Experimentelle Therapie eines Mausmodells für die Pelizaeus-Merzbacher-Erkrankung mit Lonaprisan und Curcumin

by Dirk Benedikt Epplen
Doctoral thesis
Date of Examination:2023-06-08
Date of issue:2023-06-05
Advisor:Prof. Dr. Michael Werner Sereda
Referee:Prof. Dr. Imke Metz
Referee:Prof. Dr. Thomas Meyer
Persistent Address: http://dx.doi.org/10.53846/goediss-9916

 

 

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Abstract

English

Pelizaeus-Merzbacher disease (PMD) is a severe x-linked leukodystrophy caused, in the majority of cases, by a duplication of Plp1 coding for Proteolipid Protein. Using a PMD mouse model carrying additional copies of Plp1 we investigated whether the progesterone antagonist Lonaprisan or curcumin ameliorate the course of the disease. During 10 weeks of placebo-controlled treatment with daily injections of Lonaprisan or curcumin diet motor phenotype was measured followed by mRNA expression and histological analysis of the central nervous system at the end of study. Lonaprisan reduced toxic overexpression of Plp1 mRNA in total brain and improved motor coordination. PMD mice displayed less microgliosis, astrocytosis and lymphocyte infiltration after Lonaprisan treatment. Moreover, Plp1 mRNA expression correlated inversely to the number of myelinated axons and the motor phenotype. Curcumin improved motor performance and preserved myelinated axons in the corticospinal tract of the spinal cord. Curcumin diet reduced the inflammatory response compared to Plp1 placebo controls. Curcumin did not affect increased Plp1 mRNA levels. These results indicate that PMD mice benefitted from Lonaprisan through a reduction of toxic Plp1 mRNA overexpression and the effect of curcumin was independent of Plp1 mRNA expression.
Keywords: Pelizaeus-Merzbacher disease; Lonaprisan; curcumin; myelin
 
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