Manganese Health Research Program: Phase 2, Core 18

Project Objectives:

• To determine Mn-induced changes in novel markers of cerebral oxidative damage and neuroinflammation in mice. We will explore mechanisms associated with Mn-induced neurotoxicity by probing neuronal markers of oxidative damage and associated dendritic degeneration of striatal medium spiny neurons.
• To determine whether treatments with antioxidants or anti-inflammatory agents attenuate biomarkers of oxidative damage and neuroinflammation associated with Mn exposure, and the extent to which such attenuation is accompanied by rescue from neurodegeneration.

Project Description:

Exposure to excessive manganese (Mn) levels in certain occupational or dietary conditions results in neurotoxicity to the extrapyramidal system and the development of Parkinson’s disease (PD)-like movement disorders, called manganism. Mn neurotoxicity in multiple animal models is associated with elevated levels of Mn in the brain, depletion of dopamine in the striatum, damage to neurons in the basal ganglia and/or the development of movement disorders. The specificity of Mn-induced toxicity to the globus pallidus and striatum must be a function of the transporters and the metabolic activity of these components of the basal ganglia; however, the basic mechanisms that lead to Mn-induced dopaminergic neurodegeneration have yet to be defined. The striatum and its medium spiny neurons (MSNs) is the major recipient of neuronal efferents in the basal ganglia. Since dopamine receptors are localized to the dendritic spines of striatal MSNs, alterations in their spine density and dendritic arbor is posited to alter normal neuronal processing and to play a critical role in mediating movement disorders associated with manganism and idiopathic PD. Since factors, such as oxidative stress and inflammatory activation within basal ganglia are strongly implicated in the selective degeneration of dopaminergic neurons, we use pharmacologic and morphologic approaches to test the hypothesis that suppression of oxidative damage and neuroinflammation prevent Mn-induced striatal neurodegeneration. This project is designed to probe the mechanisms of Mn neurotoxicity by using controlled methods for manipulating the cellular machinery to provide insight into both basic biology and the mechanistic events leading to clinical disease and potential therapeutic targets.

Project Status:

Publications:

Stankowski J., Leitch D., Aschner M., McLaughlin B. and Stanwood G. D. (2008) Selective vulnerability of dopaminergic systems to Manganese: Relevance to occupational exposure. Neurotoxicology And Teratology 30, 259.

Key research accomplishments:

• Mice treated with one or three injections of MnCl2 (100 mg/kg, sc) did not show signs of significant toxicity.
• Mn exposed mice showed significant increase in cerebral biomarkers of oxidative damage (F2-IsoPs) and neuroiflammation (PGE2).
• Mn exposed mice showed significant alteration in striatal medium spiny neurons morphology as evaluated by quantification of dendritic length and spine density in Golgi-impregnated tissue.
• A model was developed to assess the relationship between Mn-induced oxidative damage and neurodegeneration brain

Publications/Presentations arising from project:

• Milatovic, D., Yu, Y., Zaja-Milatovic, S., Gupta, R.C., Aschner, M. (2009) Oxidative damage and neurodegeneration in manganese-induced neurotoxicity. Society of Toxicology, abstract.
• Milatovic, D., Aschner, M. (2009) Measurement of isoprostanes as markers of oxidative stress in neuronal tissue. Current Protocols in Toxicology, unit 12.14:1-12, 2009.
• Milatovic, D., Zaja-Milatovic, S., Yu, Y., Aschner, M. (2009) Oxidative damage and neurodegeneration in manganese-induced neurotoxicity. Toxicology and Applied Pharmacology (in preparation).

Last updated: Date 04-03-2009