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The novel squamosamide derivative FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice

The aim of this study was to study the effects of compound FLZ, a novel cyclic derivative of squamosamide from Annona glabra, on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis in the hippocam... Full description

Journal Title: Acta pharmacologica Sinica 2010, Vol.31 (3), p.265-272
Main Author: Li, Ning
Other Authors: Liu, Geng-tao
Format: Electronic Article Electronic Article
Language: English
Subjects:
FLZ
Publisher: United States: Nature Publishing Group
ID: ISSN: 1671-4083
Link: https://www.ncbi.nlm.nih.gov/pubmed/20154710
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title: The novel squamosamide derivative FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice
format: Article
creator:
  • Li, Ning
  • Liu, Geng-tao
subjects:
  • Alzheimer Disease - drug therapy
  • Amyloid beta-Protein Precursor - metabolism
  • Animals
  • Annona glabra
  • apoptosis
  • Apoptosis - drug effects
  • Bcl-2
  • bcl-2-Associated X Protein - metabolism
  • Benzeneacetamides - pharmacology
  • Benzeneacetamides - therapeutic use
  • brain-derived neurotrophic factor
  • Brain-Derived Neurotrophic Factor - metabolism
  • Caspase 3 - metabolism
  • Cyclic AMP Response Element-Binding Protein - metabolism
  • Female
  • FLZ
  • Hippocampus - drug effects
  • Hippocampus - metabolism
  • Male
  • Mice
  • Neurons - cytology
  • Neurons - drug effects
  • Neuroprotective Agents - pharmacology
  • Neuroprotective Agents - therapeutic use
  • Original
  • Original Article
  • Phenols - pharmacology
  • Phenols - therapeutic use
  • phospho-CREB-binding protein
  • Presenilin-1 - metabolism
  • Proto-Oncogene Proteins c-bcl-2 - metabolism
  • Receptor, trkB - metabolism
  • Signal Transduction - drug effects
  • TrkB receptor
ispartof: Acta pharmacologica Sinica, 2010, Vol.31 (3), p.265-272
description: The aim of this study was to study the effects of compound FLZ, a novel cyclic derivative of squamosamide from Annona glabra, on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis in the hippocampus of the amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice. APP/PS1 mice at the age of 5 months and age-matched wild-type mice (WT) were intragastrically administered FLZ (150 mg/kg) or vehicle [0.05% carboxymethyl cellulose sodium (CMC-Na)] daily for 20 weeks. The levels of BDNF in the hippocampus of WT and APP/PS1 mice were then measured by immunohistochemistry and Western blot analysis. Neuronal apoptosis in mouse hippocampus was detected by Nissl staining. Expression of NGF, NT3, pTrkB (Tyr515)/TrkB, pAkt (Ser473)/Akt, pERK/ERK, pCREB (Ser133)/CREB, Bcl-2/Bax, and active caspase-3 fragment/caspase-3 in the hippocampus of WT and APP/PS1 mice was detected by Western blot analysis. Compared with vehicle-treated APP/PS1 mice, FLZ (150 mg/kg) significantly increased BDNF and NT3 expression in the hippocampus of APP/PS1 mice. In addition, FLZ promoted BDNF high-affinity receptor TrkB phosphorylation and activated its downstream ERK, thus increasing phosphorylation of CREB at Ser133 in the hippocampus of APP/PS1 mice. Moreover, FLZ showed neuroprotective effects on neuronal apoptosis by increasing the Bcl-2/Bax ratio and decreasing the active caspase-3 fragment/caspase-3 ratio in the hippocampus of APP/PS1 mice. FLZ exerted neuroprotection at least partly through enhancing the BDNF/TrkB/CREB pathway and inhibiting neuronal apoptosis in APP/PS1 mice, which suggests that FLZ can be explored as a potential therapeutic agent in long-term Alzheimer's disease therapy.
