Molecular mechanism of manganese exposure-induced dopaminergic toxicity

• Published in: Brain research bulletin 2008-07, Vol.76 (4), p.361-367
• Main Authors: Prabhakaran, K, Ghosh, D, Chapman, G.D, Gunasekar, P.G
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Cells, Cultured; Dopamine; Dopamine - metabolism; Dopamine - toxicity; Enzyme Activation - drug effects; Manganese; Manganese - toxicity; Manganese Poisoning - metabolism; Manganese Poisoning - physiopathology; Mesencephalon - cytology; Mesencephalon - drug effects; Mesencephalon - metabolism; Nerve Degeneration - chemically induced; Nerve Degeneration - metabolism; Nerve Degeneration - physiopathology; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neurotoxicity; Neurotoxins - toxicity; NF-kappa B - drug effects; NF-kappa B - metabolism; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - toxicity; Nitric Oxide Synthase Type II - drug effects; Nitric Oxide Synthase Type II - metabolism; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Transcription factor
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2008.03.004

Abstract Manganese (Mn) is an essential mineral that is found in varying amounts in aerosols or dust. Exposure to atmospheric Mn at high concentration is a risk factor in humans that can manifest as neuronal degeneration resembling Parkinson's disease (PD). Since the underlying mechanism of Mn and dopamine (DA) interaction-induced cell death remains unclear, here, we showed that Mn exposure alone to mesencephalic cells for 24 h induced minimal apoptotic cell death. However, cells pre-exposed to DA for 2 h accelerated Mn-induced apoptosis. The vulnerability of Mn-induced apoptotic cell death to DA was determined by measuring lactate dehydrogenase (LDH) and Apoptag TUNEL staining (terminaldeoxynucleotidyl transferase DNA labeling). This was further confirmed by the cell viability assay to support our hypothesis that DA at the cellular level interacts with Mn and causes cells to be more susceptible. Pretreatment with nitric oxide blocker (7-nitroindazole, 7-NI), vitamin E or NF-κB inhibitor (SN50) significantly protected the cells from Mn and DA interaction-induced reactive oxygen species (ROS) and apoptosis. Western blot analysis showed that Mn in the presence of DA markedly induced induction of NOS (iNOS) expression. Pretreatment with 7-NI, SN50 or vitamin E significantly attenuated increased iNOS expression indicating that iNOS expression is regulated by ROS and the transcription factor NF-κB. Further, the generation of ROS as an early event in Mn and DA interaction is not controlled by NF-κB as SN50 pretreatment did not prevent ROS. These findings suggest that NF-κB induction and the activation of nitric oxide synthase through ROS represent a proximate mechanism for Mn-induced neurotoxicity.