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Publicatie
Development and biological evaluation of neuromedin U analogs as tools for functional elucidation: focus on stress-related disorders
Boek - Dissertatie
It is accepted that neuropeptides have an enormous therapeutic potential due to the observation that they are preferably released when the nervous system is challenged or stressed. Since psychiatric and neurological disorders comprise a medical field with unmet therapeutic needs, peptide drug candidates could possibly offer an answer to this unrequited demand. Neuromedin U (NMU) is a highly conserved neuropeptide across species which is involved in a variety of physiological and pathophysiological processes. In the present study, we evaluated the NMU peptide system as potential target in the treatment of stress-related disorders. Our current hypothesis suggests that central-acting antagonists would reduce or normalize the functioning of the hypothalamus-pituitary-adrenal axis at the level of the paraventricular nucleus.
An elaborate structure-activity relationship study was performed around the NMU-8 sequence aiming for the development of potent, proteolytically stable and NMU receptor-subtype selective agonists and antagonists. A broad range of NMU-8 analogs have been developed, but all displayed agonist properties. One of the most promising NMU agonists has been tested for its anorexigenic properties, a function ascribed to NMU receptor agonists, in a food intake study and was found to reduce food consumption.
Finally, we demonstrated that central NMU-8 administration induces stress- related behavior in mice under normal physiological conditions. Moreover, it was found to worsen the outcome of stressful situations, such as the forced swim test. Additionally, activation of key brain regions, involved in the regulation of the stress-response, was observed.
An elaborate structure-activity relationship study was performed around the NMU-8 sequence aiming for the development of potent, proteolytically stable and NMU receptor-subtype selective agonists and antagonists. A broad range of NMU-8 analogs have been developed, but all displayed agonist properties. One of the most promising NMU agonists has been tested for its anorexigenic properties, a function ascribed to NMU receptor agonists, in a food intake study and was found to reduce food consumption.
Finally, we demonstrated that central NMU-8 administration induces stress- related behavior in mice under normal physiological conditions. Moreover, it was found to worsen the outcome of stressful situations, such as the forced swim test. Additionally, activation of key brain regions, involved in the regulation of the stress-response, was observed.
Jaar van publicatie:2018
Trefwoorden:Elucidation