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The specific NQO2 inhibitor, S29434, only marginally improves the survival of dopamine neurons in MPTP-intoxicated mice

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

Over the years, evidence has accumulated on a possible contributive role of the cytosolic quinone reductase NQO2 in models of dopamine neuron degeneration induced by parkinsonian toxin, but most of the data have been obtained in vitro. For this reason, we asked the question whether NQO2 is involved in the in vivo toxicity of MPTP, a neurotoxin classically used to model Parkinson disease-induced neurodegeneration. First, we show that NQO2 is expressed in mouse substantia nigra dopaminergic cell bodies and in human dopaminergic SH-SY5Y cells as well. A highly specific NQO2 inhibitor, S29434, was able to reduce MPTP-induced cell death in a co-culture system of SH-SY5Y cells with astrocytoma U373 cells but was inactive in SH-SY5Y monocultures. We found that S29434 only marginally prevents substantia nigra tyrosine hydroxylase+ cell loss after MPTP intoxication in vivo. The compound produced a slight increase of dopaminergic cell survival at day 7 and 21 following MPTP treatment, especially with 1.5 and 3 mg/kg dosage regimen. The rescue effect did not reach statistical significance (except for one experiment at day 7) and tended to decrease with the 4.5 mg/kg dose, at the latest time point. Despite the lack of robust protective activity of the inhibitor of NQO2 in the mouse MPTP model, we cannot rule out a possible role of the enzyme in parkinsonian degeneration, particularly because it is substantially expressed in dopaminergic neurons.

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Data availability

Data are available upon request.

Abbreviations

DN:

Dopaminergic neurons

DAB:

Diaminobenzidine

DPI:

Days post-injection

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MPP+ :

1-Methyl-4-phenylpyridinium

NQO2:

Quinone reductase 2

OD:

Optical density

PBS:

Phosphate buffer saline

PD:

Parkinson disease

ROS:

Reactive oxygen species

SEM:

Standard error of the mean

SN:

Substantia nigra

SNpc:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

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Acknowledgements

This work was realized with the equipment and services from the Histomics and ICMice platform at ICM. The authors would like to thank Nouhad Samb and Laetitia Da Costa for their technical assistance. This work was sponsored by InnovAction internal program of the Laboratoires Servier. JAB and GF wish to thank Dr. Emmanuel Canet for his support and visions.

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Authors and Affiliations

  1. Sorbonne Université, Institut du Cerveau – Paris Brain Institute -ICM, INSERM, CNRS, Paris, France

    Maeva Vallucci, Florence Blandel, Patrick P. Michel & Etienne C. Hirsch

  2. Laboratory of Neuroendocrine Endocrine and Germinal Differentiation and Communication (NorDiC), Univ Rouen Normandie, Inserm, NorDiC, UMR 1239, 76000, Rouen, France

    Jean A. Boutin

  3. Department of Health Sciences, Campus Germaneto, Magna Graecia University, 88100, Catanzaro, Italy

    Elzbieta Janda

  4. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Ruth Musgrove & Donato Di Monte

  5. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia

    Ruth Musgrove

  6. Institut de R&D, Servier Paris-Saclay, 91190, Gif-Sur-Yvette, France

    Gilles Ferry

  7. Gilles Ferry Consulting, Les Issambres, France

    Gilles Ferry

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  1. Maeva Vallucci
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  2. Jean A. Boutin
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  4. Florence Blandel
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  8. Patrick P. Michel
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  9. Etienne C. Hirsch
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Correspondence to Jean A. Boutin.

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Vallucci, M., Boutin, J.A., Janda, E. et al. The specific NQO2 inhibitor, S29434, only marginally improves the survival of dopamine neurons in MPTP-intoxicated mice. J Neural Transm 131, 1–11 (2024). https://doi.org/10.1007/s00702-023-02709-3

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