Publicação
Role of S100B in EAE pathogenesis
| Resumo: | Multiple Sclerosis (MS) is a complex chronic autoimmune disease of the central nervous system (CNS). It is the second most common cause of non-traumatic neurological, physical and cognitive disability in young adults, affecting 2.5 million people worldwide. It is characterized by the appearance of lesions on CNS resulting from the demyelination that occurs due to auto-reactive immune cell infiltration. This activation leads to inflammation, destruction of myelin sheaths with axonal degeneration and gliosis. Recently, the calcium-binding protein, S100B, has been emerging as an important inflammatory marker in neurodegenerative and neuroinflammatory disorders as MS. Indeed our group showed that this protein was present in the cerebrospinal fluid (CSF) and serum of MS patients and, recently, that increased levels were directly correlated with demyelination and inflammatory processes, using an ex vivo demyelinating model. Moreover, its inhibition with a S100B-binding drug in this demyelinating model showed that S100B may be a promising therapeutic target in MS. Following studies showed that the S100B-RAGE axis is overexpressed in the in vivo model of MS, the experimental autoimmune encephalomyelitis (EAE), indicating this as a good model for S100B modulation. So, here, we aimed to understand whether the targeting of S100B, using the specific small molecule pentamidine, could modulate and even, ameliorate MS-like pathogenesis in the EAE model. First, we observed the positive effects of pentamidine in decreasing disease severity and motor deficits in the treated animals, by ameliorating their clinical score and improving recovery. Moreover, regarding CNS pathogenesis, when evaluating the mice’s spinal cord sections, the treatment with pentamidine attenuated the appearance of demyelinated lesions, either in the peak or chronic disease phase, and also of cell infiltration at chronic stages. Further, pentamidine also prevented mature oligodendrocyte (OLs) loss and enhanced oligodendrogenesis which seemed to favour remyelination. As expected EAE-induced animals treated with pentamidine show decreased astroglial reactivity alongside with S100B expression. On the other hand, pentamidine had an enhancing effect in the microglial recruitment, mainly to the demyelinated lesion. At the peripheric level, pentamidine was also able to decrease serum EAE-induced inflammatory cytokines at chronic disease stage. Altogether our results, highlight the involvement of S100B in MS pathology. Moreover, they also suggest a neuroprotective, modulatory role of the S100B-binding drug, pentamidine, which prevented most of the detrimental effects caused by toxic levels of S100B, upon EAE induction. We can conclude that S100B inhibition may be a new therapeutic strategy not only to reduce CNS damage but also to improve recovery. |
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| Autores principais: | Soromenho, Beatriz dos Santos Pinto |
| Assunto: | Multiple Sclerosis EAE S100B Demyelination Glial reactivity Teses de mestrado - 2020 |
| Ano: | 2020 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Multiple Sclerosis (MS) is a complex chronic autoimmune disease of the central nervous system (CNS). It is the second most common cause of non-traumatic neurological, physical and cognitive disability in young adults, affecting 2.5 million people worldwide. It is characterized by the appearance of lesions on CNS resulting from the demyelination that occurs due to auto-reactive immune cell infiltration. This activation leads to inflammation, destruction of myelin sheaths with axonal degeneration and gliosis. Recently, the calcium-binding protein, S100B, has been emerging as an important inflammatory marker in neurodegenerative and neuroinflammatory disorders as MS. Indeed our group showed that this protein was present in the cerebrospinal fluid (CSF) and serum of MS patients and, recently, that increased levels were directly correlated with demyelination and inflammatory processes, using an ex vivo demyelinating model. Moreover, its inhibition with a S100B-binding drug in this demyelinating model showed that S100B may be a promising therapeutic target in MS. Following studies showed that the S100B-RAGE axis is overexpressed in the in vivo model of MS, the experimental autoimmune encephalomyelitis (EAE), indicating this as a good model for S100B modulation. So, here, we aimed to understand whether the targeting of S100B, using the specific small molecule pentamidine, could modulate and even, ameliorate MS-like pathogenesis in the EAE model. First, we observed the positive effects of pentamidine in decreasing disease severity and motor deficits in the treated animals, by ameliorating their clinical score and improving recovery. Moreover, regarding CNS pathogenesis, when evaluating the mice’s spinal cord sections, the treatment with pentamidine attenuated the appearance of demyelinated lesions, either in the peak or chronic disease phase, and also of cell infiltration at chronic stages. Further, pentamidine also prevented mature oligodendrocyte (OLs) loss and enhanced oligodendrogenesis which seemed to favour remyelination. As expected EAE-induced animals treated with pentamidine show decreased astroglial reactivity alongside with S100B expression. On the other hand, pentamidine had an enhancing effect in the microglial recruitment, mainly to the demyelinated lesion. At the peripheric level, pentamidine was also able to decrease serum EAE-induced inflammatory cytokines at chronic disease stage. Altogether our results, highlight the involvement of S100B in MS pathology. Moreover, they also suggest a neuroprotective, modulatory role of the S100B-binding drug, pentamidine, which prevented most of the detrimental effects caused by toxic levels of S100B, upon EAE induction. We can conclude that S100B inhibition may be a new therapeutic strategy not only to reduce CNS damage but also to improve recovery. |
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