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Targeting S100B reduces demyelination-associated pathogenesis in ex vivo and in vivo models mimicking multiple sclerosis
Author(s): ,
C. Barros
Affiliations:
Neuron-Glia Biology in Health and Disease, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa
,
P. Pascoal
Affiliations:
Neuron-Glia Biology in Health and Disease, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa
,
G. Santos
Affiliations:
Neuron-Glia Biology in Health and Disease, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa
,
A. Barateiro
Affiliations:
Neuron-Glia Biology in Health and Disease, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa
,
R. Freitas
Affiliations:
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa
,
D. Brites
Affiliations:
Neuron-Glia Biology in Health and Disease, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
,
L. Graça
Affiliations:
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa
A. Fernandes
Affiliations:
Neuron-Glia Biology in Health and Disease, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
ECTRIMS Online Library. Fernandes A.
Oct 12, 2018; 228932
Adelaide Fernandes
Adelaide Fernandes
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Abstract: P1092

Type: Poster Sessions

Abstract Category: Pathology and pathogenesis of MS - Neurobiology

Introduction: The autoimmune disorder Multiple Sclerosis (MS) is a complex disorder characterized by lesions on CNS, neuroinflammation and destruction of myelin sheaths with axonal degeneration. S100B, a small-calcium binding protein, may act either as an intracellular regulator or through extracellular signaling. We recently showed a direct correlation between augmented/toxic levels of S100B and its role in demyelination and inflammatory processes upon demyelination using an ex vivo demyelinating model.
Aims: Here, we aimed to understand whether targeting of S100B with a small molecule, pentamidine, could prevent the detrimental effects of this protein during demyelination.
Methods: Cerebellar organotypic slice cultures (COSC) were treated with lysophosphatidylcholine (LPC, 0.5 mg/mL) to induce demyelination. The expression of specific markers of immature and mature oligodendrocytes, neuronal integrity, and inflammation were evaluated by immunohistochemistry and qRealTime PCR. Experimental Autoimmune Encephalomyelitis (EAE) was induced in female C57BL/6J wild-type mice and two groups were formed: vehicle group (saline) and treated group (pentamidine, 4mg/kg, IP). Weight and clinical score of the animals were evaluated each day post injection. Following sacrifice brains were collected and analyzed for the expression of myelin by immunohistochemistry and qRealTime PCR.
Results: Using the ex vivo demyelinating model, we observed that pentamidine prevents demyelination and axonal impairment, as well as the exacerbated production of inflammatory mediators such as TNF-α, IL-1β and HMGB1. In the in vivo animal model of MS, the EAE, we observed that the animals treated with pentamidine reach a lower disease clinical score and have a faster recovery. In addition, EAE-induced animals treated with pentamidine show a higher myelin basic protein staining and expression, indicating less myelin damage in these animals.
Conclusions: Overall, our results indicate that S100B is involved in MS pathology and that its inhibition may be a new therapeutic strategy not only to reduce damage but, hopefully, to improve a faster recovery.
Disclosure: Funded by Medal of Honor L'Oréal for Women in Science, Innovation grant Ordem dos Farmacêuticos and GMSI-Merck to AF, and by Fundação para a Ciência e Tecnologia UID/DTP/04138/2013 to iMed.ULisboa, PhD grant SFRH/BD/91437/2012 to GS and post-doctoral grant SFRH/BPD/96794/2013 to AB.
Catarina Barros, Pedro Pascoal, Gisela Santos, Andreia Barateiro, Raquel Freitas, Luís Graça and Dora Brites: nothing to disclose. Adelaide Fernandes: Grant Multiple Sclerosis Innovation awarded by Merck.

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