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Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21

Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C...

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Autores principales: Laukkanen, Liina, Diniz, Cassiano R. A. F., Foulquier, Sebastien, Prickaerts, Jos, Castrén, Eero, Casarotto, Plinio C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400827/
https://www.ncbi.nlm.nih.gov/pubmed/34451870
http://dx.doi.org/10.3390/ph14080773
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author Laukkanen, Liina
Diniz, Cassiano R. A. F.
Foulquier, Sebastien
Prickaerts, Jos
Castrén, Eero
Casarotto, Plinio C.
author_facet Laukkanen, Liina
Diniz, Cassiano R. A. F.
Foulquier, Sebastien
Prickaerts, Jos
Castrén, Eero
Casarotto, Plinio C.
author_sort Laukkanen, Liina
collection PubMed
description Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1–10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.
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spelling pubmed-84008272021-08-29 Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21 Laukkanen, Liina Diniz, Cassiano R. A. F. Foulquier, Sebastien Prickaerts, Jos Castrén, Eero Casarotto, Plinio C. Pharmaceuticals (Basel) Article Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1–10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect. MDPI 2021-08-06 /pmc/articles/PMC8400827/ /pubmed/34451870 http://dx.doi.org/10.3390/ph14080773 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Laukkanen, Liina
Diniz, Cassiano R. A. F.
Foulquier, Sebastien
Prickaerts, Jos
Castrén, Eero
Casarotto, Plinio C.
Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21
title Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21
title_full Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21
title_fullStr Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21
title_full_unstemmed Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21
title_short Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21
title_sort facilitation of trkb activation by the angiotensin ii receptor type-2 (at2r) agonist c21
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400827/
https://www.ncbi.nlm.nih.gov/pubmed/34451870
http://dx.doi.org/10.3390/ph14080773
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