibition of Rho-kinase. It is one of the most important signaling pathways concerning stimulation of regenerative processes and increase of cell survival in neuronal tissue. In animal models of the neurodegenerative diseases SMA, Huntington's disease and Parkinson's disease, the ROCK inhibitor Fasudil and Y-27632 were already successfully tested. The aim of this study was to investigate inhibition of Rho-kinase cascade in the mouse model of ALS (SOD1-G93A). In a previous presymptomatic study with oral treatment of Fasudil an increased survival time and an improvement of motor performance was detected. In a histopathological cross-sectional study of presymptomatic Fasudil-treated animals mild neuroprotective effects were detected at the level of motoneurons, but no influence on degenerative changes in the peripheral nervous system could be observed. Presymptomatic treatment with Y-27632, another ROCK inhibitor with more specificity for the ROCK II isoform, resulted in a mild improvement of motor performance. Similarly, in a symptomatic treatment study with Fasudil an enhanced motor function was observed. However, compared to the presymptomatic study with Fasudil an increase of survival time was not observed in the presymptomatic Y-27632 treatment and symptomatic Fasudil treatment groups. In summary, best results were achieved with Fasudil in the presymptomatic treatment approach. Similarly strong results could not be reproduced after initiation of treatment in a later stage. Despite improved motor efficiencies, the ROCK inhibitor Y-27632 could not achieve a beneficial effect on the disease progress in the SOD1-G93A mouse model. However, the effects in the ALS mouse model could nevertheless positively be reinforced in humans by a comparatively longer duration of drug application. More histological investigations in the cross-sectional study with Fasudil could prove a strong modulation of glial cells and enhanced regenerative processes at the level of the neuromuscular junctions. In conjunction with in vitro experiments on microglia and motoneuron cell cultures, a strong modulation of microglia and neuroprotection of motor neurons was found as a neurobiological explanation for the clinical improvement in the Fasudil-treatment study in the SOD1-G93A mouse model (Tönges et al. 2014). The ROCK inhibition therapy strategy, especially with Fasudil, therefore represents a promising therapeutic option in the treatment of amyotrophic lateral sclerosis. | de |
| dc.contributor.coReferee | Sereda, Michael Werner Prof. Dr. | |
| dc.subject.eng | Rock inhibition | de |
| dc.subject.eng | Fasudil | de |
| dc.subject.eng | Y-27632 | de |
| dc.subject.eng | SOD1-G93A mouse model | de |
| dc.subject.eng | Amyotrophic lateral sclerosis | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0022-601B-7-3 | |
| dc.affiliation.institute | Medizinische Fakultät | de |
| dc.subject.gokfull | Medizin (PPN619874732) | de |
| dc.subject.gokfull | Neurologie - Allgemein- und Gesamtdarstellungen (PPN619876247) | de |
| dc.description.embargoed | 2015-06-30 | |
| dc.identifier.ppn | 827343272 | |