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Journal ArticleDOI

A 2-Substituted 8-Hydroxyquinoline Stimulates Neural Stem Cell Proliferation by Modulating ROS Signalling.

21 Jun 2016-Cell Biochemistry and Biophysics (Springer US)-Vol. 74, Iss: 3, pp 297-306
TL;DR: The results indicate that DMAMQ can stimulate neurogenesis via the Nox signalling pathway, which may provide therapeutic benefit in treating dementias of various types by replenishing neurones using the brain’s own reserves.
Abstract: Eight-hydroxyquinolines (8HQs) are a class of compounds that have been identified as potential therapeutics for a number of neurodegenerative diseases. Understanding the influence of structural modifications to the 8HQ scaffold on cellular behaviour will aid the identification of compounds that might be effective in treating dementias. In this study, we describe the action of 2-[(dimethylamino)methyl]-8-hydroxyquinoline (DMAMQ) on adult murine neural stem cells (NSCs) cultured in vitro. Treatment of NSCs with DMAMQ resulted in enhanced self-renewal and increased neurite outgrowth. Concurrent with the positive growth effects was an increase in intracellular reactive oxygen species, with the growth being inhibited by inactivation of the NADPH oxidase (Nox) enzyme family. Our results indicate that DMAMQ can stimulate neurogenesis via the Nox signalling pathway, which may provide therapeutic benefit in treating dementias of various types by replenishing neurones using the brain's own reserves. The narrow concentration range over which these effects were observed, however, suggests that there may exist only a small therapeutic window for neuro-regenerative applications.

Summary (2 min read)

Introduction

  • Endogenous neural stem cells (NSCs) are an as-yet untapped resource in combatting dementia.
  • Low levels of NSCs persist in the brain throughout adult life, maintaining the ability to self-replicate and to differentiate into mature brain cells.
  • During dementia, neurogenesis (the ability to form new neurones) is seen to become dysregulated [1,2].
  • Compounds that modulate or normalise the functions of NSCs represent a prime target for alleviating the symptoms associated with, or delaying the course of, neurodegenerative diseases.
  • Unbiased chemical screening of substituted 8-hydroxyquinolines (8HQs) and a range of investigations in yeast, nematodes, mice and humans have highlighted the variable mechanisms by they may act.

DMAMQ treatments

  • DMAMQ was included in the culture medium at the concentrations indicated.
  • For all assays, the compound was added as a single treatment at the start of the assay and was not replenished when the media was changed.

Neural Colony Forming Assay (NCFA)

  • The NCFA has been described previously [29].
  • For each independent experiment over 50 colonies were measured.
  • As stated above, DMAMQ was included in the matrix once only at the start of the incubation.

Neurite outgrowth assay

  • Neurite outgrowth was measured using a neurite outgrowth staining kit (Merck-Millipore) as per the manufacturer's instructions with the following modifications.
  • One hundred thousand cells per condition were incubated in high FGF (20 ng/mL), no EGF, growth media before seeding 100,000 cells per well insert (1 μm pore size) in differentiation medium with or without test compound.
  • Neurite outgrowth was permitted for two days before assay.

Dichlorofluorescein (DCF) intracellular ROS assay

  • The DCF assay has been described previously [30].
  • Fluorescence intensity was measured every 5 min for 12 hours using a FLUOstar Optima (BMG Labtech) fitted with 490 nm excitation and 520 nm emission filters and initial rates were calculated using tangents to the curve.

MTS metabolism assay

  • Five µL of One Solution MTS reagent per 100 µL media was added to test and media only background control conditions, and incubated under normal culture conditions for 90 min.
  • The cells were stained using a Cell Signaling Technologies' β-galactosidase staining kit as per the manufacturer's instructions.
  • To solubilise the stain for quantitation by spectrometry, the staining solution was removed from the wells and replaced with 350 μL of DMSO.
  • The plate was warmed with agitation at 50C for 1 hour before 100 μL of dissolved dye was transferred to three wells of a 96-well plate for triplicate reads.

Ki67 flow cytometry

  • Ki67 expression in proliferating cells was quantified using the Muse Ki67 Proliferation Kit as per the manufacturer's instructions.
  • For the final analysis the number of unstained cells gated as positive was subtracted from the stained cells and percentage change was calculated from the control cells.
  • Cell cycle phase analysis by DNA content was determined using the Muse Cell Cycle Analysis Kit as per the manufacturer's instructions.

