Olesoxime accelerates myelination and promotes repair in models of demyelination
Karine Magalon MSc
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorCeline Zimmer PhD
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorMyriam Cayre PhD
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorJoseph Khaldi MSc
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorClarisse Bourbon MSc
Biological and Medical Magnetic Resonance Center, French National Center for Scientific Research Joint Research Unit n° 6612, Faculty of Medicine, Universite de la Mediterranee
Search for more papers by this authorIsabelle Robles MSc
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorGwenaëlle Tardif MSc
Trophos SA, Luminy Biotech Enterprises, Marseille, France
Search for more papers by this authorAngèle Viola PhD
Biological and Medical Magnetic Resonance Center, French National Center for Scientific Research Joint Research Unit n° 6612, Faculty of Medicine, Universite de la Mediterranee
Search for more papers by this authorRebecca M. Pruss PhD
Trophos SA, Luminy Biotech Enterprises, Marseille, France
Search for more papers by this authorThierry Bordet PhD
Trophos SA, Luminy Biotech Enterprises, Marseille, France
Search for more papers by this authorCorresponding Author
Pascale Durbec PhD
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
IBDML, Parc Scientifique de Luminy, avenue de Luminy, case 907, 13288 Marseille cedex 9, FranceSearch for more papers by this authorKarine Magalon MSc
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorCeline Zimmer PhD
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorMyriam Cayre PhD
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorJoseph Khaldi MSc
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorClarisse Bourbon MSc
Biological and Medical Magnetic Resonance Center, French National Center for Scientific Research Joint Research Unit n° 6612, Faculty of Medicine, Universite de la Mediterranee
Search for more papers by this authorIsabelle Robles MSc
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
Search for more papers by this authorGwenaëlle Tardif MSc
Trophos SA, Luminy Biotech Enterprises, Marseille, France
Search for more papers by this authorAngèle Viola PhD
Biological and Medical Magnetic Resonance Center, French National Center for Scientific Research Joint Research Unit n° 6612, Faculty of Medicine, Universite de la Mediterranee
Search for more papers by this authorRebecca M. Pruss PhD
Trophos SA, Luminy Biotech Enterprises, Marseille, France
Search for more papers by this authorThierry Bordet PhD
Trophos SA, Luminy Biotech Enterprises, Marseille, France
Search for more papers by this authorCorresponding Author
Pascale Durbec PhD
Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit n° 6216, Universite de la Mediterranee
IBDML, Parc Scientifique de Luminy, avenue de Luminy, case 907, 13288 Marseille cedex 9, FranceSearch for more papers by this authorAbstract
Objective:
Multiple sclerosis is a neurodegenerative disease characterized by episodes of immune attack of oligodendrocytes leading to demyelination and progressive functional deficit. One therapeutic strategy to address disease progression could consist in stimulating the spontaneous regenerative process observed in some patients. Myelin regeneration requires endogenous oligodendrocyte progenitor migration and activation of the myelination program at the lesion site. In this study, we have tested the ability of olesoxime, a neuroprotective and neuroregenerative agent, to promote remyelination in the rodent central nervous system in vivo.
Methods:
The effect of olesoxime on oligodendrocyte progenitor cell (OPC) differentiation and myelin synthesis was tested directly in organotypic slice cultures and OPC–neuron cocultures. Using naive animals and different mouse models of demyelination, we morphologically and functionally assessed the effect of the compound on myelination in vivo.
Results:
Olesoxime accelerated oligodendrocyte maturation and enhanced myelination in vitro and in vivo in naive animals during development and also in the adult brain without affecting oligodendrocyte survival or proliferation. In mouse models of demyelination and remyelination, olesoxime favored the repair process, promoting myelin formation with consequent functional improvement.
Interpretation:
Our observations support the strategy of promoting oligodendrocyte maturation and myelin synthesis to enhance myelin repair and functional recovery. We also provide proof of concept that olesoxime could be useful for the treatment of demyelinating diseases. ANN NEUROL 2012;71:213–226
Supporting Information
Additional supporting information can be found in the online version of this article.
