Treating obesity using glucagon-like peptide-1-directed N-methyl-D-aspartate receptor inhibition

In a recent study published in Nature, researchers developed the MK-801 bimodal drug that successfully cures obesity, hyperglycemia, and dyslipidemia in mouse models of metabolic illness by combining N-methyl-D-aspartate (NMDA) receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor antagonism.

Study: GLP-1-directed NMDA receptor antagonism for obesity treatment. Image Credit: Inside Creative House/Shutterstock.comStudy: GLP-1-directed NMDA receptor antagonism for obesity treatment. Image Credit: Inside Creative House/Shutterstock.com

Background

The NMDA receptor is a crucial brain cation channel influencing body weight homeostasis. Obesity is associated with glutamatergic neurotransmission and synaptic plasticity mediated by NMDA receptors.

In mice, inhibiting NMDA receptor functions within the brainstem increases short-term dietary intake, but antagonizing them within the hypothalamus reduces food consumption and body weight. 

NMDA receptor inhibitors, like MK-801 and memantine, lead to weight reduction in rats and reduced palatable food choices in rodents and non-human primates. These antagonists also inhibit binge eating in humans.

About the study

In the present review, researchers developed a novel compound, MK-801, which combines a small-molecule antagonist with a peptide agonist to treat obesity.

MK-801 delivers a small-molecule modulator of an ionotropic receptor by targeting a G-protein-coupled receptor. To avoid the problems related to unspecific NMDA receptor blocking, the team created a peptide-based drug combination including MK-801, an NMDA receptor inhibitor, and a GLP-1 counterpart.

They used reducible disulfide linkage to develop redox-sensitive mechanisms to enable intracellular MK-801 release, allowing for the summative cellular activities of GLP-1 agonists and NMDA antagonists.

Researchers developed MK-801 by peptide cleavage and purification following disulfide linker production and evaluated the compound's ability to transmit protraction. They functionalized the disulfide linker after reacting with an amine-containing medication.

They evaluated in vitro using reversed-phase ultraperformance-liquid chromatography (UPLC) and bioluminescence resonance energy transfer (BRET) assays.

They also created conjugates containing various peptide analogs, including peptide YY (PYY), glucose insulinotropic peptide (GIP), and a GIP/GLP-1 co-agonist. These conjugates can increase weight loss effectiveness.

Researchers investigated the glucometabolic characteristics of MK-801 in a diabetic db/db mouse model and double-housed male Sprague-Dawley (SD) rats. They investigated MK-801-GLP-1’s adverse profile, particularly its impact on hyperthermia and hyper-locomotion.

They conducted metabolic phenotyping and indirect calorimetry investigations using DIO C57BL/6J mice. Following dosage determination, they evaluated the metabolic impacts in vivo by comparing MK-801-GLP-1 to the MK-801 and vehicular therapies.

The team confirmed MK-801-GLP-1's efficacy in managing energy balance by normalizing body weight and fat mass compared to age-matched control groups.

They conducted comparative transcriptomics investigations to determine the conjugate's effect on the brainstem and mesolimbic reward systems. The significant disparity in weight loss between the two treatments may complicate the interpretation of changes in transcriptional regulation.

Results

MK-801 subcutaneous injections once daily resulted in a dose-dependent reduction in food consumption and body weight. Chronic therapy, on the other hand, enhances hyperthermia and hyper-locomotion, making it unsuitable for obesity management.

In numerous rodent models representing metabolic diseases and obesity, treatment with the MK-801-GLP-1 combination significantly corrected obesity, diabetes, and dyslipidemia.

The considerable variations in proteomic and transcriptomic responses by hypothalamic cells, associated with synaptic plasticity and glutamatergic transmission, indicate that the drug conjugate may cause neurostructural alterations in glucagon-like peptide-1-expressing neurons.

The weight-loss advantages of MK-801 may be due to a combination of effects on energy balance and disordered dietary patterns. The bidirectional influences of NMDA inhibition on food may reduce the weight-loss effectiveness of systemic exposures to NMDA antagonism.

The significant weight-loss effectiveness of the MK-801-GLP-1 conjugate, as well as the potent hypothalamic alterations in proteins and transcripts associated with NMDA receptor-related neuroplasticity, indicate that the changes in the compound’s biodistribution driven by glucagon-like peptide-1-regulated targeting might effectively bypass MK-801 delivery to vagal afferents and targeted neuronal cells within the nucleus of tractus solitarius (NTS).

MK-801-GLP-1 lowered body weight synergistically in mice, resulting in a 23% vehicle-corrected weight reduction compared to dose-matched monotherapies.

In DIO mice, a single injection of GLP-1 or MK-801-GLP-1 lowered blood glucose levels, but equimolar MK-801 therapy had no meaningful effect on glycemia.

After nine days, the group treated with the MK-801-GLP-1 combination lost 15% of their weight, compared to 3.5% in the original GLP-1 analog group.

Conclusion

The study found that a bimodal molecular strategy combining NMDA receptor antagonism and glucagon-like peptide-1 receptor antagonism could successfully correct obesity, hyperglycemia, and dyslipidemia in mouse models of metabolic illness.

This method reveals the viability of utilizing peptide-regulated targeting to produce cell-specific ionotropic receptor modulation and the therapeutic potential of unimolecular combined glucagon-like peptide-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity management. Further research is required to investigate MK-801's weight-reducing effects in clinical settings.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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