The effect of stress hormone corticosterone on thioredoxin system
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Date
2019-08-27
Authors
Bharti, Veni
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Abstract
Chronic stress is a major risk for depression and other psychiatric disorders. Previous
studies have shown that oxidative stress and inflammation play roles in stress-caused damage.
Thioredoxin (Trx) is oxidoreductase that reverses the cysteine oxidative modifications. Trx-
interacting protein (Txnip) is a negative regulator of Trx. Txnip can also interact with Nod-like receptor protein 3 (NLRP3) and activate the NLRP3 inflammasome. The objective of this study was to investigate if chronic treatment with corticosterone (CORT) or antidepressants regulate Trx/TrxR/Txnip expression and Trx system-regulated
signaling. We found that although 5 days long CORT treatment increased Txnip protein levels in HT22 cells and primary cultured neurons, it didn’t change the protein levels of Trx/TrxR. Chronic CORT treatment increased Txnip in both nucleus and cytosol, while glucocorticoid receptor inhibitor RU486 blocked CORT-increased Txnip protein levels. Further chronic CORT treatment increased protein nitrosylation and sulfenylation while knocking out Txnip inhibited CORT-induced protein nitrosylation and sulfenylation in HT22 cells. Second, chronic treatment with antidepressants (fluoxetine and venlafaxine) increased Trx/TrxR protein levels but didn’t change TrxR and Txnip protein levels in HT22 cells. Both antidepressants reversed H2O2 and CORT-induced sulfenylation, and nitric oxide donor S-nitrosoglutathione and CORT-induced nitrosylation in HT22 cells. Third, chronic CORT treatment increased Txnip protein levels but didn’t change the protein levels of Trx/TrxR in N9 and primary cultured microglia. Txnip/NLRP3 protein binding was also increased in CORT-treated N9 cells, and hippocampus and frontal cortex of mouse exposed to chronic unpredictable stress. Chronic CORT treatment also decreased procaspase-1 levels, increased caspase-1 activity, and IL-1β protein levels, while
Txnip knockout inhibited CORT-increased caspase-1 activity and IL-1β protein levels in N9 cells. Our findings suggest that chronic CORT treatment increased oxidative modifications and activated NLRP3 inflammasome mediated by Txnip. Antidepressant treatment-increased Trx may mediate the neuroprotective effect of antidepressants against oxidative stress.
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Keywords
MDD, Major Depressive Disorder, Thioredoxin