The Flavonoid Isoquercitrin Promotes Neurite Elongation by Reducing RhoA Activity

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Author(s) Palazzolo, Gemma, Horvath, Peter, Zenobi-Wong, Marcy
Publication Type Journal Items, Publication Status: Published
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Title The Flavonoid Isoquercitrin Promotes Neurite Elongation by Reducing RhoA Activity
Author(s) Palazzolo, Gemma
Horvath, Peter
Zenobi-Wong, Marcy
Description 10 p.
Journal or Series Title Plos One
Volume Number 7
Issue Number 11
Start Page e49979
ISSN 1932-6203
Publisher Public Library of Science
Publication Place Lawrence, Kan.
Publication Date 2012-11
Abstract Background: Neurite formation and synaptic patterning are fundamental to the development of a functional nervous system. Flavonoids are natural molecules known for having beneficial effects on brain health through diverse molecular pathways. Cytoskeletal changes occurring during neuritogenesis and synapse formation often involve Rho GTPases. Here we hypothesized that the flavonoid isoquercitrin promotes neuronal differentiation through Rho signalling.
Methodology/Principal Findings: We performed time lapse imaging of NG108-15 cells during incubation with/without isoquercitrin. Isoquercitrin stimulated extensive neurites enriched in the synaptic vesicle protein synaptotagmin-1. Neurite extension was augmented by the ROCK inhibitor Y-27632 suggesting an inactivation of RhoA/Rho kinase as the mechanism. To test this, we first measured the dose-dependent effect of isoquercitrin on RhoA activity and found a 47% reduction in RhoA activity at concentrations which induced neurites (≥40 µM). Secondly, we tested the ability of isoquercitrin to rescue the neural phenotype in a model of RhoA-induced neurite retraction and found that 40 µM isoquercitrin added to cultures previously treated with the RhoA activator calpeptin produced significantly more neurite length/cell than calpeptin alone. Finally, we tested the hypothesis that isoquercitrin may affect RhoA localization preventing the translocation to the plasma membrane. Unexpectedly, immunolocalization studies showed that RhoA was present in nuclear compartments of control NG108-cells, but underwent translocation to the cytoplasm upon treatment with isoquercitrin. DNA microarrays and reverse transcription - quantitative PCR (RT-qPCR) revealed differences in global gene expression of Rho GTPase family members. These data taken together indicate that isoquercitrin is a potential stimulator of neuronal differentiation, through multiple Rho GTPase mediated mechanisms.
Conclusions/Significance: As several members of the Rho GTPase family are implicated in human neurological disorders/injuries, our results suggest that isoquercitrin could be used in the treatment of these pathological states through its effect on this family of molecular switches.
DOI 10.1371/journal.pone.0049979
Additional Notes Received 13 December 2011, Accepted 18 October 2012, Published online 29 November 2012
Document Type Article
Publication Status Published
Language English
Assigned Organisational Unit(s) 03949
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NEBIS System Number 006206116
Source Database ID WOS-000312104900015
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@article{Plzzl2012,
  author = "Palazzolo, Gemma and Horvath, Peter and Zenobi-Wong, Marcy",
  title = "{T}he {F}lavonoid {I}soquercitrin {P}romotes {N}eurite {E}longation by {R}educing {R}ho{A} {A}ctivity",
  journal = "Plos One",
  year = 2012,
  volume = "7",
  number = "11",
  pages = "e49979--",
  month = nov,
}


E-Citations record created: Mon, 14 Jan 2013, 07:41:57 CET