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Selective Aryl Hydrocarbon Receptor Modulator 3,3′-Diindolylmethane Impairs AhR and ARNT Signaling and Protects Mouse Neuronal Cells Against Hypoxia

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Abstract

The neuroprotective potential of 3,3′-diindolylmethane (DIM), which is a selective aryl hydrocarbon receptor modulator, has recently been shown in cellular and animal models of Parkinson’s disease and lipopolysaccharide-induced inflammation. However, there are no data concerning the protective capacity and mechanisms of DIM action in neuronal cells exposed to hypoxia. The aim of the present study was to investigate the neuroprotective potential of DIM against the hypoxia-induced damage in mouse hippocampal cells in primary cultures, with a particular focus on DIM interactions with the aryl hydrocarbon receptor (AhR), its nuclear translocator ARNT, and estrogen receptor β (ERβ). In the present study, 18 h of hypoxia induced apoptotic processes, in terms of the mitochondrial membrane potential, activation of caspase-3, and fragmentation of cell nuclei. These effects were accompanied by substantial lactate dehydrogenase release and neuronal cell death. The results of the present study demonstrated strong neuroprotective and anti-apoptotic actions of DIM in hippocampal cells exposed to hypoxia. In addition, DIM decreased the Ahr and Arnt mRNA expression and stimulated Erβ mRNA expression level. DIM-induced mRNA alterations were mirrored by changes in protein levels, except for ERβ, as detected by ELISA, Western blotting, and immunofluorescence labeling. We also demonstrated that DIM decreased the expression of AhR-regulated CYP1A1. Using specific siRNAs, we provided evidence that impairment of AhR and ARNT, but not ERβ plays a key role in the neuroprotective action of DIM against hypoxia-induced cell damage. This study may have implication for identifying new agents that could protect neurons against hypoxia by targeting AhR/ARNT signaling.

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Abbreviations

Ac-DEVD-pNA:

N-acetyl-asp-glu-val-asp p-nitro-anilide

AhR:

Aryl hydrocarbon receptor modulator

ANF:

α-Naphthoflavone, a selective antagonist of aryl hydrocarbon receptor

ARNT:

Aryl hydrocarbon receptor nuclear translocator

BNF:

β-Naphthoflavone, a selective agonist of aryl hydrocarbon nuclear receptor

CHAPS:

3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate hydrate

CO2 :

Carbon dioxide

CYP1A1:

Cytochrome P450 1A1

DCF:

2′,7′-Dichlorofluorescein diacetate

DIV:

Day in vitro

DMSO:

Dimethyl sulfoxide

DPN:

2,3-bis(4-Hydroxyphenyl)-propionitrile highly potent estrogen ERβ receptor agonist

DIM:

3,3′-Diindolylmethane

ELISA:

Enzyme-linked immunosorbent assay

ER:

Estrogen receptor

ERα:

Estrogen receptor alpha

ERβ:

Estrogen receptor beta

HIF-1α:

Hypoxia-inducible factor-1 alpha

HIF-1β:

Hypoxia-inducible factor-1 beta

Hprt :

Hypoxanthine phosphoribosyltransferase coding gene

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbo-cyanine iodide

LDH:

Lactate dehydrogenase

N2 :

Nitrogen

PHTPP:

4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5,-a]pyrimidin-3-yl]phenol a selective ERβ antagonist

PBS:

Phosphate-buffered saline

RT:

Reverse transcription

SERM:

Selective estrogen receptor modulator

SAhRM:

Selective aryl hydrocarbon receptor modulator

TCDD:

2,3,7,8 - Tetrachlorodibenzodioxin

qPCR:

Quantitative polymerase chain reaction

WB:

Western blot

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Acknowledgments

This study was financially supported by a grant no. 2011/01/N/NZ3/04786 from the National Science Centre, Poland. Agnieszka Wnuk and Joanna Rzemieniec received scholarships from the KNOW sponsored by the Ministry of Science and Higher Education, Poland. This publication was also supported by a funding from the Jagiellonian University within the SET project co-financed by the European Union. The authors wish to thank Professor Elzbieta Pyza for the expert suggestions and kindly providing an access to the confocal microscope LSM 510 META, Axiovert 200 M, ConfoCor 3 (Carl Zeiss MicroImaging GmbH, Jena, Germany) in the Department of Cell Biology and Imaging of Institute of Zoology at the Jagiellonian University in Krakow.

