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Manganese chloride stimulates rat microglia to release hydrogen peroxide
Ping Zhang1, Angela Hatter, Bin Liu
1Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Abstract:
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.
Insights
Manganese exposure causes neurotoxicity. This study shows manganese chloride activates brain microglia to release hydrogen peroxide, a reactive oxygen species, via mitogen-activated protein kinases (MAPK).
Area of Science:
- Neuroscience
- Toxicology
- Immunology
Background:
- Manganese exposure is linked to neurodegeneration and movement disorders (manganism).
- Microglia activation and subsequent release of neurotoxic factors, like reactive oxygen species (ROS), are implicated in manganese neurotoxicity.
- The precise mechanisms underlying manganese-induced neurotoxicity remain unclear.
Purpose of the Study:
- To investigate the role of microglia activation in manganese neurotoxicity.
- To determine if manganese chloride (MnCl2) induces reactive oxygen species (ROS) release from microglia.
- To explore the signaling pathways involved in MnCl2-induced ROS production in microglia.
Main Methods:
- Primary rat microglia cultures were exposed to varying concentrations of MnCl2.
- Hydrogen peroxide (H2O2) release was measured using biochemical assays.
- The involvement of mitogen-activated protein kinases (MAPK) and NADPH oxidase was assessed using specific inhibitors.
- Activation of extracellular signal-regulated kinase (ERK) and p38-MAPK was evaluated.
Main Results:
- MnCl2 exposure led to a time- and concentration-dependent release of H2O2 from microglia.
- MnCl2-induced H2O2 release was inhibited by MAPK inhibitors but not by NADPH oxidase inhibitors.
- MnCl2 rapidly activated ERK and p38-MAPK signaling pathways in microglia, preceding H2O2 release.
- These findings suggest MAPK pathways mediate MnCl2-induced ROS production in microglia.
Conclusions:
- Manganese chloride activates microglia to release ROS, contributing to neurotoxicity.
- Mitogen-activated protein kinases (MAPK) play a significant role in mediating manganese-induced microglial ROS production.
- These results highlight the potential involvement of microglia and MAPK signaling in the pathogenesis of manganese neurotoxicity.
