Cagrilintide and Semaglutide Target Both the Hypothalamic and Brainstem Neurons in the Rodent Brain

Results: In rats and mice both semaglutide^"750 and cagrilintide^1"750 were detected in the brain stem as well as hypothalamic regions associated with hedonic and homeostatic energy intake. Concurrently, cagrilintide increased neuronal activity in the hypothalamus in mice. Furthermore, both drugs distributed to the septum in mice and rats which is associated with hedonic energy intake. Conclusions: Semaglutide and cagrilintide has direct access to several brain regions involved in homeostatic and hedonic energy intake in rodents. Furthermore, cagrilintide directly activates neurons in the mouse hypothalamus. Thus, the body weight lowering actions of CagriSema is likely mediated by direct actions of both cagrilintide and semaglutide in both the septum, the hypothalamus and the brainstem to lower energy intake and body weight. Background: CagriSema, a combination of the long-acting analogues of amylin (cagrilintide) and glucagon-like peptide-1 (semaglutide), is in clinical development for treatment of obesity. Considerable preclinical knowledge on the access and actions of semaglutide in the brain exist, whereas the actions of amylin analogues are less explored but are reported to be primarily through the brainstem with less focus on additional brain regions. This study explored the direct access of cagrilintide and semaglutide in rodent brains as well as cagrilintide induced ex-vivo neuronal activation in mice. Methods: Male rats (Sprague Dawley) were dosed once with fluorescently labelled (VivoTag 750, VT750) cagrilintide^"750 or semaglutideVT750 (100 nmol/kg, i.v.) and euthanized at 30 min, 2 hours or 6 hours. The drug brain distribution was visualized by light sheet fluorescence microscopy and a similar study was conducted in mice (C57BL6) visualising cagrilintide^"750 distribution at 6 hours following administration. Neuronal activation in mouse hypothalamus was evaluated by microelectrode array on brain slices following cagrilintide application.