Estudi del paper de les proteïnes jnk en el desenvolupament de trastorns metabòlics i cognitius
- Autores: Oriol Busquets Figueras
- Directores de la Tesis: Antoni Camins Espuny (dir. tes.), Jaume Folch López (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Juan Carlos Laguna Egea (presid.), Xavier Xifró i Collsamata (secret.), Javier Garcia Pizarro (voc.)
- Programa de doctorado: Programa de Doctorado en Investigación, Desarrollo y Control de Medicamentos por la Universidad de Barcelona
- Materias:
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- Resumen
ABSTRACT Many past reports on the c-JUN N-terminal Kinases (JNKs) did not take into account the existing differences in the activity of each of the isoforms. And so, therapeutic proposals that regulated the JNKs unspecifically encountered setbacks of import. The aim of the present thesis was to contribute to current understanding of the role of individual JNK isoforms in the development of pathology and, to appraise any therapeutic interest derived of their modulation for temporal lobe epilepsy and the metabolic-cognitive syndrome.
Reported results demonstrated that the knock-out JNK1 had neuroprotective effects against excitotoxic damage derived of the administration of kainic acid, a model of temporal lobe epilepsy. Thus, Licochalcone A (LIC-A), a JNK1 inhibitor, was tested for its potential as a therapeutic agent. Results confirmed that when animals were pre-treated with LIC-A they were protected from the effects of kainic acid, as demonstrated by the absence of degenerating cells and sclerotic tissue, as well as lower neuroinflammatory responses in astrocytes and microglia.
Additionally, the metabolic consequences of a chronic feeding of a fat-enriched diet (High fat diet; HFD) were also assessed. Data demonstrated that HFD caused the appearance of peripheral and central insulin resistance as a result of mitochondrial and endoplasmic stress, dysregulation of autophagy and other alterations. In the end, it led to the appearance of cognitive impairments. Parallelly, the effects of the ablation of JNK2 were evaluated and, it was determined that it favoured the appearance of these same alterations, especially when combined with HFD. On the contrary, the knockout of JNK1 protected against the Abstract / Resum / Resumen X metabolic consequences of a chronic feeding with HFD, showing improved sensibility to insulin, reduced body weight and more efficient mitochondrial activity. Moreover, these animals were protected against the appearance of metabolic-derived cognitive dysfunctions.
