Transnasal Delivery of the Peptide Agonist Specific to Neuromedin-U Receptor 2 to the Brain for the Treatment of Obesity

Abstract

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.

Structural insights into the peptide selectivity and activation of human neuromedin U receptors

“…Both receptor subtypes are closely related to the regulation of food intake and energy balance. Peripheral and central administration of NMU reduced food intake and weight gain by stimulating NMUR1 and NMUR2, respectively 10 – 12 . Compared with the NMUR1-selective agonist, the NMUR2 selective agonist has a more potent body weight-lost effect and cause less diarrhea, making it a more well-balanced drug for the treatment of obesity 13 .…”

Amyloid beta cleavage by ANA‐TA9, a synthetic peptide from the ANA/BTG3 Box A region

“…Many authors have reported on direct drug delivery to the brain via nasal application. Our previous articles have clarified the efficient nasal delivery of oxytocin and CPN‐116 (the agonist peptide of type 2 neuromedin U receptor) to the brain 22,23 . Nasal application of ANA‐TA9 may allow for the development of novel therapeutic systems to treat AD and dementia.…”

Pharmacomodulation of brain neuromedin U signaling as a potential therapeutic strategy

“…There are two known, parallel mechanisms of transnasal drug transport into the brain: (1) straight influx into the cerebrospinal fluid (CSF) via epithelial cell layer and submucosa and/or entry to neuropilus using extracellular diffusion within perineuronal spaces; (2) intracellular transmission of the pharmaceutical molecules across the olfactory neurons to cortical areas (Borroto‐Escuela et al, 2015). Of note, the exchange of molecules between two parts of the recently described glymphatic system: CSF and brain extracellular fluid (BECF) may also facilitate the efficient central distribution of intranasally delivered medications (Tanaka et al, 2020, Figure 1).…”