The effect of dopamine and its agonist pramipexole on oligodendrocytes in culture and in the cuprizone mouse model

The effect of dopamine and its agonist pramipexole on oligodendrocytes in culture and in the cuprizone mouse model

Richter, Johann Sebastian

Dissertation

Angenommen am: 2014-02-18

Erschienen: 2014-02-10

Betreuer: Stadelmann-Nessler, Christine Prof. Dr.

Gutachter: Liebetanz, David Prof. Dr.

Gutachter: Oppermann, Martin Prof. Dr.

Zum Verlinken/Zitieren: http://hdl.handle.net/11858/00-1735-0000-0022-5E1D-2

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Zusammenfassung

Englisch

Oligodendrocytes are of crucial importance for the integrity and function of the central nervous system (CNS) as well as for efficacy of signal conduction and thus for brain function itself. They are responsible for axonal integrity in the CNS (Nave and Trapp 2008) and a target for pathological changes in diseases of myelin, such as multiple sclerosis (MS), the most common chronic neurological disorder in western societies (Hafler et al. 2005). Receptors of the catecholamine neurotransmitter Dopamine (DA) have been reported to exert neuroprotective function (Bongarzone et al. 1998, Missale et al. 1998). The DA agonist pramipexole, in addition to having direct antioxidative effects (Le et al. 2000, Zou et al. 1999), is known to stimulate these receptor-mediated neuroprotective effects (Ling et al. 1999). This study addresses the protective effects of pramipexole in cell cultures of the OLN-93 cell-line and primary oligodendrocytes in mixed glial cultures as well as in the cuprizone mouse model for central demyelination. It furthermore analyzes receptor-mediated influence on demyelination and remyelination in the cuprizone model by use of D2- and D3-receptor- deficient mice (D2-/-, D3-/-). Both OLN-93 cells and oligodendrocytes in primary mixed glial cell cultures were morphologically preserved when treated with pramipexole before being exposed to oxidative stress. There was, however, no significant difference in survival of pramipexole-treated OLN-93 cells in the MTT-assay. There was no difference in de- and remyelination or oligodendrocyte differentiation in D2-/- animals compared to the wildtype. Demyelination in D3-/- mice was not different from that in the wildtype. However, remyelination was less efficient in D3-/- mice. Treatment with pramipexole did not influence the extent of remyelination. Less oligodendrocyte precursor cells were observed in pramipexole treated wiltypes but not in D3-/- mice, suggesting a receptor-mediated effect. This work constitutes the first study to approach the role of the DA system in the cuprizone mouse model. It shows that pramipexole partially rescues oligodendrocytic cells from oxidative stress. While the lack of D2- and D3-receptors does not influence demyelination, remyelination is hampered in D3-/- mice. However, pramipexole-treatment does not alter the extent of de- and remyelination in cuprizone-treated mice, although it leads to a decrease in the number of oligodendrocyte precursor cells.

Keywords: Dopamine; Cuprizone; Demyelination; Remyelination; Pramipexole; Dopamine agonists; Dopamine receptors