DMF - Teses de Mestrado
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Browsing DMF - Teses de Mestrado by Author "Monteiro, Mariana Antão Ventura"
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- The potential of ABT-263 as a therapeutic agent in spinal cord injury-induced peripheral pathologyPublication . Monteiro, Mariana Antão Ventura; Saúde, Maria Leonor Tavares; Correia, Jorge Manuel de Jesus; Martins, Isaura Vanessa AntunesSpinal cord injury (SCI) is a serious neurological condition characterized by motor and sensory impairments, often associated with the induction of peripheral secondary conditions. There are two main causes identified for this peripheral pathology: the severance of the sympathetic nervous system and its supraspinal control; and a systemic and chronic inflammatory response. The elimination of SCI-induced senescent cells using the senolytic ABT-263 is responsible for significant motor, sensory and bladder improvements. These are also correlated with the reduction of detrimental cytokines, chemokines and senescent-associated secretory phenotype (SASP) factors. In our study, we hypothesized that the accumulation of SASP factors in the injured spinal cord could be responsible for its systemic spread and induction of senescence, SASP and, consequently, pathology in peripheral organs. As ABT-263 is beneficial for spinal cord repair outcome, we wanted to address if its effect was sustained in the periphery, and, therefore, attenuate secondary conditions. We evaluated the cytokine profile of the spinal cord, liver and bladder from T9 SCI mice taken from vehicle- and ABT-263-treated animals at different days post-injury (dpi). In addition to this, the histopathology and senescence profile were evaluated using H&E, and other special stainings, including SA-b-gal, respectively, as well as immunohistochemistry to assess inflammation. Image analysis and quantifications were done using QuPath. Our results showed a chronic induction of pro-inflammatory factors in the spinal cord at 30 dpi and a loss of effectiveness of ABT-263 compared with the 15 dpi. In the liver at 15 dpi, inflammatory cytokines and pro-fibrotic factors were upregulated with SCI, however, ABT-263 was not successful in decreasing their expression. At the same time, an increase in the number of senescent cells was observed in the animals treated with ABT-263 suggesting some degree of hepatotoxicity. This was onfirmed by an upregulation of pro-fibrotic and proinflammatory factors in the liver of ABT-263-treated animals at 30 dpi. Notwithstanding, at 15 dpi histopathology did not yet show significant pathological alterations. The spleen appeared to not be affected at this injury level. The bladder also revealed a chronic inflammatory and pro-fibrotic microenvironment and phenotype. However, the beneficial effects of ABT-263 were only observed at 30 dpi, suggesting an intermediate modulation by ABT-263 between 15 and 30 dpi. In conclusion, there is no irrefutable evidence that SASP becomes systemic and is responsible for the induction of senescence and pathology in other organs after SCI, at least at 15 dpi. Further studies are warranted