PMID- 25450955
OWN - NLM
STAT- MEDLINE
DCOM- 20160426
LR  - 20150805
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Linking)
VI  - 302
DP  - 2015 Aug 27
TI  - CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 
      mice and primary glial cultures exposed to beta-amyloid.
PG  - 112-20
LID - S0306-4522(14)00893-8 [pii]
LID - 10.1016/j.neuroscience.2014.10.029 [doi]
AB  - Activation of microglia associated with neuroinflammation and loss of phagocytic 
      activity is considered to play a prominent role in the pathogenesis of 
      Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition 
      and reduce brain inflammation in patients with mild cognitive impairment (MCI). 
      CHF5074 was also found to reverse impairments in recognition memory and improve 
      hippocampal long-term potentiation when administered to plaque-free Tg2576 mice 
      (5-month-old) for 4 weeks. Though, no investigation has focused on the 
      consequence of CHF5074 treatment on microglia polarization yet. In this study we 
      evaluated the effect of CHF5074 administration (375 ppm in the diet) to 
      5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, 
      Interleukin 1 beta (IL-1beta), Tumor Necrosis Factor alpha (TNFalpha) and inducible 
      Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers 
      Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid 
      cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene 
      transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected 
      in the hippocampus of young Tg2576 mice receiving normal diet, when compared to 
      wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription 
      but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects 
      appeared to be hippocampus-specific, as the M2 transcripts were only slightly 
      modified in the cerebral cortex. In primary cultures of mouse 
      astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-alpha, IL-1beta 
      and iNOS induced by 10 muM beta-amyloid1-42 (Abeta42). Moreover, CHF5074 significantly 
      increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and 
      TREM2, reduced by the Abeta42 application alone. The effect of CHF5074 was not 
      reproduced by ibuprofen (3 muM or 500 muM) or R-flurbiprofen (3 muM or 100 muM), as 
      both compounds limited the pro-inflammatory gene expression but did not modify 
      the anti-inflammatory/phagocytic transcription. These data show that CHF5074 
      specifically drives the expression of microglia M2 markers either in young Tg2576 
      hippocampus or in primary astrocyte-microglia cultures, suggesting its potential 
      therapeutic efficacy as microglial modulator in the early phase of AD.
CI  - Copyright (c) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
FAU - Porrini, V
AU  - Porrini V
AD  - Department of Molecular and Translational Medicine, University of Brescia and 
      National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy; IRCCS 
      San Camillo Hospital, Via Alberoni 70, 30126 Venice, Italy.
FAU - Lanzillotta, A
AU  - Lanzillotta A
AD  - Department of Molecular and Translational Medicine, University of Brescia and 
      National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy.
FAU - Branca, C
AU  - Branca C
AD  - Department of Molecular and Translational Medicine, University of Brescia and 
      National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy.
FAU - Benarese, M
AU  - Benarese M
AD  - Department of Molecular and Translational Medicine, University of Brescia and 
      National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy.
FAU - Parrella, E
AU  - Parrella E
AD  - Department of Molecular and Translational Medicine, University of Brescia and 
      National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy.
FAU - Lorenzini, L
AU  - Lorenzini L
AD  - Health Science and Technologies, Interdepartmental Center for Industrial Research 
      (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, 
      Bologna, Italy.
FAU - Calza, L
AU  - Calza L
AD  - Health Science and Technologies, Interdepartmental Center for Industrial Research 
      (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, 
      Bologna, Italy; Department of Pharmacy and Biotechnology, University of Bologna, 
      Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, Bologna, Italy; IRET Foundation, 
      Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, Bologna, Italy.
FAU - Flaibani, R
AU  - Flaibani R
AD  - IRCCS San Camillo Hospital, Via Alberoni 70, 30126 Venice, Italy.
FAU - Spano, P F
AU  - Spano PF
AD  - Department of Molecular and Translational Medicine, University of Brescia and 
      National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy; IRCCS 
      San Camillo Hospital, Via Alberoni 70, 30126 Venice, Italy.
FAU - Imbimbo, B P
AU  - Imbimbo BP
AD  - Research & Development, Chiesi Farmaceutici, Via Palermo 26/A, 43100 Parma, 
      Italy.
FAU - Pizzi, M
AU  - Pizzi M
AD  - Department of Molecular and Translational Medicine, University of Brescia and 
      National Institute of Neuroscience, Viale Europa 11, 25123 Brescia, Italy; IRCCS 
      San Camillo Hospital, Via Alberoni 70, 30126 Venice, Italy. Electronic address: 
      marina.pizzi@unibs.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141022
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Cyclopropanes)
RN  - 0 (Cytokines)
RN  - 5GRO578KLP (Flurbiprofen)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
SB  - IM
MH  - Alzheimer Disease/drug therapy/genetics/*pathology
MH  - Amyloid beta-Peptides/*pharmacology
MH  - Amyloid beta-Protein Precursor/genetics
MH  - Animals
MH  - Animals, Newborn
MH  - Anti-Inflammatory Agents, Non-Steroidal/pharmacology
MH  - Antipsychotic Agents/pharmacology/therapeutic use
MH  - Brain/*pathology
MH  - Case-Control Studies
MH  - Cells, Cultured
MH  - Cyclopropanes/pharmacology/*therapeutic use
MH  - Cytokines/genetics/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Flurbiprofen/*analogs & derivatives/pharmacology/therapeutic use
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mutation/genetics
MH  - Neuroglia/*drug effects
MH  - Nitric Oxide Synthase Type II/genetics/metabolism
MH  - Time Factors
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - CHF5074
OT  - CSP-1103
OT  - Microglia
OT  - Neuroinflammation
OT  - Tg2576
EDAT- 2014/12/03 06:00
MHDA- 2016/04/27 06:00
CRDT- 2014/12/03 06:00
PHST- 2014/07/30 00:00 [received]
PHST- 2014/10/06 00:00 [revised]
PHST- 2014/10/13 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2016/04/27 06:00 [medline]
AID - S0306-4522(14)00893-8 [pii]
AID - 10.1016/j.neuroscience.2014.10.029 [doi]
PST - ppublish
SO  - Neuroscience. 2015 Aug 27;302:112-20. doi: 10.1016/j.neuroscience.2014.10.029. 
      Epub 2014 Oct 22.