PAGE and Western Blotting

  • Polyacryalmide gel electrophoresis and western blotting was conducted as described previously [32].
  • Relative densitometric comparisons were normalised for total protein loading as shown in Coomassie stained images.

Calcium assay

  • Cells were seeded in 96-well plates as above.
  • At the beginning of the assay 50 μl of culture media was removed from each well and replaced with calcium assay working buffer as per manufacturer's instructions .
  • Readings were taken using 488 nm excitation and 530 nm emission filters in a FluoSTAR Optima (BMG Labtech) every 60 seconds for 1 hour from addition.
  • Statistical analyses Statistical analyses were carried out using GraphPad Prism 5 statistical software.
  • Graphs show the mean and standard error of the mean (SEM) of n independent experiments unless otherwise stated.

Results and Discussion

  • Herein the authors investigated the potential for DMAMQ to enhance the regenerative capacity of NSCs cultured in vitro.
  • The ability of DMAMQ to stimulate neurite outgrowth during differentiation was assessed using a colourimetric neurite staining protocol and showed that, over two days of differentiation, DMAMQ-treated cells displayed ca. 10% more neurite outgrowth than was observed for control cells .
  • When DPI and DMAMQ were co-incubated in the mediamatrix (single treatment at the start of the assay) the growth of the spheres was stunted, with fewer colonies formed and decreased diameter at the 2.5 μM treatment concentrations of DMAMQ.
  • Whilst their results concur with previous literature that increased ROS increases NSC growth and suggest that modulation of Nox to increase ROS signalling initiates such growth, the data presented cannot exclude intrinsic ROS production by DMAMQ that mimics, but does not outcompete inhibition of, this pathway.
  • Increased neurogenesis may represent a compensatory response by the NSCs within the brain to replenish lost neurones.

Conclusions

  • This study demonstrates that DMAMQ modulates NSC growth and neurite outgrowth during differentiation when cultured in vitro by stimulating ROS production and Nox signalling.
  • This suggests that DMAMQ and similar 8HQs may have neuro-regenerative potential in vivo; however, the very narrow concentration range in which DMAMQ modulates NSC growth presents some challenges for therapeutic administration.
  • In particular, the potential benefits of replenishing damaged brain tissue must be balanced against the possibility of overstimulating neurogenesis and the propensity for undesirable “off-target” effects.

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Figures (6)

Content maybe subject to copyright    Report

1
A 2-substituted 8-hydroxyquinoline stimulates neural stem cell proliferation by
modulating ROS signalling
Cathryn L. Haigh,
1,
* Carolin Tumpach,
2
Steven J. Collins,
1
and Simon C. Drew
2,
*
1
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Victoria
3010, Australia,
2
The Florey Department of Neuroscience and Mental Health, The University
of Melbourne, Victoria 3010, Australia.
* To whom correspondence should be addressed: sdrew@unimelb.edu.au (+61 3 9035 8684),
chaigh@unimelb.edu.au (+61 3 8344 1952)
Running Title:
8HQ stimulation of NSC proliferation
Keywords:
8-hydroxyquinoline, neural stem cells, neurosphere, proliferation, NADPH oxidase, reactive
oxygen species, 2-[(dimethylamino)methyl]-8-hydroxyquinoline, DMAMQ, PBT2

2
Abstract
Eight-hydroxyquinolines (8HQs) are a class of compounds that have been identified as
potential therapeutics for a number of neurodegenerative diseases. Understanding the
influence of structural modifications to the 8HQ scaffold on cellular behaviour will aid the
identification of compounds that might be effective in treating dementias. In this study, we
describe the action of 2-[(dimethylamino)methyl]-8-hydroxyquinoline (DMAMQ) on adult
murine neural stem cells (NSCs) cultured in vitro. Treatment of NSCs with DMAMQ
resulted in enhanced self-renewal and increased neurite outgrowth. Concurrent with the
positive growth effects was an increase in intra-cellular reactive oxygen species, with the
growth being inhibited by inactivation of the NADPH oxidase (Nox) enzyme family. Our
results indicate that DMAMQ can stimulate neurogenesis via the Nox signalling pathway,
which may provide therapeutic benefit in treating dementias of various types by replenishing
 The narrow concentration range over which these
effects were observed, however, suggests there may exist only a small therapeutic window for
neuro-regenerative applications.

