GLP-1-directed NMDA receptor antagonism for obesity treatment.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Petersen Jonas, Ludwig Mette Q, Juozaityte Vaida, Ranea-Robles Pablo, Svendsen Charlotte, Hwang Eunsang, Kristensen Amalie W, Fadahunsi Nicole, Lund Jens, Breum Alberte W, Mathiesen Cecilie V, Sachs Luisa, Moreno-Justicia Roger, Rohlfs Rebecca, Ford James C, Douros Jonathan D, Finan Brian, Portillo Bryan, Grose Kyle, Petersen Jacob E, Trauelsen Mette, Feuchtinger Annette, DiMarchi Richard D, Schwartz Thue W, Deshmukh Atul S, Thomsen Morten B, Kohlmeier Kristi A, Williams Kevin W, Pers Tune H, Frølund Bente, Strømgaard Kristian, Klein Anders B, Clemmensen Christoffer
Аннотация
The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.