title: Progesterone antagonist therapy in a Pelizaeus-Merzbacher mouse model.
abstract: Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disease, characterized by ataxia, intellectual disability, epilepsy, and premature death. In the majority of cases, PMD is caused by duplication of PLP1 that is expressed in myelinating oligodendrocytes. Despite detailed knowledge of PLP1, there is presently no curative therapy for PMD. We used a Plp1 transgenic PMD mouse model to test the therapeutic effect of Lonaprisan, an antagonist of the nuclear progesterone receptor, in lowering Plp1 mRNA overexpression. We applied placebo-controlled Lonaprisan therapy to PMD mice for 10 weeks and performed the grid slip analysis to assess the clinical phenotype. Additionally, mRNA expression and protein accumulation as well as histological analysis of the central nervous system were performed. Although Plp1 mRNA levels are increased 1.8-fold in PMD mice compared to wild-type controls, daily Lonaprisan treatment reduced overexpression at the RNA level to about 1.5-fold, which was sufficient to significantly improve the poor motor phenotype. Electron microscopy confirmed a 25% increase in the number of myelinated axons in the corticospinal tract when compared to untreated PMD mice. Microarray analysis revealed the upregulation of proapoptotic genes in PMD mice that could be partially rescued by Lonaprisan treatment, which also reduced microgliosis, astrogliosis, and lymphocyte infiltration.
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prukop
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Dirk B
authors.initials: DB
authors.lastname: Epplen
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Nientiedt
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University München, 80336 München, Germany.
authors.forename: Sven P
authors.initials: SP
authors.lastname: Wichert
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Fledrich
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany; Institute of Neuropathology, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Stassart
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University München, 80336 München, Germany.
authors.forename: Moritz J
authors.initials: MJ
authors.lastname: Rossner
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Edgar
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Hauke B
authors.initials: HB
authors.lastname: Werner
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, 37075 Göttingen, Germany; Clinic of Clinical Neurophysiology, University Medical Center Göttingen, 37075 Göttingen, Germany. Electronic address: sereda@em.mpg.de.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004963:Estrenes / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D006727:Hormone Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000235:genetics; D020371:Pelizaeus-Merzbacher Disease / Q000188:drug therapy*; D010641:Phenotype; D011374:Progesterone / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D005466:Fluorocarbons
chemical_list: D004963:Estrenes; D006727:Hormone Antagonists; D018991:Myelin Proteolipid Protein; D011374:Progesterone; D012333:RNA, Messenger; C047516:Plp1 protein, mouse; C419162:lonaprisan; D005466:Fluorocarbons