GLP-1-directed NMDA receptor antagonism for obesity treatment.
Nature
; 629(8014): 1133-1141, 2024 May.
Article
in En
| MEDLINE
| ID: mdl-38750368
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dizocilpine Maleate
/
Receptors, N-Methyl-D-Aspartate
/
Glucagon-Like Peptide 1
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Glucagon-Like Peptide-1 Receptor
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Obesity
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Nature
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: