Studies suggest that environmental contaminants, include manganese (Mn), may contribute to Idiopathic Parkinson?s Disease (IPD), but the etiology of this disease still remains elusive. Two major sources of Mn pollution in the United States arise from the reintroduction of the fuel additive methylcyclopentadienyl manganese tricarbonyl and the widespread use of Mn-containing fungicides (maneb). Recently, the investigators obtained evidence that Mn, a neurotokicant causing Parkinson?s Disease-like symptoms, increases proinflammatory cytokines and nitric oxide production by activated microglia in vitro. These findings suggest that (i) inflammation plays a role in Mn-induced neurotoxicity, and (ii) Mn exposure may be a contributing factor (via enhanced production of inflammatory mediators) to IPD. The research proposed here will explore these possibilities utilizing both in vitro and in vivo approaches. Additional studies will begin to delineate the mechanism(s) by, which Mn enhances the inflammatory response in the brain. It is hypothesized that exposure to Mn, enhances activation of microglia which are disproportionately distributed in the brain and as a result, over-production of proinflammatory cytokines and nitric oxide occurs with the final outcome being selective neuronal loss in the basal ganglia. Furthermore, exposure to Mn in the context of an inflammatory stimulus would potentiate the dopaminergic neuronal damage in the 1-methyl-4-phenyl-1,2,3,4- tetrahydropyridline (MPTP) mouse model of PD. Microglial cell line (N9), as well as primary microglia, will be used to determine whether Mn speciation plays a role in the increased inflammatory response. Microglial (N9)-dopaminergic (PC 12) cell line co-cultures, as well as mesencephalic primary cultures will be used in vitro studies and the effects of Mn in the presence of a microglial activator (endotoxin, LPS) on neuronal cell death will be assessed. Additionally, Mn influence on the sensitivity of the dopaminergic neurons to MPTP under the same in vitro conditions will be evaluated. C57BL/6 (MPTP-sensitive) and CD-1 (MPTP-resistant) mice will be used for in vivo studies and animals will be treated similarly to the cell cultures in the in vitro studies. After short (14 days) exposure to Mn, some animals will be challenged with MPTP, and the degree of basal ganglia damage, as well as microglial activation will be assessed. Successful completion of the proposed research will help revealing the role of inflammation in Mn neurotoxicity and, more importantly, establish a mechanism by which environmental contaminants may contribute to the etiology of IPD. The long-term goal of the proposed studies is to understand the role of microglia and environmental contaminants in neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Career Transition Award (K22)
Project #
5K22ES011654-02
Application #
6665194
Study Section
Special Emphasis Panel (ZES1-LKB-E (KT))
Program Officer
Shreffler, Carol K
Project Start
2002-09-27
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$105,711
Indirect Cost
Name
Mississippi State University
Department
Public Health & Prev Medicine
Type
Schools of Veterinary Medicine
DUNS #
075461814
City
Mississippi State
State
MS
Country
United States
Zip Code
39762
Filipov, Nikolay M; Dodd, Celia A (2012) Role of glial cells in manganese neurotoxicity. J Appl Toxicol 32:310-7
Crittenden, Patrick L; Filipov, Nikolay M (2011) Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells. J Appl Toxicol 31:1-10
Filipov, Nikolay M; Norwood, Allison B; Sistrunk, Shannon C (2009) Strain-specific sensitivity to MPTP of C57BL/6 and BALB/c mice is age dependent. Neuroreport 20:713-7
Crittenden, P L; Filipov, N M (2008) Manganese-induced potentiation of in vitro proinflammatory cytokine production by activated microglial cells is associated with persistent activation of p38 MAPK. Toxicol In Vitro 22:18-27
Sistrunk, Shannon C; Ross, Matthew K; Filipov, Nikolay M (2007) Direct effects of manganese compounds on dopamine and its metabolite Dopac: an in vitro study. Environ Toxicol Pharmacol 23:286-296
Filipov, Nikolay M; Seegal, Richard F; Lawrence, David A (2005) Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. Toxicol Sci 84:139-48