A possible mechanism for the transport of lipidized analogs of prolactin-releasing peptide from the periphery to the brain

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00645807" target="_blank" >RIV/61388963:_____/25:00645807 - isvavai.cz</a>

Výsledek na webu

<a href="https://hdl.handle.net/11104/0375596" target="_blank" >https://hdl.handle.net/11104/0375596</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

A possible mechanism for the transport of lipidized analogs of prolactin-releasing peptide from the periphery to the brain

Popis výsledku v původním jazyce

Faced with the pandemic of obesity and its related comorbidities, the need for new effective treatments has drawn attention to anorexigenic neuropeptides. However, their delivery from the periphery to the brain is complicated because of their peptide structure and the absence of their physiological transporter at the blood-brain barrier (BBB). This could be overcome by peptide lipidization which is a useful approach to increase peptide stability and favor its central action upon peripheral administration. Recent studies pointed out the importance of tanycytes for the access into the brain of liraglutide and semaglutide, two lipidized analogs of the anorexigenic glucagon-like peptide 1. Tanycytes are the ependymoglial cells lining the floor of 3rd ventricle and shown to play a role in the active transport of nutrients and other blood-borne molecules across the BBB. Prolactin-releasing peptide 31 (PrRP31) is a strong anorexigenic neuropeptide produced in the hypothalamus and brainstem that significantly decreases food intake after intracerebroventricular (ICV) application. To enable its anorexigenic effect after peripheral injection, a series of lipidized analogs of PrRP31 from octanoyl (oct-PrRP31) to palmitoyl (palm-PrRP31) attached to N-terminus of the peptide was designed. In the present study, we investigated the neuronal activation using c-fos immunolabeling of brain nuclei implicated in food intake regulation, such as the paraventricular nucleus of the hypothalamus (PVN), and the nucleus tractus solitarius (NTS) after intravenous (IV) injection of PrRP analogs, their anorexigenic effect, and finally potential involvement of tanycytes in the uptake of PrRP lipidized analogs to the brain. Whereas lipidized analogs with shorter fatty acids tended to, and palm-PrRP31 significantly increased c-Fos immunoreactivity in both PVN and NTS, natural PrRP31 did not activate c-Fos in any of the mentioned nuclei. Thus, palm-PrRP31 was further examined for its ability to reduce the food intake in Wistar rats fed ad libitum. Repeated peripheral application for 3 consecutive days resulted in a significant reduction of food intake. As a next step, we employed primary tanycytes isolated from 10-day-old rats. Cells were treated with fluorescently labeled analogs of PrRP31 and results were analyzed using immunocytochemistry and confocal microscopy. The results showed uptake of palm-PrRP31 in primary tanycytes 30 min after treatment, whereas no specific uptake was observed for the native PrRP31. In conclusion, unlike native PrRP31, peripheral administration of palm-PrRP31 triggered neuronal activation in the PVN and NTS, leading to a decrease in food intake. Palm-PrRP31 was uptaken into the primary tanycytes which could be important for its biological effect. The latter mechanism remains to be studied in vivo.

Název v anglickém jazyce

A possible mechanism for the transport of lipidized analogs of prolactin-releasing peptide from the periphery to the brain

Popis výsledku anglicky

Faced with the pandemic of obesity and its related comorbidities, the need for new effective treatments has drawn attention to anorexigenic neuropeptides. However, their delivery from the periphery to the brain is complicated because of their peptide structure and the absence of their physiological transporter at the blood-brain barrier (BBB). This could be overcome by peptide lipidization which is a useful approach to increase peptide stability and favor its central action upon peripheral administration. Recent studies pointed out the importance of tanycytes for the access into the brain of liraglutide and semaglutide, two lipidized analogs of the anorexigenic glucagon-like peptide 1. Tanycytes are the ependymoglial cells lining the floor of 3rd ventricle and shown to play a role in the active transport of nutrients and other blood-borne molecules across the BBB. Prolactin-releasing peptide 31 (PrRP31) is a strong anorexigenic neuropeptide produced in the hypothalamus and brainstem that significantly decreases food intake after intracerebroventricular (ICV) application. To enable its anorexigenic effect after peripheral injection, a series of lipidized analogs of PrRP31 from octanoyl (oct-PrRP31) to palmitoyl (palm-PrRP31) attached to N-terminus of the peptide was designed. In the present study, we investigated the neuronal activation using c-fos immunolabeling of brain nuclei implicated in food intake regulation, such as the paraventricular nucleus of the hypothalamus (PVN), and the nucleus tractus solitarius (NTS) after intravenous (IV) injection of PrRP analogs, their anorexigenic effect, and finally potential involvement of tanycytes in the uptake of PrRP lipidized analogs to the brain. Whereas lipidized analogs with shorter fatty acids tended to, and palm-PrRP31 significantly increased c-Fos immunoreactivity in both PVN and NTS, natural PrRP31 did not activate c-Fos in any of the mentioned nuclei. Thus, palm-PrRP31 was further examined for its ability to reduce the food intake in Wistar rats fed ad libitum. Repeated peripheral application for 3 consecutive days resulted in a significant reduction of food intake. As a next step, we employed primary tanycytes isolated from 10-day-old rats. Cells were treated with fluorescently labeled analogs of PrRP31 and results were analyzed using immunocytochemistry and confocal microscopy. The results showed uptake of palm-PrRP31 in primary tanycytes 30 min after treatment, whereas no specific uptake was observed for the native PrRP31. In conclusion, unlike native PrRP31, peripheral administration of palm-PrRP31 triggered neuronal activation in the PVN and NTS, leading to a decrease in food intake. Palm-PrRP31 was uptaken into the primary tanycytes which could be important for its biological effect. The latter mechanism remains to be studied in vivo.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/TN02000109" target="_blank" >TN02000109: Personalizovaná medicína: Translačním výzkumem k biomedicínským aplikacím</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů