Protective effect of the SOD/catalase mimetic MnTMPyP on inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuronal-glial cultures
Introduction
During the pathogenic process of Parkinson's disease (PD), inflammation in the brain is believed to play an important role McGeer et al., 1988, Liu and Hong, 2003. Microglia, the resident immune cells in the central nervous system, play a key role in neuroinflammatory process. Activated microglia produce large amounts of prostanoids, nitric oxide (NO), reactive oxygen species (ROS), and proinflammatory cytokines including tumor necrosis factor-α (TNF-α) Minghetti and Levi, 1998, Hirsch, 2000, Liu et al., 2002. These factors can then cause neuronal damage.
In previous studies, we have found that ROS, generated by activated microglia, play a major role in lipopolysaccharide (LPS)-induced neurotoxicity Liu et al., 2000, Gao et al., 2002. LPS-induced neurotoxicity is reduced by superoxide dismutase (SOD) and catalase that neutralize the reactivity of extracellular superoxide. In this study, we demonstrated that Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a cell-permeable SOD/catalase mimetic, afforded significant neuroprotection against dopaminergic neurodegeneration induced by LPS.
Section snippets
Materials
MnTMPyP was purchased from Calbiochem (La Jolla, CA). Cell culture ingredients were obtained from Invitrogen (San Diego, CA). [3H]dopamine (DA; 30 Ci/mmol) was purchased from NEN (Boston, MA). The polyclonal anti-tyrosine hydroxylase (TH) antiserum was a gift from GlaxoSmithKline (Research Triangle Park, NC). The Vectastain avidin–biotin complex (ABC) kit and biotinylated secondary antibodies were from Vector Laboratories (Burlingame, CA). All other reagents were from Sigma (St. Louis, MD).
Mesencephalic mixed neuroglia cultures
MnTMPyP dose-dependently protected dopaminergic neurons against LPS-induced neuronal toxicity
We evaluated the effect of MnTMPyP on LPS-induced dopaminergic neurodegeneration by using rat ventral mesencephalic mixed neuroglia cultures. Neuroglia cultures were treated for 7 days with vehicle or 5 ng/ml LPS. To evaluate the protective effect of SOD/catalase or MnTMPyP, cultures were pretreated for 30 min with desired concentrations of agents prior to LPS treatment. The extent of the degeneration of dopaminergic neurons was assessed by [3H]DA uptake. As shown in Fig. 1A, LPS treatment
Discussion
Accumulating evidence shows that inflammatory processes are involved in the pathogenesis of neurodegenerative diseases, including PD, Alzheimer's disease, and multiple sclerosis McGeer et al., 1988, Dickson et al., 1993, Raine, 1994, Rogers and Shen, 2000, Liu and Hong, 2003. The activation of glial cells, especially that of microglia, in response to neuronal injury or immunological challenges is the hallmark of neuroinflammation Kreutzberg, 1996, Aloisi, 1999, Hauss-Wegrzyniak et al., 1998,
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