Contributions
Abstract: EP1513
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 20 Repairing mechanisms
Background: Remyelination occurs in patients with multiple sclerosis (MS), though it often fails or is incomplete. Therapies that favour endogenous oligodendrogenesis and promote remyelination may become attractive neuroprotective strategies for MS patients. In a previous study based on a Connectivity Map approach, we defined a gene expression signature of mature myelinating oligodendrocytes and identified five drugs (perhexiline, deptropine, picrotoxinin, pimozide, valproic acid) with potential to enhance remyelination. Three out of the five drugs (deptropine, pimozide, valproic acid) showed the ability to induce in vitro oligodendrocyte maturation in oligodendrocyte progenitor cells cultures, and were further selected for in vivo validation of their remyelinating potential in two animal models.
Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6J mice with MOG35-55 peptide. At day 12 post-immunization, once the EAE clinical sings were detected, animals were randomized and treated with the compounds for 21 days. A lysolecithin mouse model was induced by injecting lysolecithin in the spinal cord. Animals were randomised and treated for 10 or 24 days. Deptropine, pimozide, valproic acid or vehicle (DMSO) were administered intraperitoneally daily to both mouse models. Spinal cords were removed and sectioned for immunostaining with MBP and Olig2. The demyelinated lesion area was measured and Olig2+ cell density assessed.
Results: Administration of selected compounds in a therapeutic setting did not result in an improvement of the EAE clinical course, which was similar in mice treated with deptropine, pimozide, valproic acid compared with the vehicle group. In the EAE model an autoimmune response against myelin is induced, which could mask a positive effect of the drugs on remyelination. In order to avoid the effect of the immune system, we also tested the selected compounds in a lysolecithin model in which focal demyelination is due to a secondary toxic effect in oligodendrocytes. In the lysolecithin model, we observed that the density of Olig2+ cells was comparable in all groups, albeit showing a tendency to slight increase in animals treated with valproic acid, although statistically not significant.
Conclusions: Although deptropine, pimozide, valproic acid showed good remyelinating capacity in vitro, they failed to enhance remyelination in immune-mediated and toxic-induced demyelination experimental models.
Disclosure: Disclosure of conflict of interest:
CC, HP, HE, CM and CE declare no competing financial interests.
XM has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall.
Founding source: this study has been supported by Fundació Marato the TV3 (493/C/2012).
Abstract: EP1513
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 20 Repairing mechanisms
Background: Remyelination occurs in patients with multiple sclerosis (MS), though it often fails or is incomplete. Therapies that favour endogenous oligodendrogenesis and promote remyelination may become attractive neuroprotective strategies for MS patients. In a previous study based on a Connectivity Map approach, we defined a gene expression signature of mature myelinating oligodendrocytes and identified five drugs (perhexiline, deptropine, picrotoxinin, pimozide, valproic acid) with potential to enhance remyelination. Three out of the five drugs (deptropine, pimozide, valproic acid) showed the ability to induce in vitro oligodendrocyte maturation in oligodendrocyte progenitor cells cultures, and were further selected for in vivo validation of their remyelinating potential in two animal models.
Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6J mice with MOG35-55 peptide. At day 12 post-immunization, once the EAE clinical sings were detected, animals were randomized and treated with the compounds for 21 days. A lysolecithin mouse model was induced by injecting lysolecithin in the spinal cord. Animals were randomised and treated for 10 or 24 days. Deptropine, pimozide, valproic acid or vehicle (DMSO) were administered intraperitoneally daily to both mouse models. Spinal cords were removed and sectioned for immunostaining with MBP and Olig2. The demyelinated lesion area was measured and Olig2+ cell density assessed.
Results: Administration of selected compounds in a therapeutic setting did not result in an improvement of the EAE clinical course, which was similar in mice treated with deptropine, pimozide, valproic acid compared with the vehicle group. In the EAE model an autoimmune response against myelin is induced, which could mask a positive effect of the drugs on remyelination. In order to avoid the effect of the immune system, we also tested the selected compounds in a lysolecithin model in which focal demyelination is due to a secondary toxic effect in oligodendrocytes. In the lysolecithin model, we observed that the density of Olig2+ cells was comparable in all groups, albeit showing a tendency to slight increase in animals treated with valproic acid, although statistically not significant.
Conclusions: Although deptropine, pimozide, valproic acid showed good remyelinating capacity in vitro, they failed to enhance remyelination in immune-mediated and toxic-induced demyelination experimental models.
Disclosure: Disclosure of conflict of interest:
CC, HP, HE, CM and CE declare no competing financial interests.
XM has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall.
Founding source: this study has been supported by Fundació Marato the TV3 (493/C/2012).