3
Introduction
Endogenous neural stem cells (NSCs) are an as-yet untapped resource in combatting
dementia. Low levels of NSCs persist in the brain throughout adult life, maintaining the
ability to self-replicate and to differentiate into mature brain cells. During dementia,
neurogenesis (the ability to form new neurones) is seen to become dysregulated [
1
,
2
]. In
rodent models of Alzheimer's disease (AD), production of beta-amyloid, one hallmark of AD,
changes the growth and differentiation of these cells [
3
,
4
,
5
,
6
,
7
]. Neurogenesis has been
extensively linked with both learning and forgetting [
8
,
9
,
10
]; therefore, changes in these
processes might contribute significantly to the cognitive changes that occur during
neurodegenerative diseases, including AD. Compounds that modulate or normalise the
functions of NSCs represent a prime target for alleviating the symptoms associated with, or
delaying the course of, neurodegenerative diseases.
Unbiased chemical screening of substituted 8-hydroxyquinolines (8HQs) and a range of
investigations in yeast, nematodes, mice and humans have highlighted the variable
mechanisms by they may act. Side-chain modifications to the 8HQ backbone may lead to
functional differences in vivo, with applications of substituted 8HQs as anti-microbial agents
[
11
,
12
], anti-cancer agents [
13
,
14
], epigenetic modulators [
15
,
16
], dementia treatments
[
17
,
18
,
19
,
20
], artificial nucleobases [
21
] and medical imaging agents [
22
,
23
]. Moreover,
biosynthesis of substituted 8HQs has been identified in mammals (eg. xanthurenic acid [
24
]),
bacteria (eg. quinolobactin [
25
]) and insects (eg. 2-carboxy-8HQ [
26
]). In dementia
applications, studies utilising 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline
reported an increased neurite number following treatment of cultured PC12 cells and a
restoration of hippocampal dendritic spine density (but not number) in transgenic mouse
model of AD [18].

4
In the current study, we sought to further understand the action of this class of 8HQ by
treating adult murine NSC cultures with 2-[(dimethylamino)methyl]-8-hydroxyquinoline
(DMAMQ; Figure 1). We specifically assessed the ability of these cells to self-renew,
essential for maintaining their numbers in the brain throughout life, and to differentiate into
new CNS lineage cells. Our findings show that whilst neurogenesis is unchanged, NSCs
treated with DMAMQ demonstrate a dose-dependent increase in NSC proliferation and
increased neurite outgrowth during neurogenesis that was signalled by increased production
of reactive oxygen species (ROS) signalling intermediates by the NADPH oxidase (Nox)
enzyme family. These effects were only observed within a narrow concentration range,
suggesting a small therapeutic window for neuro-regenerative applications.

5
Materials and Methods:
Synthesis
2-[(dimethylamino)methyl]-8-hydroxyquinoline (DMAMQ) was synthesised as described
previously [
27
].
Cell culture
Murine NSCs were harvested from the brains of 6-8 week old Balb/c mice and grown without
modification as neurospheres in liquid culture as described previously [
28
].
DMAMQ treatments
DMAMQ was included in the culture medium at the concentrations indicated. For all assays,
the compound was added as a single treatment at the start of the assay and was not
replenished when the media was changed.
Neural Colony Forming Assay (NCFA)
The NCFA has been described previously [
29
]. For each independent experiment over 50
colonies were measured. As stated above, DMAMQ was included in the matrix once only at
the start of the incubation.
Neurite outgrowth assay
Neurite outgrowth was measured using a neurite outgrowth staining kit (Merck-Millipore) as
per the manufacturer's instructions with the following modifications. One hundred thousand
cells per condition were incubated in high FGF (20 ng/mL), no EGF, growth media before

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  • ...Indeed, studies using a homologous terdentate 8HQ resulted in a significant increase in pGSK 3β only at cytotoxic concentrations (Haigh et al., 2016)....

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  • ...…in the presence of the biological reductant such as ascorbate, the dominant ternary metal complexes can produce as many hydroxyl radicals as Cu(Aβ1−x) in vitro (Mital et al., 2016) and ROS production can be observed following addition of such 8HQs to neural stem cell cultures (Haigh et al., 2016)....

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  • ..., 2016) and ROS production can be observed following addition of such 8HQs to neural stem cell cultures (Haigh et al., 2016)....

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Cites background from "A 2-Substituted 8-Hydroxyquinoline ..."

