TE ROLE OF S100B IN MULTIPLE SCLEROSIS: FROM A BIOMARKER TO A THERAPEUTIC TARGET

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Target S100B to reduce Experimental Autoimmune Encephalomyelitis pathogenesis

Publication . Barros, Catarina da Silva; Borralho, Adelaide Maria Afonso Fernandes; Barateiro, Andreia Pereira

Multiple Sclerosis (MS) is a complex chronic immune disease in the central nervous system (CNS), causing neurological disability in young people aged between 20 to 40 years. It is considered one of the world’s most common neurological disorder that affect approximately 2.3 million people worldwide. The disease symptoms result from attacks that damaged the nerve fibers in the CNS, due to the overactivation of the immune system. Furthermore, the inappropriate activation of the immune system results in focal lesions on CNS, inflammation and destruction of myelin sheaths of neurons, main features of MS pathology. Recently, the inflammatory molecule S100B, in toxic levels, was directly correlated with demyelination and inflammatory processes using an ex vivo demyelinating model. The beneficial outcome of its inhibition with pentamidine, an S100B-binding drug, in our demyelinating model indicates S100B as an emerging therapeutic target in MS. In here, we aimed to target S100B in the animal model of MS, the experimental autoimmune encephalomyelitis (EAE), once we already demonstrated the involvement of S100B-RAGE axis. Indeed, we will use EAE to study whether by targeting S100B we may ameliorate the disease course and MS-like pathogenesis. Firstly, we observed that the animals treated with pentamidine reach a lower disease clinical score and have a faster recovery. Moreover, histological analysis showed that EAEinduced animals have an increased percentage of demyelination, which was reduced upon pentamidine treatment. These results were corroborated by the loss of MBP marker, as well as protein expression when compared with pentamidine treated mice. Regarding gliosis, pentamidine decreased glia reactivity (both astrocytes and microglia) and the density of S100B-expressing astrocytes in EAE-induced animals. Furthermore, the inflammatory response was attenuated in pentamidine treated animals preventing the exacerbated expression of pro-inflammatory cytokines and even increasing the anti-inflammatory response. Overall, our results indicate that S100B is involved in MS pathology and that, by using pentamidine, we could prevent the detrimental effects of this protein when in pathological levels. So, its inhibition may be a new therapeutic strategy not only to reduce damage but, hopefully, to improve recovery.

2018-11-20Dissertação de mestrado

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Brain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effects

Publication . Mahú, Inês; Barateiro, Andreia; Rial-Pensado, Eva; Martinéz-Sánchez, Noelia; Vaz, Sandra H.; Cal, Pedro M.S.D.; Jenkins, Benjamin; Rodrigues, Tiago M.; Cordeiro, Carlos; Costa, Miguel F.; Mendes, Raquel; Seixas, Elsa; Pereira, Mafalda M.A.; Kubasova, Nadiya; Gres, Vitka; Morris, Imogen; Temporão, Carolina; Olivares, Marta; Sanz, Yolanda; Koulman, Albert; Corzana, Francisco; Sebastião, Ana M; López, Miguel; Bernardes, Gonçalo J. L.; Domingos, Ana I.

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.

2020Artigo científico

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BPD/96794/2013