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Authors and Affiliations

  1. Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Krakow, Poland

    J. Rzemieniec, E. Litwa, A. Wnuk, W. Lason & M. Kajta

  2. Department of Cell Biology and Imaging, Confocal Microscopy Laboratory, Institute of Zoology, Jagiellonian University, 9 Gronostajowa Street, 30-387, Krakow, Poland

    W. Krzeptowski

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  1. J. Rzemieniec
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Correspondence to M. Kajta.

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Compliance with Ethical Standards

This article does not contain any studies with human participants performed by any of the authors. The animal care was conducted according to official governmental guidelines, and all efforts were made to minimize suffering and the number of animals used. All procedures were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals, and the protocols were approved through the Bioethics Commission in compliance with Polish Law (21 August 1997). All members of the research team had the approval of the local ethical committee on animal testing.

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Fig. 13

Effect of DIM in concentrations higher than 10 μM on LDH release in primary hippocampal cell cultures in normoxia. Hippocampal cells were treated with DIM (25-100 μM) or vehicle (0.1 % DMSO) for 18 h. The results are presented the percentage of control. Each bar represents the mean ± SEM of three to four independent experiments. The number of replicates for each experiment ranged from 7 to 10. ***p < 0.001 versus control normoxic cultures. (XLSX 14 kb)

Fig. 14

Western-Blot verification of ERβ- and ARNT-specific siRNA silencing in mouse hippocampal cells. Primary hippocampal cultures were transfected with 50 nM ARNT and ERβ or negative siRNAs in INTERFERin-containing medium without antibiotics for 7 h. Protein samples were collected from hippocampal cultures at 24 h of post-treatment, denatured, electrophoretically separated, transferred to PVDF membrane, and subjected to immunolabeling. The signals were developed using chemiluminescence and visualized using Luminescent Image Analyzer Fuji-Las 4000 (Fuji, Japan). Immunoreactive bands were quantified using an image analyzer (ScienceLab, MultiGauge V3.0), and the relative protein levels of ERβ and ARNT were presented as a percentage of the control. Each value represents the mean of three independent experiments ± SEM. The number of replicates in each experiment ranged from 2 to 3. $$p < 0.01 versus negative siRNA-transfected cells. (PPTX 73 kb)

Fig. 15

Impact of hypoxia (18 h) on the ROS formation in mouse hippocampal cells. To determine ROS production in the hippocampal neurons, 5 μM H2DCFDA was used. The cells were incubated in medium containing H2DCFDA for 40 min before hypoxia. The results are presented as the percentage of the normoxic control. Each bar represents the mean ± SEM of three to four independent experiments. The number of replicates for each experiment ranged from 7 to 10. (XLSX 13 kb)

Fig. 16

Alterations in protein levels of AhR, ARNT, and ERβ in the cells subjected to DIM in normoxia. Primary hippocampal cultures were subjected to DIM (1, 10 μM) in normoxia for 18 h. Protein samples were collected from hippocampal cultures at 24 h of post-treatment, denatured, electrophoretically separated, transferred to PVDF membrane, and subjected to immunolabeling. The signals were developed using chemiluminescence and visualized using Luminescent Image Analyzer Fuji-Las 4000 (Fuji, Japan). Immunoreactive bands were quantified using an image analyzer (ScienceLab, MultiGauge V3.0), and the relative protein levels of AhR, ERβ, and ARNT were presented as a percentage of the control. Each value represents the mean of three independent experiments ± SEM. The number of replicates in each experiment ranged from 2 to 3. (PPTX 131 kb)

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Rzemieniec, J., Litwa, E., Wnuk, A. et al. Selective Aryl Hydrocarbon Receptor Modulator 3,3′-Diindolylmethane Impairs AhR and ARNT Signaling and Protects Mouse Neuronal Cells Against Hypoxia. Mol Neurobiol 53, 5591–5606 (2016). https://doi.org/10.1007/s12035-015-9471-0

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