  • ...Interestingly, the generation of ROS can be detected by adding such ligands to the culture of neural stem cells [324], in contrast to the founding principle of therapeutic chelation therapy [325]....

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References
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TL;DR: A novel mechanism in which Nox2 modulates cardiomyocyte SR Ca2+ uptake and contractile function through redox-regulated changes in phospholamban phosphorylation is identified, which can drive increased contractility in the short term in disease states characterized by enhanced renin-angiotensin system activation.

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"A 2-Substituted 8-Hydroxyquinoline ..." refers background in this paper

  • ...functions of heart muscle [50, 51] and systemic immune responses [37, 52], whilst acute and chronic Nox activity is associated with neuroinflammation [53]....

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Journal ArticleDOI
01 Aug 2014-Brain
TL;DR: In a mouse model of prion disease, Gomez-Nicola et al. detect increased neurogenesis in the dentate gyrus that partially counteracts neuronal loss and may have therapeutic potential.
Abstract: The study of neurogenesis during chronic neurodegeneration is crucial in order to understand the intrinsic repair mechanisms of the brain, and key to designing therapeutic strategies. In this study, using an experimental model of progressive chronic neurodegeneration, murine prion disease, we define the temporal dynamics of the generation, maturation and integration of new neurons in the hippocampal dentate gyrus, using dual pulse-chase, multicolour γ-retroviral tracing, transmission electron microscopy and patch-clamp. We found increased neurogenesis during the progression of prion disease, which partially counteracts the effects of chronic neurodegeneration, as evidenced by blocking neurogenesis with cytosine arabinoside, and helps to preserve the hippocampal function. Evidence obtained from human post-mortem samples, of both variant Creutzfeldt-Jakob disease and Alzheimer’s disease patients, also suggests increased neurogenic activity. These results open a new avenue into the exploration of the effects and regulation of neurogenesis during chronic neurodegeneration, and offer a new model to reproduce the changes observed in human neurodegenerative diseases.

73 citations


"A 2-Substituted 8-Hydroxyquinoline ..." refers background in this paper

  • ...During dementia, neurogenesis (the ability to form new neurones) is seen to become dysregulated [1, 2]....

    [...]

Journal ArticleDOI
TL;DR: ROS formation is involved in the apoptotic and cell differentiation responses to NSC3852 in MCF-7 cells, and the flavoprotein inhibitor diphenylene iodonium suppressed ROS production, providing evidence for the involvement of a flavin-dependent enzyme system in the ROS response to N SC3852.
Abstract: NSC3852 (5-nitroso-8-quinolinol) has cell differentiation and antiproliferative activity in human breast cancer cells in tissue culture and antitumor activity in mice bearing P388 and L1210 leukemic cells. We investigated the mechanism of NSC3852 action in MCF-7 human breast cancer cells using electron spin resonance (ESR). Reactive oxygen species (ROS) were detected in MCF-7 cell suspensions incubated with NSC3852 using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Formation of the DMPO-OH adduct was quenched by the addition of superoxide dismutase but not by catalase, and we concluded that superoxide was generated in the NSC3852-treated cells. The flavoprotein inhibitor diphenylene iodonium suppressed ROS production, providing evidence for the involvement of a flavin-dependent enzyme system in the ROS response to NSC3852. A biologically significant oxidative response to NSC3852 occurred in MCF-7 cells. An early marker of oxidative stress was a decrease in the [glutathione]/[glutathione disulfide] ratio 1 h after NSC3852 addition. Oxidative DNA damage, marked by the presence of 8-oxoguanine, and DNA-strand breakage occurred in cells exposed to NSC3852 for 24 h. Apoptosis peaked 48 h after exposure to NSC3852. Pretreatment with the glutathione precursor N-acetyl-l-cysteine (NAC) prevented DNA-strand breakage and apoptosis. Pretreatment with NAC also reversed NSC3852 decreases in E2F1, Myc, and phosphorylated retinoblastoma protein, indicative of redox-sensitive pathway(s) in MCF-7 cells during G(1) phase of the cell cycle. We conclude that ROS formation is involved in the apoptotic and cell differentiation responses to NSC3852 in MCF-7 cells.

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"A 2-Substituted 8-Hydroxyquinoline ..." refers background in this paper

  • ...Moreover, substituted 8HQs can have anti-proliferative/cytotoxic properties depending on their local concentrations (Figure S1) [13,14,15] or have the potential to cause neuronal damage by interfering with epigenetic regulation (eg....

