Abstract
3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase that has been used to explore the primary mechanisms of cell death associated with mitochondrial dysfunction and neurodegeneration in Huntington's disease. In this study we investigated the ability of brain-derived neurotrophic factor (BDNF) to suppress mitochondrial-dependent cell death induced by 3-NP in primary cortical neurons. This neurotrophin prevented 3-NP-induced release of cytochrome c and Smac/Diablo, caspase-3-like activity and nuclear condensation/fragmentation. Furthermore, it greatly increased phosphorylation of Akt and MAPK, suggesting the involvement of these signalling pathways in BDNF neuroprotection. Interestingly, BDNF decreased the levels of the pro-apoptotic protein Bim in mitochondrial and total cell lysates through the activation of the MEK1/2 pathway. This effect was due to an increase in the degradation rates of Bim. Our data support an important role for BDNF, in protecting cortical neurons against apoptotic cell death caused by inhibition of mitochondrial complex II.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Brain-Derived Neurotrophic Factor / metabolism*
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Carrier Proteins / metabolism
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Caspase 3 / metabolism
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Cells, Cultured
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Central Nervous System Agents / toxicity
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Cerebral Cortex / drug effects
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Cerebral Cortex / physiology*
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Chromatin / drug effects
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Chromatin / metabolism
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Cytochromes c / metabolism
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MAP Kinase Signaling System / physiology
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Membrane Proteins / metabolism*
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Mitochondria / drug effects
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Mitochondria / physiology
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Mitochondrial Proteins / metabolism
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Neurons / drug effects
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Neurons / physiology*
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Nitro Compounds / toxicity
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Phosphorylation
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Propionates / toxicity
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Wistar
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Succinate Dehydrogenase / antagonists & inhibitors
Substances
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, rat
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Brain-Derived Neurotrophic Factor
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Carrier Proteins
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Central Nervous System Agents
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Chromatin
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DIABLO protein, rat
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Membrane Proteins
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Mitochondrial Proteins
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Nitro Compounds
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Propionates
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Proto-Oncogene Proteins
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Cytochromes c
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Succinate Dehydrogenase
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Proto-Oncogene Proteins c-akt
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Casp3 protein, rat
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Caspase 3
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3-nitropropionic acid