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Project description:The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.
2024-04-26 | PXD045816 | Pride
Project description:The N-methyl-d-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.
2024-05-14 | GSE245727 | GEO
Project description:The N-methyl-d-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.
2024-05-14 | GSE244607 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-12-13 | GSE108043 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-02-16 | GSE225102 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-12-21 | GSE251794 | GEO
Project description:Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules.
| S-EPMC6448809 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2012-12-15 | E-GEOD-42594 | biostudies-arrayexpress
Project description:Abstract Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes, and we investigated metabolic and cognitive effects of the GLP-1RA, exenatide once weekly, in nondiabetic, antipsychotic-treated, obese patients with schizophrenia. Methods: In this investigator-initiated trial, antipsychotic-treated, obese, nondiabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was body weight loss after treatment. Secondary endpoints comprised blood pressure, biochemistry, measurements of body composition, and cognition. Results: Forty patients completed the trial. At baseline, the mean body weight was 118.3?±?16.0?kg in the exenatide group and 111.7?±?18.0?kg in the placebo group, with no group differences (P = .23). After 3 months of treatment, the exenatide and placebo groups experienced significant (P = .004), but, similar (P = .98) weight losses of 2.24?±?3.3?kg and 2.23?±?4.4?kg, respectively. The exenatide group had a significant decrease in central 24-h systolic blood pressure of 6.8?mm/Hg (P = .004) and a decrease in the pulse wave velocity (a measure of arterial stiffness) of 0.3 m/s (P = .007). Changes in biochemistry, body composition, and cognition were similar in the groups (P < .47). Exenatide once weekly was well tolerated. Conclusion: Treatment with exenatide once weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. This suggests that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling and implies that antiobesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia. ClinicalTrials.gov identifier: NCT01794429.
| S-EPMC5476046 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-05-13 | E-GEOD-70350 | biostudies-arrayexpress