The angiotensin receptor 2 agonist, compound 21, facilitates TRKB activation and reduces the consequences of stress in mice

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Title: The angiotensin receptor 2 agonist, compound 21, facilitates TRKB activation and reduces the consequences of stress in mice
Author: Laukkanen, Liina
Contributor: University of Helsinki, Faculty of Medicine
Publisher: Helsingin yliopisto
Date: 2021
Language: eng
Thesis level: master's thesis
Degree program: Translationaalisen lääketieteen maisteriohjelma (Translational Medicine)
Master's Programme in Translational Medicine
Magisterprogrammet i translationell medicin
Specialisation: Neuroscience and psychobiology
Neuroscience and psychobiology
Neuroscience and psychobiology
Abstract: This study investigated the in vitro and in vivo effects of direct angiotensin II (ANG) receptor type 2 (AGTR2) agonist Compound 21 (C21). The blockade of ANG receptor type 1 (AGTR1) by AGTR1 antagonists has long been associated with antidepressant and anxiolytic effects. Furthermore, it has been suggested that the therapeutic effects of the AGTR1 antagonists are partially dependent on enhancing the signaling through neuroprotective AGTR2. This suggests that as a specific AGTR2 agonist C21 could be used as a potential therapeutic tool to treat mood disorders that would greatly benefit from new effective treatments. Brain-derived neurotrophic factor (BDNF) is a neurotrophic that binds to tropomyosin receptor kinase B (TRKB). This study aimed to test how C21 affects BDNF:TRKB signaling that has been shown to regulate the therapeutic effects of different antidepressants that act on mood disorders. In vitro effects of C21 on BDNF:TRKB signaling were investigated with ELISA in the cortical cell cultures. Acute AGTR2 stimulation significantly elevated the amount of surface TRKB whereas a prolonged treatment of C21 for three consecutive days induced activation of TRKB. Similarly, combined treatment of C21 and a non-therapeutic treatment of BDNF induced TRKB activation, further linking the AGTR2 stimulation by this compound to the BDNF:TRKB signaling. In vivo effects of C21 on conditioned and unconditioned fear were investigated in mice by using contextual fear conditioning and elevated plus-maze (EPM) respectively. The therapeutic effect of C21 protected mice from conditioned fear but failed to provide similar results for unconditioned fear in the EPM. Interestingly, these stress-protective effects of AGTR2 stimulation were lost in the BDNF-deficient animals. To conclude, AGTR2 stimulation by C21 elevates the amount of surface TRKB that enhances the BDNF:TRKB signaling similar to antidepressants, which further leads to the therapeutic, stress-protective effects. Furthermore, these AGTR2-induced effects were absent without exposure to stress or when BDNF was diminished, indicating that both fear conditioning and BDNF are crucially involved. This study suggests that the AGTR2 is indeed a potential therapeutic target for treating mood disorders, and that in the future C21 could be translated for this use. To achieve this result, the cell types that regulate this effect need to be identified.
Subject: Compound 21 (C21)
angiotensin receptor type 2 (AGTR2)
angiotensin receptor agonist
brain-derived neurotrophic factor (BDNF)
tropomyosin receptor kinase B (TRKB)

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