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Home - 03.10.2013 - Repairing mechanisms

Repairing mechanisms

Thursday, October 03, 2013, 15:45 - 17:00

Increased remyelination with oestrogen receptor beta ligand (KB3944) treatment in the cuprizone demyelination mouse model of multiple sclerosis

D. Ichwan, D. Nguyen, V. Yu, L. Martinez, A. Khalaj, P. Fagergren, M. Österlund, S. Tiwari-Woodruff (Los Angeles, US; Huddinge, SE)

Estrogen receptor (ER) beta agonist treatment has been shown to elicit remyelination and neuroprotective responses without being antiinflammatory in an animal model, experimental autoimmune encephalomyelitis (EAE), of multiple sclerosis (MS). It is not yet known whether the effect of an ERbeta ligand inhibits demyelination or facilitates remyelination. Because EAE has ongoing demyelination in the presence of some remyelination and ongoing inflammation, it is extremely difficult to dissect out the potential action of an ERbeta ligand on demyelination or remyelination during EAE. In this report, we made an attempt to dissect out the protective role of an ERbeta ligand on demyelination and remyelination using the cuprizone diet model. The selective ERbeta agonist KB3944, tool compound diarylpropionitrile; DPN, and vehicle were given to separate groups of 8 week old female C57Bl/6 mice either during predominantly demyelinating events (3 week cuprizone diet) or predominantly remyelinating events (3 week cuprizone followed by 3 week normal diet). KB3944 treatment during demyelination and remyelination showed a small but significant difference in callosal conduction as compared to vehicle treated groups. Immunohistochemical analysis of myelin proteins revealed no differences between treated and untreated demyelinating groups but a significant improvement in ERbeta ligand treated remyelinating group was observed by an increase in myelin staining intensity in the corpus callosum, hippocampus and cortical layers. Furthermore, an increase in oligodendrocyte progenitor cells (OPCs) and a decrease in microglia and astrocytes during demyelination were observed in the corpus callosum of KB3944 treated remyelination group. In addition to the positive effects on remyelination observed in vivo, KB3944 was also shown to increase proliferation of OPCs and the differentiation into mature oligodendrocytes in primary co-cultures of central neurons-OPCs-oligodendrocytes from rat fetal forebrains. Our results show that KB3944 treatment has significant beneficial effects during remyelinating events. This is an important finding as normal endogenous remyelination in MS can be enhanced and maintained by ERbeta ligand treatment.

The study was funded by Karo Bio AB Daniel Ichwan (nothing to disclose) Duc Nguyen (nothing to disclose) Vincent Yu (nothing to disclose) Leonardo Martinez (nothing to disclose) Anna Khalaj (nothing to disclose) Pernilla Fagergren (full-time employee at Karo Bio AB) Marie Österlund (full-time employee at Karo Bio AB) Seema Tiwari-Woodruff (nothing to disclose)