التفاصيل البيبلوغرافية
| العنوان: |
GLP-1-directed NMDA receptor antagonism for obesity treatment |
| المؤلفون: |
Jonas Petersen, Mette Q. Ludwig, Vaida Juozaityte, Pablo Ranea-Robles, Charlotte Svendsen, Eunsang Hwang, Amalie W. Kristensen, Nicole Fadahunsi, Jens Lund, Alberte W. Breum, Cecilie V. Math |
| المصدر: |
Nature, Nature. 629(8014):1133-1141 |
| سنة النشر: |
2024 |
| الوصف: |
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. |
| نوع الوثيقة: |
redif-article |
| اللغة: |
English |
| DOI: |
10.1038/s41586-024-07419 |
| الإتاحة: |
https://ideas.repec.org/a/nat/nature/v629y2024i8014d10.1038_s41586-024-07419-8.html |
| رقم الأكسشن: |
edsrep.a.nat.nature.v629y2024i8014d10.1038.s41586.024.07419.8 |
| قاعدة البيانات: |
RePEc |
