Dysregulation of CREB activation and histone acetylation in 3-nitropropionic acid-treated cortical neurons: prevention by BDNF and NGF.
3-Nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II, leads to metabolic impairment and neurodegeneration. In this study, we investigated the roles of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the dysregulation of transcription factors and histone modifying enzymes induced by 3-NP in primary cortical neurons. BDNF prevented the 3-NP-induced decrease in cAMP response-element binding protein (CREB) phosphorylation and CREB-binding protein levels. Both NGF and BDNF counteracted the increase in the levels of histone H3 and H4 acetylations and reduced histone deacetylase (HDAC) activity induced by 3-NP. BDNF further led to hyperphosphorylation of HDAC2. Our results support an important role for neurotrophins, particularly BDNF, in preventing detrimental changes in transcription factors and histone acetylation states in cortical neurons that have been subjected to selective mitochondrial inhibition.
Center for Neuroscience and Cell Biology, Faculty of Medicine, Institute of Biochemistry, University of Coimbra, 3004-504 Coimbra, Portugal.
Sandra
S
Almeida
Teresa
T
Cunha-Oliveira
Mário
M
Laço
Catarina R
CR
Oliveira
A Cristina
AC
Rego
D000107:Acetylation / Q000187:drug effects; D000704:Analysis of Variance; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003292:Convulsants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D009574:Nitro Compounds / Q000633:toxicity*; D009842:Oligopeptides / Q000494:pharmacology; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D000813:Anilides; D019208:Brain-Derived Neurotrophic Factor; D003292:Convulsants; D006657:Histones; D009574:Nitro Compounds; D009842:Oligopeptides; D011422:Propionates; C430230:acetyl-aspartyl-glutamyl-valyl-aspartic acid p-nitroanilide; D020932:Nerve Growth Factor; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D020169:Caspases; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2; C015392:3-nitropropionic acid