Efecto del tauroursodeoxicolato en la regulación de la neuroinflamación aguda

• Autores: N. Yanguas Casás
• Directores de la Tesis: M. Nieto Sampedro (dir. tes.), L. Romero Ramírez (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2015
• Idioma: español
• Tribunal Calificador de la Tesis: Amparo Cano (presid.), Luis Miguel García Segura (secret.), Carmen Guaza Rodridguez (voc.), Jörg Michael Mey (voc.), Bernardo Castellano López (voc.)
• Materias:
  • Química
    • Bioquímica
      • Inmunoquímica
  • Ciencias de la vida
    • Inmunología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Maintenance of CNS homeostasis is essential for the correct system function. The Blood Brain Barrier (BBB) limits the infiltration into the neural parenchyma of blood cells and substances. Resident cells, particularly microglia and astrocytes, continuously scan the CNS and can rapidly respond to any variation in the homeostatic balance (caused by an infection, trauma or others) by turning on the reactive state and starting an acute neuroinflammatory process. Acute neuroinflammation stops once the insult has been removed, and homeostasis is restored. However, when homeostasis is not restored, exacerbated activation of microglia and astrocytes, and neuroinflammation may become chronic. The reactive cells release inflammatory mediators that disrupt the BBB permeability, favoring the migration of immune cells (lymphocytes and monocytes) into the CNS, which can cause cell death and damage the CNS tissue.

    Bile acids are very interesting therapeutic tools, because they are synthesized by the human body, they can cross the BBB and their therapeutic use is approved by the FDA. The neuroprotective effect of bile acids and their anti-inflammatory effect on microglial cell lines have been described previously. However, their effect on primary glial cells remained unknown. We undertook a study of the effect of a biliary salt, named TUDCA, on an acute model of neuroinflammation and on several in vitro models of microglia and astrocyte activation.

    TUDCA could be a beneficial therapy for neuroinflammatory diseases. We found that it binds to GPBAR1/TGR5 receptor in microglia and astrocytes, activating cAMP cascade. It inhibited the proinflammatory response in both glial types by inhibiting the NF¿B activation induced by LPS. Besides, it decreased cell infiltration in the injured area both by limiting the microglial migratory capacity and the entrance of peripheral cells into the CNS tissue. TUDCA also brought about an anti-inflammatory environment by promoting a switch in the microglial phenotype towards a M2 phenotype and activating the TGFß pathway. Lastly, in vitro, TUDCA inhibited the neuronal cell death caused by reactive microglia through in.