Behavioural pharmacologyAntidepressant effects of TBE-31 and MCE-1, the novel Nrf2 activators, in an inflammation model of depression
Introduction
Accumulating evidence suggests that inflammation plays a role in the pathophysiology of depression (Dantzer et al., 2008, Hashimoto, 2009, Hashimoto, 2015, Miller et al., 2009, Raison et al., 2010). Systemic administration of lipopolysaccharide (LPS) can induce depression-like behavior in rodents after the induction of inflammation (Dantzer et al., 2008, O'Connor et al., 2009, Zhang et al., 2016). The current antidepressants such as serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) can block alterations in serum pro-inflammatory cytokines and depression-like behaviors induced by LPS (de Paiva et al., 2010, Dong et al., 2016, Ma et al., 2014, Ohgi et al., 2013, Yao et al., 2015). Taken together, it is likely that inflammation plays a role in the depression-like phenotype in rodents, and anti-inflammatory drugs could show antidepressant effect in inflammation model of depression.
Nuclear factor (erythroid 2-derived)-like 2 (Nrf2) is a transcription factor that plays a central role in cellular defense against oxidative and electrophilic insults (Ma and He, 2012, Ma, 2013, Suzuki et al., 2013; Suzuki and Yamamoto, 2015). Nrf2 binds to antioxidant response elements (ARE) located in the promoter region of genes encoding many phase II detoxifying or antioxidant enzymes and related stress-responsive proteins (Ma and He, 2012, Ma, 2013, Suzuki et al., 2013; Suzuki and Yamamoto, 2015). Under normal conditions, Nrf2 is repressed by Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1), which is an adaptor protein for the degradation of Nrf2 (Suzuki et al., 2013; Suzuki and Yamamoto, 2015). During oxidative stress, Nrf2 is de-repressed and activates the transcription of cytoprotective genes (Suzuki et al., 2013; Suzuki and Yamamoto, 2015). Interestingly, it is recognized that Keap1-Nrf2 system plays a role in inflammation (Kobayashi et al., 2013, Innamorato et al., 2008, Suzuki et al., 2013; Suzuki and Yamamoto, 2015; O’Connell and Hayes, 2015; Wardyn et al., 2015). Recently, we reported that sulforaphane, a natural compound with Nrf2 activator, shows antidepressant effect in inflammation model of depression (Zhang et al., in press), and that pretreatment with sulforaphane confers resilience to social defeat stress in rodents (Yao et al., 2016). These results suggest that Nrf2 activators would be potential therapeutic drugs for depression.
TBE-31 [(±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile] is a novel Nrf2 activator (Fig. 1) (Dinkova-Kostova et al., 2010, Honda et al., 2007, Honda et al., 2011, Kostov et al., 2015; Ma and He, 2012). It retains and even exceeds the potency of CDDO (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid) analogs, which are the most potent compounds in pool of semi-synthetic triterpenoids in various in vitro and in vivo assays, including induction of cytoprotective enzymes. Furthermore, TBE-31 showed anti-inflammation effect in cells, and blocked the formation of aflatoxin-B1 (AFB1)-DNA adducts and AFB1-induced tumorigenesis in vivo (Liby et al., 2008). MCE-1 [(±)-3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile] is also a novel Nrf2 activator (Fig. 1) (Dinkova-Kostova et al., 2010, Zheng et al., 2012). A recent study showed that MCE-1 is a highly reactive Michael acceptor leading to reversible adducts with nucleophiles, which displays equal or greater potency than CDDO in inflammation and carcinogenesis related assays (Zheng et al., 2012).
The present study was undertaken to examine whether TBE-31 and MCE-1 show antidepressant effects in inflammation model of depression. First, we examined the effects of these compounds on nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells. Second, we examined whether these compounds could attenuate alterations in serum pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), after LPS administration. Finally, we examined the effects of TBE-31 and MCE-1 in inflammation-induced model of depression.
Section snippets
Quantification of neurite outgrowth in PC12 cells
PC12 cells (RIKEN Cell Bank, Tsukuba, Japan) were cultured at 37 ℃, 5% CO2 in Dulbecco's modified Eagle's medium (DMEM), supplemented with 5% heat-inactivated fetal bovine serum (FBS), 10% heat-inactivated horse serum and 1% penicillin. Medium was changed two to three times a week. PC12 cells were plated onto 24-well tissue culture plates coated with poly-D-lysine/laminin. Cells were plated at relatively low density (0.25×104 cells cm-2) in DMEM medium containing 0.5% FBS, 1%
Effects of TRB-31 and MCE-1 on NGF-induced neurite outgrowth in PC12 cells
Since neurite outgrowth is involved in the antidepressant's mechanisms, we examined the effects of TBE-31 and MCE-1 on NGF-induced neurite outgrowth in PC12 cells. MAP-2 (microtubule associated protein-2) immunocytochemistry showed that TBE-31 or MCE-1 increased the number of cells with NGF-induced neurite outgrowth in PC12 cells (Fig. 2A, B and C). One-way ANOVA revealed that TBE-31 and MCE-1 significantly (TBE-31: F3,39 =27.49, P<0.001, MCE-1: F3,39 =28.58, P<0.001) increased NGF-induced
Discussion
This study highlighted TBE-31 and MCE-1 as potential therapeutic drugs for inflammation-induced depression. First, TBE-31 and MCE-1 can potentiate NGF-induced neurite outgrowth in PC12 cells, through Nrf2 activation, suggesting that Nrf2 activators such as TBE-31 and MCE-1 are capable of enhancing the neuronal plasticity associated with antidepressant effect. Second, TBE-31 and MCE-1 have anti-inflammatory effects on the serum levels of TNF-α after LPS injection. Third, TBE-31 and MCE-1 showed
Acknowledgments and disclosures
This study was supported by a Grant-in-Aid from the Minister of Education, Culture, Sports, Science, and Technology of Japan (to K.H.), a Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan (to K.H.) and funds from Stony Brook Foundation and Reata Pharmaceuticals (to T.H.). Dr. Wei Yao was supported by Ishidsu Shun Memorial Scholarship (Tokyo, Japan). Dr. Kenji Hashimoto has received research support from Abbvie,
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