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Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination.

Abstract Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo.
PMID
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Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 29253893
OWN - NLM
STAT- MEDLINE
DCOM- 20180108
LR  - 20180108
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 12
DP  - 2017
TI  - Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and
      remyelination.
PG  - e0189380
LID - 10.1371/journal.pone.0189380 [doi]
AB  - BACKGROUND: Agents promoting oligodendrocyte precursor cell differentiation have 
      the potential to restore halted and/or delayed remyelination in patients with
      multiple sclerosis. However, few therapeutic targets have been identified. The
      objective of this study was to identify novel targets for promotion of
      remyelination and characterize their activity in vitro and in vivo. METHODS: A
      high-content screening assay with differentiation of primary rat oligodendrocyte 
      precursor cells was used to screen GSK-proprietary annotated libraries for
      remyelination-promoting compounds. Compounds were further validated in vitro and 
      in vivo models; clinical relevance of target was confirmed in human post-mortem
      brain sections from patients with MS. RESULTS: Of ~1000 compounds screened, 36
      promoted oligodendrocyte precursor cell differentiation in a
      concentration-dependent manner; seven were histamine receptor-3 (H3R)
      antagonists. Inverse agonists of H3R but not neutral antagonists promoted
      oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed
      throughout OPC differentiation; H3R expression was transiently upregulated on
      Days 3-5 and subsequently downregulated. H3R gene knockdown in OPCs increased the
      expression of differentiation markers and the number of mature oligodendrocytes. 
      Overexpression of full-length H3R reduced differentiation marker expression and
      the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular
      cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB)
      phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and
      Hes-5 were identified as key downstream targets of H3R during OPC
      differentiation. In the mouse cuprizone/rapamycin model of demyelination,
      systemic administration of brain-penetrable GSK247246 enhanced remyelination and 
      subsequently protected axons. Finally, we detected high H3R expression in
      oligodendroglial cells from demyelination lesions in human samples of patients
      with MS, and validated a genetic association between an exonic single nucleotide 
      polymorphism in HRH3 and susceptibility to multiple sclerosis. CONCLUSIONS: From 
      phenotypic screening to human genetics, we provide evidence for H3R as a novel
      therapeutic target to promote remyelination in patients with multiple sclerosis.
FAU - Chen, Yongfeng
AU  - Chen Y
AD  - Neuro-immunology Discovery Performance Unit, GSK, Shanghai, China.
FAU - Zhen, Wei
AU  - Zhen W
AD  - RD Platform Technology & Science, GSK, Shanghai, China.
FAU - Guo, Tony
AU  - Guo T
AD  - RD Platform Technology & Science, GSK, Shanghai, China.
FAU - Zhao, Yonggang
AU  - Zhao Y
AD  - Genetics, Projects Clinical Platforms & Sciences, GSK, Stevenage, Herts, United
      Kingdom.
FAU - Liu, Ailian
AU  - Liu A
AD  - RD Platform Technology & Science, GSK, Shanghai, China.
FAU - Rubio, Justin P
AU  - Rubio JP
AD  - Genetics, Projects Clinical Platforms & Sciences, GSK, Stevenage, Herts, United
      Kingdom.
FAU - Krull, David
AU  - Krull D
AD  - Pathology, RD Platform Technology & Science, GSK, Research Triangle Park, NC,
      United States of America.
FAU - Richardson, Jill C
AU  - Richardson JC
AD  - Neuroinflammation DPU, Neurosciences TAU, GSK, Stevenage, Herts, United Kingdom.
FAU - Lu, Hongtao
AU  - Lu H
AD  - Neuro-immunology Discovery Performance Unit, GSK, Shanghai, China.
FAU - Wang, Ryan
AU  - Wang R
AUID- ORCID: http://orcid.org/0000-0002-1896-994X
AD  - Neuro-immunology Discovery Performance Unit, GSK, Shanghai, China.
LA  - eng
PT  - Journal Article
DEP - 20171218
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Receptors, Histamine H3)
RN  - EC 2.5.1.18 (Glutathione Transferase)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Brain/pathology
MH  - Cell Differentiation
MH  - Cell Proliferation
MH  - Glutathione Transferase/metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Multiple Sclerosis/drug therapy/*genetics/metabolism
MH  - Myelin Sheath/*metabolism
MH  - Oligodendroglia/*cytology/metabolism
MH  - Phenotype
MH  - Polymorphism, Single Nucleotide
MH  - Prosencephalon/pathology
MH  - Rats
MH  - Receptors, Histamine H3/genetics/*metabolism
MH  - Signal Transduction
PMC - PMC5734789
EDAT- 2017/12/19 06:00
MHDA- 2018/01/09 06:00
CRDT- 2017/12/19 06:00
PHST- 2017/06/20 00:00 [received]
PHST- 2017/11/24 00:00 [accepted]
PHST- 2017/12/19 06:00 [entrez]
PHST- 2017/12/19 06:00 [pubmed]
PHST- 2018/01/09 06:00 [medline]
AID - 10.1371/journal.pone.0189380 [doi]
AID - PONE-D-17-16822 [pii]
PST - epublish
SO  - PLoS One. 2017 Dec 18;12(12):e0189380. doi: 10.1371/journal.pone.0189380.
      eCollection 2017.