Manganese chloride stimulates rat microglia to release hydrogen peroxide.
Elevated exposure to manganese is known to cause neurodegeneration in the basal ganglia and to induce movement abnormalities called manganism. However, the underlying mechanism of action is not fully understood. Activation of the resident immune cells in the brain, microglia that release a variety of neurotoxic factors, has been implicated to contribute to neurodegeneration. Of the various neurotoxic factors released by activated microglia, reactive oxygen species such as superoxide and hydrogen peroxide are particularly detrimental to the survival of the oxidative damage-prone neurons. In this study, we report that exposure of rat microglia to manganese chloride (MnCl(2)) resulted in a time- and concentration-dependent release of hydrogen peroxide (H(2)O(2)). The MnCl(2)-stimulated microglial H(2)O(2) release was sensitive to inhibitors of mitogen-activated protein kinases (MAPK) but not that of NADPH oxidase. MnCl(2)-induced a rapid activation of the extracellular signal-regulated kinase (ERK) and p38-MAPK in microglia that appeared to precede the MnCl(2)-induced H(2)O(2) release, suggesting that ERK and p38-MAPK influenced the MnCl(2)-induced H(2)O(2) release in microglia. In summary, these results demonstrate that manganese chloride is capable of activating microglia to release ROS and MAPK may, in part, be key regulators of the process. These findings may shed significant light on the potential role of microglia in the manganese-induced neurotoxicity.
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Ping
P
Zhang
Angela
A
Hatter
Bin
B
Liu
D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D017895:Manganese Compounds; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000873:Anthracenes; D002070:Butadienes; D002712:Chlorides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017895:Manganese Compounds; D009570:Nitriles; D009861:Onium Compounds; D011725:Pyridines; C113580:U 0126; C432165:pyrazolanthrone; C007517:diphenyleneiodonium; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C025340:manganese chloride