title: Nuclear Factor-kappaB-Dependent Sestrin2 Induction Mediates the Antioxidant Effects of BDNF Against Mitochondrial Inhibition in Rat Cortical Neurons.
abstract: Brain-derived neurotrophic factor (BDNF), in addition to its neurotrophic action, also possesses antioxidant activities. However, the underlying mechanisms remain to be fully defined. Sestrin2 is a stress-responsive gene implicated in the cellular defense against oxidative stress. Currently, the potential functions of sestrin2 in nervous system, in particular its correlation with neurotrophic factors, have not been well established. In this study, we hypothesized that BDNF may enhance sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, and characterized the molecular mechanisms underlying BDNF induction of sestrin2 in primary rat cortical cultures. We found that BDNF-mediated sestrin2 expression in cortical neurons required formation of nitric oxide (NO) with subsequent production of 3',5'-cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG). BDNF induced localization of nuclear factor-kappaB (NF-κB) subunits p65 and p50 into neuronal nuclei that required PKG activities. Interestingly, BDNF exposure led to formation of a protein complex containing at least PKG-1 and p65/p50, which bound to sestrin2 promoter with resultant upregulation of its protein products. Finally, BDNF preconditioning mitigated production of reactive oxygen species (ROS) as a result of 3-NP exposure; this antioxidative effect of BDNF was dependent upon PKG activity, NF-κB, and sestrin2. Taken together, our results indicated that BDNF enhances sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-NP through attenuation of ROS formation; furthermore, BDNF induction of sestrin2 requires activation of a pathway involving NO/PKG/NF-κB.
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.|Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shang-Der
authors.initials: SD
authors.lastname: Chen
authors.affiliation: Department of Neurology, Cheng Hsin General Hospital, Taipei, Taiwan.|Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Jiu-Haw
authors.initials: JH
authors.lastname: Yin
authors.affiliation: Department of Neurology, Taipei City Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chi-Shin
authors.initials: CS
authors.lastname: Hwang
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan. diyang@ym.edu.tw.|Institute of Brain Science, National Yang-Ming University, Number 155, Section 2, Linong Street, Beitou District, Taipei, 11221, Taiwan. diyang@ym.edu.tw.
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology*; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D000066829:Neuroprotection / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011422:Propionates; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000084622:Sestrins
chemical_list: D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; D006152:Cyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D016328:NF-kappa B; D009569:Nitric Oxide; D009574:Nitro Compounds; D009687:Nuclear Proteins; D011422:Propionates; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C583887:Sesn2 protein, rat; D000084622:Sestrins; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; Free radicals; Nitric oxide; Reactive oxygen species; Soluble guanylate cyclase; cGMP-dependent protein kinase