language: eng
source:
identifier: ISSN: 1671-4083
fulltext: no_fulltext
issn:
  • 1671-4083
  • 1745-7254
url: Link


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titleThe novel squamosamide derivative FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice
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descriptionThe aim of this study was to study the effects of compound FLZ, a novel cyclic derivative of squamosamide from Annona glabra, on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis in the hippocampus of the amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice. APP/PS1 mice at the age of 5 months and age-matched wild-type mice (WT) were intragastrically administered FLZ (150 mg/kg) or vehicle [0.05% carboxymethyl cellulose sodium (CMC-Na)] daily for 20 weeks. The levels of BDNF in the hippocampus of WT and APP/PS1 mice were then measured by immunohistochemistry and Western blot analysis. Neuronal apoptosis in mouse hippocampus was detected by Nissl staining. Expression of NGF, NT3, pTrkB (Tyr515)/TrkB, pAkt (Ser473)/Akt, pERK/ERK, pCREB (Ser133)/CREB, Bcl-2/Bax, and active caspase-3 fragment/caspase-3 in the hippocampus of WT and APP/PS1 mice was detected by Western blot analysis. Compared with vehicle-treated APP/PS1 mice, FLZ (150 mg/kg) significantly increased BDNF and NT3 expression in the hippocampus of APP/PS1 mice. In addition, FLZ promoted BDNF high-affinity receptor TrkB phosphorylation and activated its downstream ERK, thus increasing phosphorylation of CREB at Ser133 in the hippocampus of APP/PS1 mice. Moreover, FLZ showed neuroprotective effects on neuronal apoptosis by increasing the Bcl-2/Bax ratio and decreasing the active caspase-3 fragment/caspase-3 ratio in the hippocampus of APP/PS1 mice. FLZ exerted neuroprotection at least partly through enhancing the BDNF/TrkB/CREB pathway and inhibiting neuronal apoptosis in APP/PS1 mice, which suggests that FLZ can be explored as a potential therapeutic agent in long-term Alzheimer's disease therapy.
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languageeng
publisherUnited States: Nature Publishing Group
subjectAlzheimer Disease - drug therapy ; Amyloid beta-Protein Precursor - metabolism ; Animals ; Annona glabra ; apoptosis ; Apoptosis - drug effects ; Bcl-2 ; bcl-2-Associated X Protein - metabolism ; Benzeneacetamides - pharmacology ; Benzeneacetamides - therapeutic use ; brain-derived neurotrophic factor ; Brain-Derived Neurotrophic Factor - metabolism ; Caspase 3 - metabolism ; Cyclic AMP Response Element-Binding Protein - metabolism ; Female ; FLZ ; Hippocampus - drug effects ; Hippocampus - metabolism ; Male ; Mice ; Neurons - cytology ; Neurons - drug effects ; Neuroprotective Agents - pharmacology ; Neuroprotective Agents - therapeutic use ; Original ; Original Article ; Phenols - pharmacology ; Phenols - therapeutic use ; phospho-CREB-binding protein ; Presenilin-1 - metabolism ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Receptor, trkB - metabolism ; Signal Transduction - drug effects ; TrkB receptor
ispartofActa pharmacologica Sinica, 2010, Vol.31 (3), p.265-272
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descriptionThe aim of this study was to study the effects of compound FLZ, a novel cyclic derivative of squamosamide from Annona glabra, on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis in the hippocampus of the amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice. APP/PS1 mice at the age of 5 months and age-matched wild-type mice (WT) were intragastrically administered FLZ (150 mg/kg) or vehicle [0.05% carboxymethyl cellulose sodium (CMC-Na)] daily for 20 weeks. The levels of BDNF in the hippocampus of WT and APP/PS1 mice were then measured by immunohistochemistry and Western blot analysis. Neuronal apoptosis in mouse hippocampus was detected by Nissl staining. Expression of NGF, NT3, pTrkB (Tyr515)/TrkB, pAkt (Ser473)/Akt, pERK/ERK, pCREB (Ser133)/CREB, Bcl-2/Bax, and active caspase-3 fragment/caspase-3 in the hippocampus of WT and APP/PS1 mice was detected by Western blot analysis. Compared with vehicle-treated APP/PS1 mice, FLZ (150 mg/kg) significantly increased BDNF and NT3 expression in the hippocampus of APP/PS1 mice. In addition, FLZ promoted BDNF high-affinity receptor TrkB phosphorylation and activated its downstream ERK, thus increasing phosphorylation of CREB at Ser133 in the hippocampus of APP/PS1 mice. Moreover, FLZ showed neuroprotective effects on neuronal apoptosis by increasing the Bcl-2/Bax ratio and decreasing the active caspase-3 fragment/caspase-3 ratio in the hippocampus of APP/PS1 mice. FLZ exerted neuroprotection at least partly through enhancing the BDNF/TrkB/CREB pathway and inhibiting neuronal apoptosis in APP/PS1 mice, which suggests that FLZ can be explored as a potential therapeutic agent in long-term Alzheimer's disease therapy.
