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Long-Term Systemic Exposure to Rotenone Induces Central and Peripheral Pathology of Parkinson’s Disease in Mice

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Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease with motor and non-motor symptoms that precede the onset of motor symptoms. Rotenone is often used to induce PD-like pathology in the central nervous system (CNS) and enteric nervous system (ENS). However, there is little or no information on the temporal changes in other neural tissues and the spread of pathology throughout the entire body organs. Here, we recorded the serial immunohistochemical changes in neurons and glial cells of the striatum, substantia nigra (SN), olfactory bulb (OB), thoracic cord (ThC) and ascending colon (AC) induced by 1-, 3- and 6-week administration of rotenone (50 mg/kg/day) infused subcutaneously in C57BL mice using an osmotic pump. Rotenone exposure for 3 or 6 weeks caused neurodegeneration in the striatum, whereas neuronal damage was seen in the SN and OB only after 6 weeks. Moreover, rotenone induced neurodegeneration in the myenteric plexus of AC but not in ThC. Rotenone also activated glial cells before any apparent neurodegeneration in the CNS but not in the ENS. Our results demonstrated that subcutaneous administration of rotenone can cause progressive neurodegeneration in the OB and AC, in addition to the nigrostriatal pathway, and temporal differential glial activation, and that these changes do not spread retrogradely from OB or ENS to nigrostriatal pathway. The results suggested that the different vulnerability of neurons to the neurotoxic effects of rotenone administrated subcutaneously are due to glial activation in these neural tissues.

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Abbreviations

α-syn:

Alpha-synuclein

AC:

Ascending colon

ChAT:

Choline acetyltransferase

CNS:

Central nervous system

DAB:

3,3′-Diaminobenzidine

ENS:

Enteric nervous system

GFAP:

Glial fibrillary acidic protein

OB:

Olfactory bulb

PB:

Phosphate buffer

PBS-T:

Phosphate buffered saline with 0.2 % Triton X-100

PD:

Parkinson’s disease

PNS:

Peripheral nervous system

RT:

Room temperature

SN:

Substantia nigra

SNpc:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

ThC:

Thoracic cord

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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. We thank T. Osato, M. Shigeyasu, M. Hori and R. Tsurubou for excellent technical assistance.

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Correspondence to Masato Asanuma.

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Murakami, S., Miyazaki, I., Miyoshi, K. et al. Long-Term Systemic Exposure to Rotenone Induces Central and Peripheral Pathology of Parkinson’s Disease in Mice. Neurochem Res 40, 1165–1178 (2015). https://doi.org/10.1007/s11064-015-1577-2

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  • DOI: https://doi.org/10.1007/s11064-015-1577-2

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