Keith Erikson - US grants

Manganese is an essential nutrient for humans and other mammals, and it functions as a critical cofactor for many key enzymes involved in cellular metabolism. However, exceedingly high brain manganese concentrations are known to cause neurotoxicity with symptoms similar to Parkinson's disease (PD). Recent rodent studies have linked dietary iron deficiency with excessive brain manganese accumulation, specifically in dopamine-rich brain regions. To date, it is still unknown how and why manganese accumulation occurs primarily in these brain regions, although it has been hypothesized that the dopamine transporter may mediate this process. The objective of this project is to specifically determine the mechanism by which manganese accumulation targets dopamine-rich brain regions and establish neurochemical changes associated with manganese neurotoxicity. The first aim of the project is to ascertain the role of the dopamine transporter in the accumulation of manganese into dopamine-rich brain regions. Both in vivo and in vitro studies are proposed which will utilize dietary and pharmacological manipulations to accomplish this aim. The second aim of the project is to identify neurochemical alterations in dopaminergic regions due to both manganese neurotoxicity and manganese accumulation caused by dietary iron deficiency. Recent studies suggest that the extrapyramidal symptoms of manganese neurotoxicity are due to abnormal gamma-aminobutryic acid (GABA) metabolism which may indirectly alter dopamine neurobiology causing PD-like behaviors. Disturbances in GABA metabolism have also been linked to manganese accumulation due to iron deficiency. Proposed in vivo microdialysis studies will determine whether iron status represents a risk factor for neurochemical alterations that are exacerbated by manganese accumulation. If successful, these studies will lay the foundation for the development of a pharmacological therapy aimed at the prevention of manganese-accumulation in vulnerable populations.

[unreadable] DESCRIPTION (provided by applicant): The overall goal of this project is to characterize the mechanism(s) in the brain involved in oxidative stress (e.g., lipid peroxidation) due to manganese (Mn) overexposure and the role(s) of glutathione in this process. Manganese is an essential nutrient for humans and other mammals, and it functions as a critical cofactor for many key enzymes involved in cellular metabolism. However, exceedingly high brain Mn concentrations are known to cause neurotoxicity (manganism) with symptoms similar to Parkinson's disease (PD). These similarities between Parkinson's disease and manganism include the presence of generalized bradykinesia and widespread rigidity. While the etiologies of both manganism and PD are not fully understood, recent evidence suggests that oxidative stress may be a factor in both disease processes. [unreadable] Glutathione (GSH) is a ubiquitous antioxidant that functions in conjugation and elimination of toxic molecules, thereby maintaining cellular redox homeostasis. GSH is one of the most important endogenous antioxidants in the brain with the astrocytes (cells that function as caretakers of neurons) being the cell with the richest supply of GSH. Alterations in GSH metabolism in the brain have been linked with oxidative stress and neurodegenerative diseases such as PD. Biochemical analyses of post-mortem brain tissues from PD patients and manganese exposed rats revealed significantly lowered GSH levels compared to controls. [unreadable] The objective of this project is to link alterations in GSH metabolism due to Mn exposure with lipid peroxidation, a known contributor to the neurodegenerative process. Our first Aim will use twenty-one day, three month, and twelve month old rats in order to assess in vivo GSH-redox status and the formation of isoprostanes a biomarker of lipid peroxidation in brain regions known to be vulnerable to Mn accumulation. Furthermore, some of the rats will be treated with antioxidants and we hypothesize that they will be spared from Mn-induced lipid peroxidation. Our second Aim is designed to specifically look at cellular mechanisms of these alterations in GSH metabolism due to Mn by utilizing both astrocyte and neuronal cell culture models. As in Aim one, we will expose both cell types to doses of Mn that are representative to those seen in cases of Mn neurotoxicity and assess the effects of antioxidant treatment on the formation of isoprostanes and alterations in GSH metabolism. Being that the astrocyte is the cell in the brain that handles the majority of GSH metabolism, it is likely that this model will reveal potential mechanisms in which manganese alters brain GSH and by performing parallel studies in neurons, we can assess the effects of Mn in these two brain cell types known to be targets of Mn accumulation. Together, both of these experimental approaches will build a foundation to hone future studies on mechanisms of neurodegenerative processes. PROJECT NARRATIVE: Idiopathic Parkinson's disease (IPD) represents a common neurodegenerative disorder affecting individuals aged 65 or older. Since this age group has increased 12% in the past decade and is projected to increase to 20% by the year 2030, it is likely that the incidence rate for IPD will dramatically increase. Environmental exposures to pesticides and toxic metals, including manganese (Mn), have been implicated in the development of IPD. Disturbances in brain glutathione (a natural antioxidant) metabolism have been reported in both Mn toxicity and in IPD. The overall goal of this study is to characterize the mechanism(s) in the brain involved in oxidative stress (e.g., lipid peroxidation) due to manganese (Mn) overexposure and the role(s) of glutathione in this process. If successful, these studies will lay the foundation for the development of a pharmacological therapy aimed at the prevention of neurodegenerative diseases that may be related to brain manganese accumulation. [unreadable] [unreadable] [unreadable]