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1Amyloid beta-Protein Precursor - metabolism
2Animals
3Annona glabra
4apoptosis
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6Bcl-2
7bcl-2-Associated X Protein - metabolism
8Benzeneacetamides - pharmacology
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11Brain-Derived Neurotrophic Factor - metabolism
12Caspase 3 - metabolism
13Cyclic AMP Response Element-Binding Protein - metabolism
14Female
15FLZ
16Hippocampus - drug effects
17Hippocampus - metabolism
18Male
19Mice
20Neurons - cytology
21Neurons - drug effects
22Neuroprotective Agents - pharmacology
23Neuroprotective Agents - therapeutic use
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27Phenols - therapeutic use
28phospho-CREB-binding protein
29Presenilin-1 - metabolism
30Proto-Oncogene Proteins c-bcl-2 - metabolism
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32Signal Transduction - drug effects
33TrkB receptor
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titleThe novel squamosamide derivative FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice
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28phospho-CREB-binding protein
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30Proto-Oncogene Proteins c-bcl-2 - metabolism
31Receptor, trkB - metabolism
32Signal Transduction - drug effects
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abstractThe aim of this study was to study the effects of compound FLZ, a novel cyclic derivative of squamosamide from Annona glabra, on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis in the hippocampus of the amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice. APP/PS1 mice at the age of 5 months and age-matched wild-type mice (WT) were intragastrically administered FLZ (150 mg/kg) or vehicle [0.05% carboxymethyl cellulose sodium (CMC-Na)] daily for 20 weeks. The levels of BDNF in the hippocampus of WT and APP/PS1 mice were then measured by immunohistochemistry and Western blot analysis. Neuronal apoptosis in mouse hippocampus was detected by Nissl staining. Expression of NGF, NT3, pTrkB (Tyr515)/TrkB, pAkt (Ser473)/Akt, pERK/ERK, pCREB (Ser133)/CREB, Bcl-2/Bax, and active caspase-3 fragment/caspase-3 in the hippocampus of WT and APP/PS1 mice was detected by Western blot analysis. Compared with vehicle-treated APP/PS1 mice, FLZ (150 mg/kg) significantly increased BDNF and NT3 expression in the hippocampus of APP/PS1 mice. In addition, FLZ promoted BDNF high-affinity receptor TrkB phosphorylation and activated its downstream ERK, thus increasing phosphorylation of CREB at Ser133 in the hippocampus of APP/PS1 mice. Moreover, FLZ showed neuroprotective effects on neuronal apoptosis by increasing the Bcl-2/Bax ratio and decreasing the active caspase-3 fragment/caspase-3 ratio in the hippocampus of APP/PS1 mice. FLZ exerted neuroprotection at least partly through enhancing the BDNF/TrkB/CREB pathway and inhibiting neuronal apoptosis in APP/PS1 mice, which suggests that FLZ can be explored as a potential therapeutic agent in long-term Alzheimer's disease therapy.
copUnited States
pubNature Publishing Group
pmid20154710
doi10.1038/aps.2010.3
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