Study On Molecular Mechanism Of Thioredoxin Against The Glucocorticoid-induced Neurotoxicity

Major depression is a common mental disorder which gives the spirit and economical burden on family and society. Major depression will be the most cause of death except cancer by2020. Exposure to stress condition represents a major environment which contributes to development of major depression. Under physiological conditions, stress exposure activates the hypothalamus-pituitary-adrenal (HPA) axis, which leads to glucocorticoid (GC) release from the adrenal glands. Over stress results in overrelease of glucocorticoid, then leads to neuronal cell damage and depressed mood, insomnia, forgetfulness, sexual dysfunction, and other symptoms of depression.Endoplasmic reticulum(ER) is a principal site for calcium store, protein synthesis, folding, plays important roles in regulating intracellular calcium signaling and glycosylation. It is highly sensitive to alterations in homeostasis in its environment. Unfolded and misfolded proteins accumulate in the ER can lead to self-protective signal pathway which termed the unfolded protein response (UPR), then result in ER stress, finally induce apoptosis by activating C/EBP homologous protein (CHOP) and procaspasel2. It has been found that the abnormal expressions of GRP78, GRP94, and calreticulin in the mice model of depression and cortex of major depressive disorders who died by suicide. These findings indicate that ER stress is closely related with pathogenesis of depression.Thioredoxin (Trx) is a12kDa protein with its active site sequence,-Cys-Gly-Pro-Cys-. Trx-1is induced in response to a variety of stresses, such as X-ray and ultraviolet irradiation, hydrogen peroxide, viral infection and ischemic reperfusion. It has various functions, for example, regulatingthe cellular redox status as well as growth promotion, neuroprotection, inflammatory modulation, anti-apoptosis. As an ubiquitous and multifunctional protein, Trx-1is expressed in all forms of life executing its function through its antioxidative, protein reducing, signal transducing activities.Rencet study have showed that major depression is associated with oxidative stress and ER stress. Trx-1can resist oxidative stress and ER stress. However, the relationship between depression and Trx-1has not been reported. The aim of our study is to examine the alteration of ER stress and Trx-1in cell model by dexamethasone. At the same time, to detect the effects of Fluoxetine, a antidepression drug,on dexamethasone-induced neuron toxicity as well as to further observe effects of geranylgeranylacetone, GGA, an inducer of Trx-1,on dexamethasone-induced neuron toxicity.The main results of this study were as follows:(1) ER stress and neuron damage caused by dexamethasone. Dexamethsone stimulated PC12cells, the viability of PC12cells were decreased in a dose-dependent manner, dexamethsone induced activation of Procaspase3and Procaspase12, the marker of ER apoptosis pathway, but had no effect on Procaspase9, the marker of mitochondrial apoptosis pathway.These results suggest that:dexamethasone induces apoptosis and neuron damage through inducing ER stress pathway.(2) Dexamethasone decreased the expression of Trx-1. Trx-1plays role in resisting oxidative stress and inhibiting oxidative stress-induced cells damage. After dexamethasone stimulated PC12cells24hours, the expression of Trx-1was significantly suppressed, expression of monoamine oxidase was increased. Thess results suggest that:dexamethasone induced neuronal apoptosis may be related to the decrease of Trx-1expression.(3) Fluoxetine, antidepressant drug resists to dexamethasone-induced ER stress and cell apoptosis.Fluoxetine is clinically used a common antidepressant drug, After fluoxetine stimulated cells, the Trx-1expression was increased in PC12cells Fluoxetine pretreatment may resist neuron damage by examethasone, reverse expression level of Trx-1,inhibit of monoamine oxidase increase. Moreever, Fluoxetine can suppress GRP78expression and the activation of Procaspasel2induced by dexamethasone, inhibition of ER stress-related protein. Thess results suggest that:Fluoxetine can induce the expression of Trx-1, and inhibit dexamethasone-induced ER stress and cell damage.(4) The Trx-1inducer GGA resists dexamethasone-induced ER stress. GGA pretreatment may resist dexamethasone-induced neuron damage, and reverse decreased expression of Trx-1, inhibit of monoamine oxidase increase. Moreever,GGA can resist dexamethasone induced ER stress, inhibit GRP78expression and the activation of Procaspase12. Thess results indicated that:Trx-1inducer, GGA can induce the expression of Trx-1, and inhibit dexamethasone induced ER stress and cell damage.Conclusion:dexamethasone decreased the expression of Trx-1and induced ER stress and cell apoptosis. Fluoxetine, antidepressant drug induce expression of Trx-1and inhibit ER stress by dexamethasone. The Trx-1inducer GGA may suppress ER stress and neuron damage by inducing Trx-1expression.