Research Institute for Medicines (iMed.ULisboa)

Author Of 1 Presentation

Pathogenesis – Role of Glia Poster Presentation

P0988 - Pentamidine as a new therapeutic strategy against Multiple Sclerosis-like pathology  (ID 1036)

Speakers
Presentation Number
P0988
Presentation Topic
Pathogenesis – Role of Glia

Abstract

Background

Multiple Sclerosis (MS), an autoimmune disorder, is characterized by the formation of demyelinated plaques due to auto-reactive immune cell infiltration across the blood-brain barrier that elicits inflammation, gliosis and axonal degeneration. We recently correlated excessive S100B, a small inflammatory molecule, with demyelination and associated inflammatory processes. Moreover, using an ex vivo demyelination model, its inhibition by pentamidine, an S100B-binding drug, showed promising results indicating S100B as an emerging therapeutic target in MS.

Objectives

Here, we investigated the potential pharmacological value of pentamidine in targeting excessive S100B using the in vivo model of MS, the experimental autoimmune encephalomyelitis (EAE), and further understanding whether we could ameliorate MS-like pathogenesis.

Methods

EAE was induced in female C57BL/6J wild-type mice and three groups were formed: control (CTRL), vehicle group (EAE) and treated group (EAE+Pnt, 4mg/kg, intraperitoneal, daily). We evaluated clinical score and body weight during 30-days of experiment, and further CNS pathogenesis at EAE peak and chronic phases.

Results

Our results clearly demonstrated that disease emergence was delayed in EAE-treated animals, significantly preventing more aggressive clinical symptoms and improving recovery. Pathologically, when evaluating spinal cord sections, we observed that pentamidine significantly prevented the number of demyelinating lesions elicited by EAE induction at the peak and chronic disease stages. Moreover, pentamidine also acted in the prevention of oligodendrogenesis impairment at lesion plaque in chronic disease phases possibly favoring remyelination. Further, the pentamidine-treated group showed less astrocyte reactivity and S100B expression. Regarding microglia, pentamidine enhanced EAE-induced microglia recruitment to lesion areas during chronic EAE stages, but reduced their pro-inflammatory phenotype, possibly facilitating a more regenerative microglia population. Besides reverting the glial reactivity scenario, pentamidine also increased regulatory T cells density in the CNS suggesting an additional immunomodulatory action. To note, at the periphery, pentamidine was able to decrease serum EAE-induced inflammatory cytokines mainly at chronic disease stage.

Conclusions

Overall, our results strengthened the involvement of S100B in MS pathology and the possibility to use pentamidine as a remyelinating and anti-inflammatory therapy for MS.

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