Abstract
In this study, we investigated the effects of nicotine on rat brain mitochondria. The polarographic studies determined the effects on the respiratory chain, whereas enzymatic assays and [3H]-nicotine binding allowed us to precisely identify its target and site of action. The measurements of oxygen consumption showed a significantly concentration-dependent inhibition by nicotine (EC50 was 4.95x10(-11) M), and a maximal decrease of 23.90% at 10(-7) M. Nicotine bound to complex I of the respiratory chain and inhibited the NADH-Ubiquinone reductase activity. We also showed that nicotine and NADH were competitive on complex I. Effects of cotinine, the main nicotine metabolite, and nornicotine, were also investigated: nornicotine inhibited the mitochondrial respiration whereas cotinine did not. Because the complex I generates superoxide anion, we investigated the effects of nicotine, following NBT oxidation, and showed that nicotine was able to inhibit this reactive oxygen species (ROS) generation by 15.74% with an EC50 of 2.02x10(-11) M. In conclusion, the present study shows that nicotine interacts with the complex I of brain mitochondrial respiratory chain and decreases ROS generation. This may explain a part of the beneficial and protective effects of nicotine in few neurodegenerative diseases, as suggested by many epidemiological studies.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / metabolism
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Alkaloids / pharmacology
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Animals
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Anthraquinones / pharmacology
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Antimycin A / pharmacology
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Azocines
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Carrier Proteins*
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Cotinine / pharmacology
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Electron Transport Complex I
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Electron Transport Complex II
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Hexamethonium / pharmacology
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Male
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Membrane Proteins / metabolism
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondrial Proton-Translocating ATPases
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Multienzyme Complexes / metabolism
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NAD / metabolism
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NADH, NADPH Oxidoreductases / metabolism
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Neuroprotective Agents / pharmacology
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Nicotine / analogs & derivatives*
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Nicotine / pharmacology*
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Oxidation-Reduction
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Oxidative Phosphorylation / drug effects*
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Oxidoreductases / metabolism
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Oxygen Consumption / drug effects
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Prosencephalon / ultrastructure
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Pyridines / pharmacology
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Quinolizines
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Rats
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Rats, Wistar
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Reactive Oxygen Species
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Receptors, Nicotinic / drug effects
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Receptors, Nicotinic / metabolism
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Rotenone / pharmacology
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Succinate Dehydrogenase / metabolism
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Superoxides / metabolism*
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Synaptosomes / drug effects
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Synaptosomes / metabolism
Substances
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Alkaloids
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Anthraquinones
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Azocines
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Bridged Bicyclo Compounds, Heterocyclic
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Carrier Proteins
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Membrane Proteins
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Multienzyme Complexes
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Neuroprotective Agents
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Pyridines
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Quinolizines
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Reactive Oxygen Species
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Receptors, Nicotinic
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Rotenone
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NAD
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Superoxides
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Hexamethonium
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cytisine
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Antimycin A
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Nicotine
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nornicotine
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Oxidoreductases
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Electron Transport Complex II
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Succinate Dehydrogenase
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NADH, NADPH Oxidoreductases
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Adenosine Triphosphatases
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Mitochondrial Proton-Translocating ATPases
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Electron Transport Complex I
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oligomycin sensitivity-conferring protein
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Cotinine
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epibatidine
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rhein