PMID- 29550391 OWN - NLM STAT- MEDLINE DCOM- 20190204 LR - 20190215 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 135 DP - 2018 Jun TI - Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN. PG - 163-171 LID - S0028-3908(18)30118-7 [pii] LID - 10.1016/j.neuropharm.2018.03.011 [doi] AB - The renin-angiotensin system (RAS) is associated with peripheral fluid homeostasis and cardiovascular function, but recent evidence also suggests a functional role in the brain. RAS regulates physiological and behavioral parameters related to the stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain-derived neurotrophic factor (BDNF) and TRKB, which are important in the neurobiology of depression and antidepressant action. However, the interaction between the BDNF/TRKB system and RAS in depression has not been investigated before. Accordingly, in the forced swimming test, we observed an antidepressant-like effect of systemic losartan but not with captopril or enalapril treatment. Moreover, infusion of losartan into the ventral hippocampus (vHC) and prelimbic prefrontal cortex (PL) mimicked the consequences of systemically injected losartan, whereas K252a (a blocker of TRK) infused into these brain areas impaired such effect. PD123319, an antagonist of AT2 receptor (AGTR2), also prevented the systemic losartan effect when infused into PL but not into vHC. Cultured cortical cells of rat embryos revealed that angiotensin II (ANG2), possibly through AGTR2, increased the surface levels of TRKB and its coupling to FYN, a SRC family kinase. Higher Agtr2 levels in cortical cells were reduced after stimulation with glutamate, and only under this condition an interaction between losartan and ANG2 was achieved. TRKB/AGTR2 heterodimers were also observed, in MG87 cells GFP-tagged AGTR2 co-immunoprecipitated with TRKB. Therefore, the antidepressant-like effect of losartan is proposed to occur through a shift of ANG2 towards AGTR2, followed by coupling of TRK/FYN and putative TRKB transactivation. Thus, the blockade of AGTR1 has therapeutic potential as a novel antidepressant therapy. CI - Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Diniz, Cassiano R A F AU - Diniz CRAF AD - School of Medicine, Campus USP, Ribeirao Preto, SP 14049-900, Brazil. Electronic address: cassianodiniz4@hotmail.com. FAU - Casarotto, Plinio C AU - Casarotto PC AD - School of Medicine, Campus USP, Ribeirao Preto, SP 14049-900, Brazil; Neuroscience Center, University of Helsinki, Finland. Electronic address: plinio@gmx.com. FAU - Fred, Senem M AU - Fred SM AD - Neuroscience Center, University of Helsinki, Finland. Electronic address: merve.fred@helsinki.fi. FAU - Biojone, Caroline AU - Biojone C AD - Neuroscience Center, University of Helsinki, Finland; Department of Physics and Chemistry, School of Pharmaceutical Sciences, Campus USP, Ribeirao Preto, SP 14040-904, Brazil. Electronic address: caroline.biojone@helsinki.fi. FAU - Castren, Eero AU - Castren E AD - Neuroscience Center, University of Helsinki, Finland. Electronic address: eero.castren@helsinki.fi. FAU - Joca, Samia R L AU - Joca SRL AD - Department of Physics and Chemistry, School of Pharmaceutical Sciences, Campus USP, Ribeirao Preto, SP 14040-904, Brazil; Department of Clinical Medicine - Translational Neuropsychiatry Unit, Aarhus University, Denmark. Electronic address: samia@usp.br. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180314 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Angiotensin II Type 2 Receptor Blockers) RN - 0 (Antidepressive Agents) RN - 0 (Carbazoles) RN - 0 (Imidazoles) RN - 0 (Indole Alkaloids) RN - 0 (Pyridines) RN - 0 (Receptor, Angiotensin, Type 2) RN - 11128-99-7 (Angiotensin II) RN - 130663-39-7 (PD 123319) RN - 69PN84IO1A (Enalapril) RN - 97161-97-2 (staurosporine aglycone) RN - 9G64RSX1XD (Captopril) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.2 (Fyn protein, rat) RN - EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn) RN - JMS50MPO89 (Losartan) SB - IM MH - Angiotensin II/pharmacology MH - Angiotensin II Type 2 Receptor Blockers/*pharmacology MH - Animals MH - Antidepressive Agents/pharmacology MH - Captopril/pharmacology MH - Carbazoles/pharmacology MH - Cells, Cultured MH - Cerebral Cortex/drug effects MH - Enalapril/pharmacology MH - Hippocampus/drug effects MH - Imidazoles/pharmacology MH - Immobility Response, Tonic/drug effects MH - Indole Alkaloids/pharmacology MH - Losartan/antagonists & inhibitors/*pharmacology MH - Male MH - Mice MH - Microinjections MH - Prefrontal Cortex/drug effects MH - Proto-Oncogene Proteins c-fyn/*metabolism MH - Pyridines/pharmacology MH - Rats MH - Receptor, Angiotensin, Type 2/*metabolism MH - Receptor, trkB/*metabolism MH - Transcriptional Activation/*drug effects OTO - NOTNLM OT - AGTR2 OT - Angiotensin receptor blocker OT - Losartan OT - TRKB EDAT- 2018/03/20 06:00 MHDA- 2019/02/05 06:00 CRDT- 2018/03/19 06:00 PHST- 2017/08/08 00:00 [received] PHST- 2018/02/06 00:00 [revised] PHST- 2018/03/12 00:00 [accepted] PHST- 2018/03/20 06:00 [pubmed] PHST- 2019/02/05 06:00 [medline] PHST- 2018/03/19 06:00 [entrez] AID - S0028-3908(18)30118-7 [pii] AID - 10.1016/j.neuropharm.2018.03.011 [doi] PST - ppublish SO - Neuropharmacology. 2018 Jun;135:163-171. doi: 10.1016/j.neuropharm.2018.03.011. Epub 2018 Mar 14.