Tierexperimentelle Behandlungsversuche der Charcot-Marie-Tooth-Erkrankung 1A

Weiss, Bernhard G.

dc.contributor.advisor	Sereda, Michael Werner Prof. Dr.
dc.contributor.author	Weiss, Bernhard G.
dc.date.accessioned	2014-02-27T07:57:51Z
dc.date.available	2014-03-10T23:50:04Z
dc.date.issued	2014-02-27
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0022-5E41-E
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-4385
dc.language.iso	deu	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject.ddc	610	de
dc.title	Tierexperimentelle Behandlungsversuche der Charcot-Marie-Tooth-Erkrankung 1A	de
dc.type	doctoralThesis	de
dc.title.translated	Experimental therapy trials of the Carcot-Marie-Tooth Disease 1A in vivo	de
dc.contributor.referee	Sereda, Michael Werner Prof. Dr.
dc.date.examination	2014-03-03
dc.description.abstracteng	Charcot-Marie-Tooth Disease is the most common inherited demyelinating neuropathy of the peripheral nervous system. The most frequent subform is caused by an intrachromosomal du-plication, leading to toxic overexpression of the PMP22 gene (CMT1A). Transgenic rats overexpressing Pmp22 mimic typical features of the disease (`CMT rats´). Like in humans, a 1.6 fold Pmp22 overexpression leads to progressive demyelination with axonal loss causing distally pronounced muscle atrophy and weakness. Four experimental therapy trials of the Carcot-Marie-Tooth Disease 1A and one pilot experi-ment have been carried out. Treating the CMT rats with Lonaprisan lowered the Pmp22 overexpression and compared to Placebo treated animals the bar- and grip strength test showed an improved motor perform-ance, electrophysiological examinations revealed an increased compound muscle action po-tential, in peripheral nerves a preserved axonnumber and less macrophages were detected and in spinal cord cross sections a prevention of alpha-motoneuron loss could be observed. This implies neuroprotective properties of the progesterone antagonist in CMT1A. With the col-lected biological material a full range of ongoing experiments can be built on this study to lighten the underlying molecular mechanisms of this neuroprotection. With Igfbp5 a bio-marker (diagnostic marker) was established as an additional readout of a clinical trial next to the CMTNS. This marker could monitor the response to a therapy trial. In particular Curcumin has to be accentuated, because also in high dosages no adverse side effects were shown in patients. In the experimental therapy trial the reduced axonal loss im-pressed, compound muscle action potential and nerve conduction velocity were increased. To show also an improvement of the clinical phenotype that is not covered by a delayed gain of weight and thereby to pave the way for a translation to humans, a new experimental therapy trial with the increased bio-available Meriva Curcumin will be proposed. The neuroprotective properties of erythropoietin and the anti-inflammatory acting acetyl-salicylic acid achieved in the CMT rats no beneficial effect. With both substances the dosages, the treatment scheme and in case of acetylsalicylic acid also the choice of the anti-inflammatory substance need to be reconsidered. Promising and at the beginning of further investigation arise the liver x receptor (LXR) agonist T0901317 since it was able to reduce the Pmp22 overexpression. An experimental therapy trial would be the following step, but GW3965, another LXR agonist would be considered since it exhibited to have less adverse side effects on liver metabolism. With Lonaprisan and Curcumin new therapeutics sharing a striking effect on CMT1A have been introduced and need to be considered for a translation into humans.	de
dc.contributor.coReferee	Henneke, Marco PD Dr.
dc.subject.eng	Carcot-Marie-Tooth Disease 1A	de
dc.subject.eng	Peripheral myelin protein 22	de
dc.subject.eng	PMP22	de
dc.subject.eng	experimental therapy trial	de
dc.subject.eng	Curcumin	de
dc.subject.eng	progesterone antagonist	de
dc.subject.eng	CMT rat	de
dc.subject.eng	CMT1A	de
dc.subject.eng	acetylsalicylic acid	de
dc.subject.eng	erythropoietin	de
dc.subject.eng	liver x receptor agonist	de
dc.subject.eng	in vivo	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5E41-E-4
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Medizin (PPN619874732)	de
dc.subject.gokfull	Neurologie - Allgemein- und Gesamtdarstellungen (PPN619876247)	de
dc.description.embargoed	2014-03-10
dc.identifier.ppn	779596323

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