RESUMO
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.
Assuntos
Maleato de Dizocilpina , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Obesidade , Receptores de N-Metil-D-Aspartato , Animais , Humanos , Masculino , Camundongos , Ratos , Tronco Encefálico/metabolismo , Tronco Encefálico/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/efeitos adversos , Maleato de Dizocilpina/farmacologia , Maleato de Dizocilpina/uso terapêutico , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
AIM: Heart Failure with preserved Ejection Fraction (HFpEF) is characterized by diastolic dysfunction and reduced cardiac output, but its pathophysiology remains poorly understood. Animal models of HFpEF are challenging due to difficulties in assessing the degree of heart failure in small animals. This study aimed at inducing HFpEF in a mouse model to probe preload-dependency. METHODS: Increased body mass and arterial hypertension were induced in mice using a Western diet and NO synthase inhibition. Preload dependence was tested ex vivo. RESULTS: Mice with obesity and hypertension exhibited reduced cardiac output, indicating a failing heart. Increased left ventricular filling pressure during diastole suggested reduced compliance. Notably, the ejection fraction was preserved, suggesting the development of HFpEF. Spontaneous physical activity at night was reduced in HFpEF mice, indicating exercise intolerance; however, the cardiac connective tissue content was comparable between HFpEF and control mice. The HFpEF mice showed increased vulnerability to reduced preload ex vivo, indicating that elevated left ventricular filling pressure compensated for the rigid left ventricle, preventing a critical decrease in cardiac output. CONCLUSION: This animal model successfully developed mild HFpEF with a reduced pump function that was dependent on a high preload. A model of mild HFpEF may serve as a valuable tool for studying disease progression and interventions aimed at delaying or reversing symptom advancement, considering the slow development of HFpEF in patients.