PMID- 25698444
OWN - NLM
STAT- MEDLINE
DCOM- 20160614
LR  - 20211203
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 22
IP  - 10
DP  - 2015 Oct
TI  - The CB(1) cannabinoid receptor signals striatal neuroprotection via a 
      PI3K/Akt/mTORC1/BDNF pathway.
PG  - 1618-29
LID - 10.1038/cdd.2015.11 [doi]
AB  - The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and 
      cannabis active components, is the most abundant G protein-coupled receptor in 
      the mammalian brain. In particular, the CB1 receptor is highly expressed in the 
      basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays 
      a key neuromodulatory function. The CB1 receptor also confers neuroprotection in 
      various experimental models of striatal damage. However, the assessment of the 
      physiological relevance and therapeutic potential of the CB1 receptor in basal 
      ganglia-related diseases is hampered, at least in part, by the lack of knowledge 
      of the precise mechanism of CB1 receptor neuroprotective activity. Here, by using 
      an array of pharmacological, genetic and pharmacogenetic (designer receptor 
      exclusively activated by designer drug) approaches, we show that (1) CB1 receptor 
      engagement protects striatal cells from excitotoxic death via the 
      phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 
      pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) 
      expression through the selective activation of BDNF gene promoter IV, an effect 
      that is mediated by multiple transcription factors. To assess the possible 
      functional impact of the CB1/BDNF axis in a neurodegenerative-disease context in 
      vivo, we conducted experiments in the R6/2 mouse, a well-established model of 
      Huntington's disease, in which the CB1 receptor and BDNF are known to be severely 
      downregulated in the dorsolateral striatum. Adeno-associated viral 
      vector-enforced re-expression of the CB1 receptor in the dorsolateral striatum of 
      R6/2 mice allowed the re-expression of BDNF and the concerted rescue of the 
      neuropathological deficits in these animals. Collectively, these findings unravel 
      a molecular link between CB1 receptor activation and BDNF expression, and support 
      the relevance of the CB1/BDNF axis in promoting striatal neuron survival.
FAU - Blazquez, C
AU  - Blazquez C
AD  - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas 
      (CIBERNED) and Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), 
      Madrid, Spain.
AD  - Department of Biochemistry and Molecular Biology I, School of Biology, 
      Complutense University, and the Instituto Universitario de Investigacion 
      Neuroquimica (IUIN), Madrid, Spain.
FAU - Chiarlone, A
AU  - Chiarlone A
AD  - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas 
      (CIBERNED) and Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), 
      Madrid, Spain.
AD  - Department of Biochemistry and Molecular Biology I, School of Biology, 
      Complutense University, and the Instituto Universitario de Investigacion 
      Neuroquimica (IUIN), Madrid, Spain.
FAU - Bellocchio, L
AU  - Bellocchio L
AD  - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas 
      (CIBERNED) and Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), 
      Madrid, Spain.
AD  - Department of Biochemistry and Molecular Biology I, School of Biology, 
      Complutense University, and the Instituto Universitario de Investigacion 
      Neuroquimica (IUIN), Madrid, Spain.
FAU - Resel, E
AU  - Resel E
AD  - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas 
      (CIBERNED) and Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), 
      Madrid, Spain.
AD  - Department of Biochemistry and Molecular Biology I, School of Biology, 
      Complutense University, and the Instituto Universitario de Investigacion 
      Neuroquimica (IUIN), Madrid, Spain.
FAU - Pruunsild, P
AU  - Pruunsild P
AD  - Institute of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
FAU - Garcia-Rincon, D
AU  - Garcia-Rincon D
AD  - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas 
      (CIBERNED) and Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), 
      Madrid, Spain.
AD  - Department of Biochemistry and Molecular Biology I, School of Biology, 
      Complutense University, and the Instituto Universitario de Investigacion 
      Neuroquimica (IUIN), Madrid, Spain.
FAU - Sendtner, M
AU  - Sendtner M
AD  - Institute of Clinical Neurobiology, University of Wurzburg, Wurzburg, Germany.
FAU - Timmusk, T
AU  - Timmusk T
AD  - Institute of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
FAU - Lutz, B
AU  - Lutz B
AD  - Institute of Physiological Chemistry, University Medical Center of the Johannes 
      Gutenberg University Mainz, Mainz, Germany.
FAU - Galve-Roperh, I
AU  - Galve-Roperh I
AD  - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas 
      (CIBERNED) and Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), 
      Madrid, Spain.
AD  - Department of Biochemistry and Molecular Biology I, School of Biology, 
      Complutense University, and the Instituto Universitario de Investigacion 
      Neuroquimica (IUIN), Madrid, Spain.
FAU - Guzman, M
AU  - Guzman M
AD  - Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas 
      (CIBERNED) and Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), 
      Madrid, Spain.
AD  - Department of Biochemistry and Molecular Biology I, School of Biology, 
      Complutense University, and the Instituto Universitario de Investigacion 
      Neuroquimica (IUIN), Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150220
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Receptor, Cannabinoid, CB1)
RN  - 7171WSG8A2 (BDNF protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*genetics
MH  - Corpus Striatum/metabolism/*physiology
MH  - Disease Models, Animal
MH  - Huntington Disease/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes/metabolism
MH  - *Neuroprotection
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptor, Cannabinoid, CB1/*physiology
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Transgenes
PMC - PMC4563779
EDAT- 2015/02/24 06:00
MHDA- 2016/06/15 06:00
PMCR- 2015/10/01
CRDT- 2015/02/21 06:00
PHST- 2014/07/15 00:00 [received]
PHST- 2015/01/15 00:00 [revised]
PHST- 2015/01/19 00:00 [accepted]
PHST- 2015/02/21 06:00 [entrez]
PHST- 2015/02/24 06:00 [pubmed]
PHST- 2016/06/15 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - cdd201511 [pii]
AID - 10.1038/cdd.2015.11 [doi]
PST - ppublish
SO  - Cell Death Differ. 2015 Oct;22(10):1618-29. doi: 10.1038/cdd.2015.11. Epub 2015 
      Feb 20.