Therapeutic potential of pituitary adenylate cyclase-activating polypeptide and epigallocatechin gallate in motor and cognitive deficits of huntington's disease models
- Autores: Nuria Cabezas Llobet
- Directores de la Tesis: Xavier Xifró i Collsamata (dir. tes.)
- Lectura: En la Universitat de Girona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Antoni Camins Espuny (presid.), Oscar Campuzano Larrea (secret.), Albert Giralt Torroella (voc.)
- Programa de doctorado: Programa de Doctorado en Biología Molecular, Biomedicina y Salud por la Universidad de Girona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Huntington's disease (HD) is a progressive neurodegenerative disorder characterised by motor cognitive and psychiatric dysfunction. HD is hereditary, caused by mutation in a gene encoding for a protein called huntingtin (htt). Nowadays, there is no effective therapeutic treatment, being essential the study of new compounds with therapeutic potential to help people who suffer from the disease. At a neuropathological level, it has been described that cognitive disorders are associated with cortical and hippocampal function and motor symptoms with cortico-striatal function. It has been proposed that restoring hippocampal and striatal function would be the key to recover cognitive and motor function, respectively. Therefore, throughout this doctoral thesis we propose a dual study that allows us to define different therapeutic compounds with the ability to restore synaptic plasticity and protect against neuronal death.
Firstly, we have studied the possible therapeutic role of the adenylate cyclase activating polypeptide (PACAP). The neuroprotective ability of PACAP has been described in different neuronal models, but no data of its role in HD. In addition, the ability of PACAP to promote synaptic plasticity and improve cognitive deficits is poorly understood. The study of long-term learning and memory shows that R6/1 mice treated with PACAP improve cognitively as well as decrease motor deficits. We suggest that the effect of PACAP would be through the restoration of PAC1 levels in the hippocampus and in the striatum inducing genes transcription and promoting the synthesis of neurotrophic factors. Moreover, the recovery of the neuronal activity would allow diminishing the formation of mhtt aggregates, leading to a correct neuronal function.
Finally, the possible therapeutic role of epigallocatechin gallate (EGCG) in HD has been evaluated. EGCG is a catechin highly present in green tea. Its mechanism of action is not well-established, since it can interact through multiple targets that promote a correct neuronal function. It has been observed that EGCG exerts its therapeutic function by inhibiting the activity of the Fatty Acid Synthase (FASN) enzyme. We have observed that EGCG protects from mhtt toxicity, and it has seen that this neuroprotective effect was through the inhibition of apoptosis. Using an activity assay, it has been found that the increase in FASN levels correlates with an increase in enzymatic activity. EGCG treatment in a mouse model shows an improvement in motor and cognitive functions. Our results suggest that this EGCG action would be through the inhibition of the FASN enzyme in the striatum, whose activity is increased in HD.
Altogether, in this thesis we have described two new compounds with therapeutic potential in HD models, PACAP and EGCG; and we have proposed two new therapeutic targets, PAC1 receptor and the FASN enzyme, respectively. Thus, the results obtained with this thesis open two new doors for the treatment of HD cognitive and motor symptoms.