| Filename | Description |
|---|---|
| ANA_22593_sm_SuppFig1.tif6 MB | Supplementary Fig S1. Time-course of myelination in neonatal mouse forebrain slices. (A) Coronal brain slices from P2 mice were cultured for 1, 2, 3, 4, 7, 10 days in vitro (div) then immunostained with anti-MBP (green) and with anti-NF (red) antibodies. The presence of the first myelinated bundles was seen in the deepest layer of the cingulate cortex and the cingulum at 4 div, region denoted by dotted boxes. Myelination process was more extensive at 10 div. Scale bar: 50 μm. (B) Higher magnification images represent the boxed region in the upper panel in A. At 1 to 3 div we observed a progressive increase of the number of MBP-positive cells. By 4 div many axons were myelinated in the cingulate cortex then from 7 to 10 div myelination spread to the entire corpus callosum and cortex. Scale bar: 25 μm. |
| ANA_22593_sm_SuppFig2.tif854.3 KB | Supplementary Fig S2. Schematic representation of the experimental protocol in healthy (A) neonate or (B) adult animals. (n) Number of animals treated in each case. Animals were sacrificed at different time points for immunohistological (Histo) or electron microscopy (EM) analysis. |
| ANA_22593_sm_SuppFig3.tif259.3 KB | Supplementary Fig S3. Schematic representation of the experimental protocol in mouse models of demyelination. (A-B) LPC or (C) cuprizone models. Animals were sacrificed at different time points for immunohistological (Histo) or electron microscopy (EM) analysis. In B the same animals were analyzed at both time points by MRI. (n) Number of animals treated in each case. |
| ANA_22593_sm_SuppFig4.tif3.4 MB | Supplementary Fig S4. Typical axial T2-weighted MRI of vehicle-treated or olesoxime-treated mice injected with LPC. BI, before LPC injection; W1, 7 days after LPC injection; W2, 14 days after LPC injection. Arrows point at the lesion induced by LPC in the corpus callosum. |
| ANA_22593_sm_SuppTab1.doc30.5 KB | Supplementary Table S1. Effect of olesoxime on OPC survival and proliferation in organotypic slice culture. Brain sections were maintained in the presence of olesoxime for 4 days (as described in figure 1) and BrdU was added to the culture media 12h before fixation. Caspase analysis was performed at the same time point. Values shown are means ± SEM (n=3). There was no statistically significant effect of olesoxime on cell survival or proliferation in this in vitro system. |
| ANA_22593_sm_SuppTab2.doc30 KB | Supplementary Table S2. Effect of olesoxime on cell survival and proliferation in newborn mice. Neonatal mice were fed for 2 weeks with olesoxime and injected with BrdU 24 hours before sacrifice. The number of proliferating OPCs in the corpus callosum remained unchanged and in addition, there was no difference in the number of apoptotic cells. Values shown are means ± SEM (n=5). There was no statistically significant effect of olesoxime on cell survival or proliferation in vivo during development. |
| ANA_22593_sm_SuppTab3.doc31 KB | Supplementary Table S3. Effect of olesoxime on cell survival and proliferation in adult mice. Adult mice were treated for 2 weeks with olesoxime and BrdU was administrated in drinking water for the last 5 days before sacrifice. We quantified cycling cells in the SVZ (PH3+ cells), BrdU+ cells and apoptotic caspase3+ cells in the corpus callosum and found no differences in olesoxime-treated animals compared to controls. Values shown are means ± SEM (n=3). There was no statistically significant effect of olesoxime on cell survival or proliferation. |
| ANA_22593_sm_SuppTab4.doc30.5 KB | Supplementary Table S4. Effect of olesoxime on cell survival and proliferation in the LPC mouse model. We quantified 7 days after LPC injection, cycling progenitors (PH3+/PDGFRa+ cells) and dying cells (Caspase3+ cells) at the lesion site and proliferating progenitors within the SVZ (PH3+ cells). We found no differences in olesoxime-treated animals compared to controls at the two doses. Values shown are means ± SEM (n=3). |
| ANA_22593_sm_SuppTab5.doc30.5 KB | Supporting Information Table 5. Supplementary Table S5. Effect of olesoxime on cell proliferation in the cuprizone mouse model. We quantified cycling cells in demyelinated the CC (PH3+ cells) and found no differences in olesoxime-treated animals compared to controls at the W5 and W7. We observed a 37% but non-significant increase in the number of proliferating cells in the corpus callosum of olesoxime treated animals. This effect in proliferation is not observed anymore at W7. This result could indicate that olesoxime has a transient effect on progenitor proliferation leading to a transient increase in the number of Olig2+cells in the CC of treated animal. Values shown are means ± SEM (n=4 at W5 and n=3 at W7). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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