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Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons
1Department of Neuroscience and Anatomy, College of Medicine, The Pennsylvania State University, Hershey, PA, USA. eam10@psu.edu
Abstract:
Manganese (Mn) in excess is toxic to neurons of the globus pallidus, leading to a Parkinsonian-like syndrome. We used rat primary neuron cultures to examine the cellular events following manganese exposure. Following exposure to Mn(2+) for 48 h, striatal neurons showed dose-dependent losses of mitochondrial membrane potential and complex II activity. The Mn exposure effect on mitochondrial membrane potential was significant at every concentration measured (5, 50, and 500 microM), and the manganese exposure effect on complex II activity was significant at 50 and 500 microM. Exposure of striatal neurons to both Mn(2+) and the complex II inhibitor 3-nitropropionic acid resulted in additive toxicity. Striatal neurons exposed to 5 microM Mn(2+) for 48 h exhibited DNA fragmentation and decreases in the immunohistochemically detectable microtubule-associated protein MAP-2. These results indicate that manganese may trigger apoptotic-like neuronal death secondary to mitochondrial dysfunction. Rescue of neurons by apoptosis inhibitors may be helpful in treating manganese toxicity and similar neurodegenerative processes.
Insights
Excess manganese (Mn) causes neurotoxicity, leading to Parkinsonian-like symptoms. This study shows Mn induces neuronal death via mitochondrial dysfunction and apoptosis, suggesting potential therapeutic targets.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Excessive manganese (Mn) exposure is linked to neurotoxicity, specifically Parkinsonian-like syndromes affecting the globus pallidus.
- Understanding the cellular mechanisms of manganese neurotoxicity is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the cellular events and mechanisms underlying manganese-induced neurotoxicity in rat primary neuron cultures.
- To determine the role of mitochondrial dysfunction and apoptosis in manganese toxicity.
Main Methods:
- Primary striatal neuron cultures were exposed to varying concentrations of manganese (Mn(2+)) for 48 hours.
- Assessed mitochondrial membrane potential, complex II activity, DNA fragmentation, and microtubule-associated protein MAP-2 levels.
- Investigated the combined toxicity of Mn(2+) and the complex II inhibitor 3-nitropropionic acid.
Main Results:
- Manganese exposure caused dose-dependent decreases in mitochondrial membrane potential and complex II activity in striatal neurons.
- Significant effects on mitochondrial function were observed at concentrations of 50 and 500 microM Mn(2+).
- Manganese exposure led to DNA fragmentation and reduced MAP-2 expression, indicative of apoptotic-like neuronal death.
Conclusions:
- Manganese toxicity in neurons appears to be mediated by mitochondrial dysfunction, triggering apoptotic-like cell death pathways.
- Apoptosis inhibitors may offer a therapeutic strategy for managing manganese toxicity and related neurodegenerative conditions.