PMID- 31273936
OWN - NLM
STAT- MEDLINE
DCOM- 20200424
LR  - 20240229
IS  - 1757-4684 (Electronic)
IS  - 1757-4676 (Print)
IS  - 1757-4676 (Linking)
VI  - 11
IP  - 7
DP  - 2019 Jul
TI  - Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads 
      to stroke neuroprotection.
PG  - e9950
LID - 10.15252/emmm.201809950 [doi]
LID - e9950
AB  - Neuroprotective strategies aimed to pharmacologically treat stroke, a prominent 
      cause of death, disability, and dementia, have remained elusive. A promising 
      approach is restriction of excitotoxic neuronal death in the infarct penumbra 
      through enhancement of survival pathways initiated by brain-derived neurotrophic 
      factor (BDNF). However, boosting of neurotrophic signaling after ischemia is 
      challenged by downregulation of BDNF high-affinity receptor, full-length 
      tropomyosin-related kinase B (TrkB-FL), due to calpain-degradation, and, 
      secondarily, regulated intramembrane proteolysis. Here, we have designed a 
      blood-brain barrier (BBB) permeable peptide containing TrkB-FL sequences 
      (TFL(457) ) which prevents receptor disappearance from the neuronal surface, 
      early induced after excitotoxicity. In this way, TFL(457) interferes TrkB-FL 
      cleavage by both proteolytic systems and increases neuronal viability via a 
      PLCgamma-dependent mechanism. By preserving downstream CREB and MEF2 promoter 
      activities, TFL(457) initiates a feedback mechanism favoring increased levels in 
      excitotoxic neurons of critical prosurvival mRNAs and proteins. This 
      neuroprotective peptide could be highly relevant for stroke therapy since, in a 
      mouse ischemia model, it counteracts TrkB-FL downregulation in the infarcted 
      brain, efficiently decreases infarct size, and improves neurological outcome.
CI  - (c) 2019 The Authors. Published under the terms of the CC BY 4.0 license.
FAU - Tejeda, Gonzalo S
AU  - Tejeda GS
AUID- ORCID: 0000-0002-2900-6276
AD  - Instituto de Investigaciones Biomedicas "Alberto Sols", Consejo Superior de 
      Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, 
      Spain.
FAU - Esteban-Ortega, Gema M
AU  - Esteban-Ortega GM
AD  - Instituto de Investigaciones Biomedicas "Alberto Sols", Consejo Superior de 
      Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, 
      Spain.
FAU - San Antonio, Esther
AU  - San Antonio E
AD  - Instituto de Investigaciones Biomedicas "Alberto Sols", Consejo Superior de 
      Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, 
      Spain.
FAU - Vidaurre, Oscar G
AU  - Vidaurre OG
AD  - Instituto de Investigaciones Biomedicas "Alberto Sols", Consejo Superior de 
      Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, 
      Spain.
FAU - Diaz-Guerra, Margarita
AU  - Diaz-Guerra M
AUID- ORCID: 0000-0002-4478-0956
AD  - Instituto de Investigaciones Biomedicas "Alberto Sols", Consejo Superior de 
      Investigaciones Cientificas-Universidad Autonoma de Madrid (CSIC-UAM), Madrid, 
      Spain.
LA  - eng
GR  - BFU2013-43808-R/Ministerio de Economia y Competitividad/International
GR  - BFU2016-75973-R/Ministerio de Economia y Competitividad/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190603
PL  - England
TA  - EMBO Mol Med
JT  - EMBO molecular medicine
JID - 101487380
RN  - 0 (Creb1 protein, mouse)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (MEF2 Transcription Factors)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Peptides)
RN  - EC 2.7.10.1 (Ntrk2 protein, mouse)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 3.4.22.- (Calpain)
SB  - IM
MH  - Animals
MH  - *Brain Ischemia/metabolism/pathology/prevention & control
MH  - Calpain/metabolism
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - MEF2 Transcription Factors/metabolism
MH  - Male
MH  - Membrane Glycoproteins/*metabolism
MH  - Mice
MH  - Neurons/*metabolism/pathology
MH  - *Neuroprotection
MH  - Peptides/*pharmacology
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - *Proteolysis
MH  - *Stroke/metabolism/pathology/prevention & control
PMC - PMC6609917
OTO - NOTNLM
OT  - TrkB
OT  - cell-penetrating peptides
OT  - excitotoxicity
OT  - neuroprotection
OT  - stroke
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/07/06 06:00
MHDA- 2020/04/25 06:00
PMCR- 2019/07/01
CRDT- 2019/07/06 06:00
PHST- 2018/10/15 00:00 [received]
PHST- 2019/05/02 00:00 [revised]
PHST- 2019/05/03 00:00 [accepted]
PHST- 2019/07/06 06:00 [entrez]
PHST- 2019/07/06 06:00 [pubmed]
PHST- 2020/04/25 06:00 [medline]
PHST- 2019/07/01 00:00 [pmc-release]
AID - EMMM201809950 [pii]
AID - 10.15252/emmm.201809950 [doi]
PST - ppublish
SO  - EMBO Mol Med. 2019 Jul;11(7):e9950. doi: 10.15252/emmm.201809950. Epub 2019 Jun 
      3.