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.

More Insight into BDNF against Neurodegeneration: Anti-Apoptosis, Anti-Oxidation, and Suppression of Autophagy

“…Nevertheless, it has been shown that treatments with phosphodiesterase-5 inhibitors (sildenafil or vardenafil), which selectively blocks degradation of cGMP, improved neurologic scores and reduced loss of striatal lesion volumes that were produced by the systemic infusion of 3-NP in rats and, importantly, the striatal expression of BDNF was significantly increased in the sildenafil-treated rats [66]. This in vivo study appears to be consistent with our contention that the cGMP/PKG pathway is important for the neuroprotective effects against 3-NP toxicity in vitro [20,31]. Previous studies have also demonstrated that 3-NP exposure may reduce the tissue contents of BDNF in vivo.…”

“…In our recent study [20], we validated the hypothesis that BDNF may increase sestrin2 expression to convey the protective effect against oxidative stress induced by 3-NP and demonstrated the molecular mechanisms of BDNF to induce sestrin2 expression in rat primary cortical cultures. In this work, we demonstrated that the NO/PKG-1 signaling pathway is engaged in BDNF-mediated sestrin2 induction [20]. It was known that PKG is a member of AGC family of serine/threonine protein kinases.…”

“…In the past decade, we have been working in this field in an attempt to reveal the neuroprotective mechanisms of BDNF [19,20,21,29,30,31,32], as well as other trophic factors such as oncostatin M that is beyond the range of the current review [33], against neurodegeneration using a pharmacological model with 3-NP challenge to mimic oxidative stress. We showed that BDNF-dependent protective effects against 3-NP toxicity could be eliminated by a nonselective nitric oxide (NO) synthase (NOS) inhibitor l -nitroarginine methylester ( l -NAME).…”

“…BDNF-induced NF-κB activation requires NO/sGMP/PKG activity and, interestingly, the PKG-1 indeed forms a protein complex with p65/p50 and together translocates into the nucleus to trans-activate sestrin2 expression in the cortical neurons exposed to BDNF. Thus, we provided evidence to support a novel signaling pathway of “BDNF/TrkB → NO/cGMP/PKG → NF-κB → sestrin2” that ultimately play a role in suppressing the generation of ROS and neurotoxicity from 3-NP exposure in cortical neurons [20]. …”

“…In this review, we briefly introduce the recent advance in the molecular mechanisms of the BDNF-mediated protective effects against neuronal dysfunction induced by 3-NP, including our previous studies [19]. We also discuss our recent works on sestrin2 [20], which is an acute stress response protein, as well as autophagy inhibition [21] in the paradigm of BDNF and 3-NP in fetal cortical neurons. Clarification of BDNF-mediated protective actions against 3-NP-induced neurotoxicity may aid in developing a therapeutic regimen for HD in which mitochondrial dysfunction plays a critical role in the pathogenesis of this devastating disease [20].…”