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  • ...Side-chain modifications to the 8HQ backbone may lead to functional differences in vivo, with applications of substituted 8HQs as anti-microbial agents [11,12], anti-cancer agents [13,14], epigenetic modulators [15,16], dementia treatments [17,18,19,20], artificial nucleobases [21] and medical imaging agents [22,23]....

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TL;DR: The findings suggest a molecular basis for the strong metal chaperone activity of PBT2, its ability to attenuate Cu(2+)/Aβ interactions, and its potential to promote neuroprotective and neuroregenerative effects.
Abstract: 8-Hydroxyquinolines (8HQ) have found widespread application in chemistry and biology due to their ability to complex a range of transition metal ions. The family of 2-substituted 8HQs has been proposed for use in the treatment of Alzheimer's disease (AD). Most notably, the therapeutic PBT2 (Prana Biotechnology Ltd.) has been shown to act as an efficient metal chaperone, disaggregate metal-enriched amyloid plaques comprised of the Aβ peptide, inhibit Cu/Aβ redox chemistry, and reverse the AD phenotype in transgenic animal models. Yet surprisingly little is known about the molecular interactions at play. In this study, we show that the homologous ligand 2-[(dimethylamino)methyl]-8-hydroxyquinoline (HL) forms a CuL complex with a conditional (apparent) dissociation constant of 0.33 nM at pH 6.9 and is capable of forming ternary Cu(2+) complexes with neurotransmitters including histamine (HA), glutamic acid (Glu), and glycine (Gly), with glutathione disulfide (GSSG), and with histidine (His) side chains of proteins and peptides including the Aβ peptide. Our findings suggest a molecular basis for the strong metal chaperone activity of PBT2, its ability to attenuate Cu(2+)/Aβ interactions, and its potential to promote neuroprotective and neuroregenerative effects.

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"A 2-Substituted 8-Hydroxyquinoline ..." refers methods in this paper

  • ...Synthesis 2-[(dimethylamino)methyl]-8-hydroxyquinoline (DMAMQ) was synthesised as described previously [27]....

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TL;DR: It is proposed that compounds selectively targeting cancer stem/progenitor cells when combined with standard chemotherapy drugs may produce an improved treatment of cancer without significant relapse.
Abstract: Increasing evidence suggests that breast cancer is caused by cancer stem cells and the cure of breast cancer requires eradication of breast cancer stem cells. In this study, we established and characterized a sphere culture model derived from side population cells from the human breast cancer cell line MCF7. The sphere culture could be maintained long term and was enriched in cells expressing known breast cancer stem cell marker CD44+CD24−. These sphere cells showed higher colony formation ability in vitro and higher tumorigenicity in vivo than MCF7 cells, suggesting the enrichment of breast cancer stem/progenitor cells. To identify compounds that preferentially inhibit the sphere cells, we performed a compound library screening. Two lead compounds, NSC24076 and NSC125034 and an analog of NSC125034, 8-quinolinol (8Q), were identified as having preferential activity against the sphere cells. 8Q showed some antitumor activity alone but had much better therapeutic effect and relapse prevention when combined with paclitaxel than either 8Q or paclitaxel alone in both MCF7 and MDA-MB-435 xenograft models. We propose that compounds selectively targeting cancer stem/progenitor cells when combined with standard chemotherapy drugs may produce an improved treatment of cancer without significant relapse.

48 citations


"A 2-Substituted 8-Hydroxyquinoline ..." refers background in this paper

  • ...Side-chain modifications to the 8HQ backbone may lead to functional differences in vivo, with applications of substituted 8HQs as anti-microbial agents [11, 12], anti-cancer agents [13, 14], epigenetic modulators [15, 16], dementia treatments [17–20], artificial nucleobases [21] and medical imaging agents [22, 23]....

    [...]

Frequently Asked Questions (2)
Q1. What are the contributions mentioned in the paper "A 2-substituted 8-hydroxyquinoline stimulates neural stem cell proliferation by modulating ros signalling" ?

In this paper, the effect of substituted 8-hydroxyquinolines ( 8HQs ) on NSC proliferation and neurite outgrowth was investigated. 

In particular, the potential benefits of replenishing damaged brain tissue must be balanced against the possibility of overstimulating neurogenesis and the propensity for undesirable “ off-target ” effects.