PMID- 31053872
OWN - NLM
STAT- MEDLINE
DCOM- 20200416
LR  - 20200416
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Print)
IS  - 0012-186X (Linking)
VI  - 62
IP  - 8
DP  - 2019 Aug
TI  - Novel therapeutic potential of angiotensin receptor 1 blockade in a rat model of 
      diabetes-associated depression parallels altered BDNF signalling.
PG  - 1501-1513
LID - 10.1007/s00125-019-4888-z [doi]
AB  - AIMS/HYPOTHESIS: Diabetes is a worldwide epidemic linked with diverse diseases of 
      the nervous system, including depression. A few studies suggested a connection 
      between renin-angiotensin-aldosterone system blockers and reduced depressive 
      symptoms, although underlying mechanisms are unclear. Here we investigated the 
      antidepressant effect and the mechanisms of action of the angiotensin receptor 1 
      blocker (ARB) losartan in an experiential model of diabetes-associated 
      depression. METHODS: Experimental diabetes was induced by streptozotocin in adult 
      male Wistar rats. After 5 weeks of diabetes, rats were treated for 2 weeks with a 
      non-pressor oral dose of losartan (20 mg/kg). In protocol 1, cerebrovascular 
      perfusion and glial activation were evaluated by single-photon emission computed 
      tomography-MRI and immunohistochemistry. In protocol 2, behaviour studies were 
      performed (forced swim test and open field test). Hippocampal proinflammatory 
      response and brain-derived neurotrophic factor (BDNF) signalling were also 
      assessed. RESULTS: Here, we show that diabetic rats exhibit depression-like 
      behaviour, which can be therapeutically reversed by losartan. This action of 
      losartan occurs via changes in diabetes-induced neuroinflammatory responses 
      rather than altered cerebral perfusion. We also show that as a part of its 
      protective effect losartan restores BDNF production in astrocytes and facilitates 
      BDNF-tropomyosin receptor kinase B-cAMP response element-binding protein 
      signalling in the diabetic brain. CONCLUSIONS/INTERPRETATION: We identified a 
      novel effect of losartan in the nervous system that may be implemented to 
      alleviate symptoms of diabetes-associated depression. These findings explore a 
      new therapeutic horizon for ARBs as possible antidepressants and suggest that 
      BDNF could be a target of future drug development in diabetes-induced 
      complications.
FAU - Lenart, Lilla
AU  - Lenart L
AD  - 1st Department of Pediatrics, Semmelweis University, Bokay Janos u. 53-54, 
      Budapest, 1083, Hungary.
AD  - MTA-SE Lendulet Diabetes Research Group, Budapest, Hungary.
FAU - Balogh, Dora B
AU  - Balogh DB
AD  - 1st Department of Pediatrics, Semmelweis University, Bokay Janos u. 53-54, 
      Budapest, 1083, Hungary.
AD  - MTA-SE Lendulet Diabetes Research Group, Budapest, Hungary.
FAU - Lenart, Nikolett
AU  - Lenart N
AD  - "Momentum" Laboratory of Neuroimmunology, IEM HAS, Szigony u. 43, Budapest, 1083, 
      Hungary.
FAU - Barczi, Adrienn
AU  - Barczi A
AD  - 1st Department of Pediatrics, Semmelweis University, Bokay Janos u. 53-54, 
      Budapest, 1083, Hungary.
FAU - Hosszu, Adam
AU  - Hosszu A
AD  - 1st Department of Pediatrics, Semmelweis University, Bokay Janos u. 53-54, 
      Budapest, 1083, Hungary.
AD  - MTA-SE Lendulet Diabetes Research Group, Budapest, Hungary.
FAU - Farkas, Tamas
AU  - Farkas T
AD  - Progressio Ltd, Budapest, Hungary.
FAU - Hodrea, Judit
AU  - Hodrea J
AD  - 1st Department of Pediatrics, Semmelweis University, Bokay Janos u. 53-54, 
      Budapest, 1083, Hungary.
AD  - MTA-SE Lendulet Diabetes Research Group, Budapest, Hungary.
FAU - Szabo, Attila J
AU  - Szabo AJ
AD  - 1st Department of Pediatrics, Semmelweis University, Bokay Janos u. 53-54, 
      Budapest, 1083, Hungary.
AD  - MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary.
FAU - Szigeti, Krisztian
AU  - Szigeti K
AD  - Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 
      Hungary.
FAU - Denes, Adam
AU  - Denes A
AD  - "Momentum" Laboratory of Neuroimmunology, IEM HAS, Szigony u. 43, Budapest, 1083, 
      Hungary. denesa@koki.hu.
FAU - Fekete, Andrea
AU  - Fekete A
AUID- ORCID: 0000-0002-0210-153X
AD  - 1st Department of Pediatrics, Semmelweis University, Bokay Janos u. 53-54, 
      Budapest, 1083, Hungary. fekete.andrea@med.semmelweis-univ.hu.
AD  - MTA-SE Lendulet Diabetes Research Group, Budapest, Hungary. 
      fekete.andrea@med.semmelweis-univ.hu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190503
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Bdnf protein, rat)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - JMS50MPO89 (Losartan)
SB  - IM
MH  - Administration, Oral
MH  - Angiotensin II Type 1 Receptor Blockers/*therapeutic use
MH  - Animals
MH  - Apoptosis
MH  - Behavior, Animal
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Depression/complications/*drug therapy/*metabolism
MH  - Diabetes Complications/*drug therapy/psychology
MH  - Diabetes Mellitus, Experimental
MH  - Disease Models, Animal
MH  - Hippocampus/drug effects
MH  - Inflammation
MH  - Losartan/*therapeutic use
MH  - Male
MH  - Rats
MH  - Rats, Wistar
MH  - Signal Transduction
PMC - PMC6647092
OTO - NOTNLM
OT  - Angiotensin receptor 1 blocker
OT  - Brain-derived neurotrophic factor
OT  - Depression
OT  - Neuroinflammation
OT  - Renin-angiotensin-aldosterone system
EDAT- 2019/05/06 06:00
MHDA- 2020/04/17 06:00
PMCR- 2019/05/03
CRDT- 2019/05/05 06:00
PHST- 2018/11/27 00:00 [received]
PHST- 2019/04/02 00:00 [accepted]
PHST- 2019/05/06 06:00 [pubmed]
PHST- 2020/04/17 06:00 [medline]
PHST- 2019/05/05 06:00 [entrez]
PHST- 2019/05/03 00:00 [pmc-release]
AID - 10.1007/s00125-019-4888-z [pii]
AID - 4888 [pii]
AID - 10.1007/s00125-019-4888-z [doi]
PST - ppublish
SO  - Diabetologia. 2019 Aug;62(8):1501-1513. doi: 10.1007/s00125-019-4888-z. Epub 2019 
      May 3.