Study of two analogues of pituitary adenylate cyclase-activating polypeptide as novel therapeutic compounds for Huntington’s disease

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Huntington’s disease (HD) is a neurodegenerative genetic disorder with no effective treatment characterized by motor discoordination, deficits in cognitive function (acquiring new knowledges, memory, understanding…), and psychiatric alterations. The cause of HD is the expression of the mutant huntingtin (mHTT) which leads to the malfunctioning and degeneration of different brain regions. The loss of neurons in the striatum (striatal neurons) is a key feature in the development and progression of motor discoordination, whereas the malfunction of hippocampus has been associated with cognitive deficits in HD. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed throughout the central nervous system considered a potential therapeutic agent for protecting neurons through the activation of three receptors: PAC1R, VPAC1R, and VPAC2R. However, the pharmacological use of PACAP is limited because the molecule is rapidly metabolized and because the activation of peripheral VPACRs has been associated to cardiovascular and respiratory secondary effects. As PAC1R is suggested to be the main effector of the neuroprotective effect of PACAP, more stable analogues of PACAP with higher affinity for PAC1R have been proposed as promising therapeutic tools. In this thesis we first showed that PACAP protects striatal cells against mHTT-induced toxicity and that although all PACAP receptors take part in neuroprotection, PAC1R plays a key role. Additionally, we demonstrated for the first time that the intranasal administration of metabolically stable analogues of PACAP displaying higher affinity for PAC1R improves cognitive and motor functions in a HD mouse model promoting beneficial actions in the hippocampus and the striatum ​
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