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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.

journal_name

Mol Neurobiol

journal_title

Molecular neurobiology

authors

Wu CL,Chen SD,Yin JH,Hwang CS,Yang DI

doi

10.1007/s12035-015-9357-1

subject

Has Abstract

pub_date

2016-08-01 00:00:00

pages

4126-4142

issue

eissn

0893-7648

issn

1559-1182

pii

10.1007/s12035-015-9357-1

journal_volume

pub_type

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Nuclear Factor-kappaB-Dependent Sestrin2 Induction Mediates the Antioxidant Effects of BDNF Against Mitochondrial Inhibition in Rat Cortical Neurons.