The effect of stress hormone corticosterone on thioredoxin system
| dc.contributor.author | Bharti, Veni | |
| dc.contributor.examiningcommittee | Miller, Donald (Pharmacology and Therapeutics) Jackson, Michael (Pharmacology and Therapeutics) Kong, Jiming (Human Anatomy and Cell Science) Honer, William G. (University of British Columbia) | en_US |
| dc.contributor.supervisor | Wang, Jun-Feng (Pharmacology and Therapeutics) | en_US |
| dc.date.accessioned | 2019-09-06T16:19:15Z | |
| dc.date.available | 2019-09-06T16:19:15Z | |
| dc.date.issued | 2019-08-27 | en_US |
| dc.date.submitted | 2019-08-27T13:40:23Z | en |
| dc.degree.discipline | Pharmacology and Therapeutics | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.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. | en_US |
| dc.description.note | October 2019 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/34175 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | MDD | en_US |
| dc.subject | Major Depressive Disorder | en_US |
| dc.subject | Thioredoxin | en_US |
| dc.title | The effect of stress hormone corticosterone on thioredoxin system | en_US |
| dc.type | doctoral thesis | en_US |