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Neuroprotective Effects of Metallothionein Against Rotenone-Induced Myenteric Neurodegeneration in Parkinsonian Mice

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disease with motor symptoms as well as non-motor symptoms that precede the onset of motor symptoms. Mitochondrial complex I inhibitor, rotenone, has been widely used to reproduce PD pathology in the central nervous system (CNS) and enteric nervous system (ENS). We reported previously that metallothioneins (MTs) released from astrocytes can protect dopaminergic neurons against oxidative stress. The present study examined the changes in MT expression by chronic systemic rotenone administration in the striatum and colonic myenteric plexus of C57BL mice. In addition, we investigated the effects of MT depletion on rotenone-induced neurodegeneration in CNS and ENS using MT-1 and MT-2 knockout (MT KO) mice, or using primary cultured neurons from MT KO mice. In normal C57BL mice, subcutaneous administration of rotenone for 6 weeks caused neurodegeneration, increased MT expression with astrocytes activation in the striatum and myenteric plexus. MT KO mice showed more severe myenteric neuronal damage by rotenone administration after 4 weeks than wild-type mice, accompanied by reduced astroglial activation. In primary cultured mesencephalic neurons from MT KO mice, rotenone exposure induced neurotoxicity in dopaminergic neurons, which was complemented by addition of recombinant protein. The present results suggest that MT seems to provide protection against neurodegeneration in ENS of rotenone-induced PD model mice.

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Abbreviations

ANOVA:

Analysis of variance

ChAT:

Choline acetyltransferase

CNS:

Central nervous system

DAT:

Dopamine transporter

DMSO:

Dimethylsulphoxide

ENS:

Enteric nervous system

GFAP:

Glial fibrillary acidic protein

KO:

Knockout

LB:

Lewy-body

LN:

Lewy-neurite

MT:

Metallothionein

PB:

Phosphate buffer

PBS-T:

Phosphate buffered saline with 0.2 % Triton X-100

PD:

Parkinson’s disease

PEG:

Polyethylenglycol

RT:

Room temperature

SNpc:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

WT:

Wild-type

4HNE:

4-Hydroxynonenal

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Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research (C) (KAKENHI #21591082, #22590934, #25461279) from Japan Society for the Promotion of Science, by Grant-in Aid for Scientific Research on Innovative Areas “Brain Environment” (KAKENHI #24111533) from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and by a Research Grant from the Okayama Medical Foundation.

Conflict of interest

All authors have no actual or potential conflicts of interest, including financial, personal or other relationships with other people or organizations.

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Author notes

  1. Ko Miyoshi

    Present address: Molecular Research Center for Children’s Mental Development, Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan

Authors and Affiliations

  1. Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Shinki Murakami, Ikuko Miyazaki, Ko Miyoshi & Masato Asanuma

  2. Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Norio Sogawa

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  1. Shinki Murakami
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Correspondence to Masato Asanuma.

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Murakami, S., Miyazaki, I., Sogawa, N. et al. Neuroprotective Effects of Metallothionein Against Rotenone-Induced Myenteric Neurodegeneration in Parkinsonian Mice. Neurotox Res 26, 285–298 (2014). https://doi.org/10.1007/s12640-014-9480-1

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