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ToxSci Advance Access published online on March 21, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj150
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 19, 2006
Accepted February 21, 2006

Neurotoxicology

Manganese-Induced Neurotoxicity: The Role of Astroglial-Derived Nitric Oxide in Striatal Interneuron Degeneration

Xuhong Liu 1, Kelly A. Sullivan 2, James E. Madl 2, Marie Legare 2, and Ronald B. Tjalkens 3 *

1 Toxicology Program, Department of Integrative Biosciences, Texas A&M University, College Station, Texas
2 Molecular, Cellular, and Integrative Neuroscience, Colorado State University, Fort Collins, CO
3 Molecular, Cellular, and Integrative Neuroscience, Colorado State University, Fort Collins, CO; Toxicology Program, Department of Integrative Biosciences, Texas A&M University, College Station, Texas

* To whom correspondence should be addressed.
Ronald B. Tjalkens, E-mail: Ron.Tjalkens{at}colostate.edu


  Abstract

Chronic exposure to excessive manganese (Mn) is the cause of a neurodegenerative movement disorder, termed manganism, resulting from degeneration of neurons within the basal ganglia and loss of dopamine. Pathogenic mechanisms underlying this disorder are not fully understood but involve inflammatory activation of glial cells within the basal ganglia. It was postulated in the present studies that reactive astrocytes are involved in neuronal injury from exposure to Mn through increased release of nitric oxide (NO). C57Bl/6J mice subchronically exposed to Mn by intragastric gavage had increased levels of Mn in the striatum and displayed diminutions in both locomotor activity and striatal dopamine content. Mn exposure resulted in neuronal injury in the striatum and globus pallidus, particularly in regions proximal to the microvasculature, indicated by histochemical staining with fluorojade and cresyl fast violet. Neuropathological assessment revealed marked perivascular edema, with hypertrophic endothelial cells and diffusion of serum albumin into the perivascular space. Immunofluorescence studies employing terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling revealed the presence of apoptotic neurons expressing neuronal nitric oxide synthase, choline acetyltransferase, and enkephalin in both the striatum and globus pallidus. In constrast, soma and terminals of dopaminergic neurons were morphologically unaltered in either the substantia nigra or striatum, as indicated by immunohistochemical staining for tyrosine hydroxylase. Regions with evident neuronal injury also displayed increased numbers of reactive astrocytes that co-expressed inducible nitric oxide synthase (NOS2) and localized with areas of increased neuronal staining for 3-nitrotyrosine protein adducts, a marker of NO formation. These data suggest a role for astrocyte-derived NO in injury to striatal-pallidal interneurrons from Mn intoxication.

Keywords: Astrocytes; manganese; nitric oxide; neurodegeneration; apoptosis; dopamine; basal ganglia; movement disorders; inflammation; blood-brain barrier.
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