| Major depression disorders (MDD) is characterized by anhedonia and several additional symptoms for diagnosis such as psychomotor slowing, changes in sleep/appetite, excessive feelings of guilt or worthlessness, anergia, in more severe cases, suicidality. It is the major mental disorders, its incidence is as high as 20%. WHO studies predict that depression will be the second common disease burden in all life until 2020. Thus, it is worth to study this disease. Its molecular mechanism is still unknown. It is chronic, recurrent brain disorders with dysfunction of biochemistry. Genetic and stress vulnerabilities interplay to initiate cascades of mentality, social, environment, and biological factors disruption, which result in changes of nerve endocrine abnormalities, immune response, neurotransmitter metabolism, neuron plasticity, receptor abnormal, neuron apoptosis, oxidative stress and neurodegeneration, finally, brain structural and functional abnormalities.Heat shock protein70 (HSP70) functions as a molecular chaperone which is induced under cellular responses to various stimuli. Several reports have shown that HSP70 have protective roles in helping the fold, translocation, recovery, and degradation of ptotein, various models of nervous system injury, including suppressing oxidative stress and ischemic-reperfusion injury, HSP 70 binds to apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase, as upstream activator of c-jun NH2-terminal kinase and p38 in various cell types, stables cAMP-dependent protein kinase C (PKC), and inhibits caspase-3 pathway. As the molecular chaperones, HSP70 is involved in the endoplasmic reticulum stress and role of brain-derived neurotrophic factor (BDNF), so it is related to depression.Thioredoxin-1 (Trx-1) is a ubiquitous protein with a conserved redox-active disulfide/dithiol center. Trx-1 is an important protein that maintains the cellular redox status.Trx-1 is an anti-oxidant and anti-apoptotic molecule. Trx-1 redox regulating role is through activate site of Cys-Gly-Pro-Cys, and protecting role is through binding to apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase, as upstream activator of c-jun NH2-terminal kinase and p38 in various cell types and then suppressing apoptosis. Trx-1 is a downstream of cAMP-responsive element-binding protein(CREB) and acts as a neurotrophic co-factor which augments the effect of nerve growth factor on neuronal differentiation and regeneration and in involved in endoplasmic reticulum (ER) stress.Geranylgeranylacetone (GGA), an acylic isoprenoid compound with a retinoid skeleton, is widely used in the clinic for treating ulcer. It has been reported that GGA is a lipid-soluble reagent and can easily pass the blood-brain barrier to exert neuroprotective effects. The cytoprotective effect of GGA is dependent on the inductions of HSP70 and Trx-1. Chronic mild stress (CMS) has been utilized to make the model of depression-like behavior, followed by behavioral measures of anhedonia (sucrose preference test) and psychomotor slowing (open field test). Monoamine oxidase(MAO) is an oxidation enzyme of monoamine neurotransmitter, which administrates the degradation of monoamine neurotransmitter and is looked as one of the molecular hallmark of depressive disorders. Analysis of postmortem tissue and rodent models has provided some evidence with apoptotic cell death in depression and stress. The pathways of apoptosis included the mitochondrial pathway and ER-mediated pathway.The main results were as followings:(1) The level of HSP70 on the hippocampus and frontal lobes of the rats after CMS detected by Western Blot and immunohistochemistry was lower than that of control rats (p<0.05). It means that the HSP70 protection was lowered in MDD. The rats showed that the favoritism of sucrose consumption was decreased because of the descent of HSP70 in hippocampus where was the brain area related to the interest. The rats showed that the movement in open field test was decreased because of the descent of HSP70 in frontal lobes where was the brain area related to the intention (p<0.05).The sucrose favoritism in sucrose consumption test was increased in lenthened CMS, while that was decreased in standard time CMS, so there was significantly different between two groups. And the scores of crossing and the time for rats’retention in the center grid of open field test in lenthened group were higher than those in standard group (p<0.05). The HSP70 on the hippocampus and frontal lobes of lenthened group detected by Western Blot and immunohistochemistry was higher than that of standard group; The HSP70 on the hippocampus of lenthened group detected by RT-PCR was higher than that of standard group (p<0.05).The sucrose favoritism in sucrose consumption test was significantly decreased in aging rats, and the scores of vertical and crossing and the time for rats’retention in the center grid of open field test in aging rats were lower than those in young group (p<0.05). The level of HSP70 on the hippocampus and frontal lobes of aging rats detected by Western Blot, RT-PCR and immunohistochemistry was also lower than that of young group (p<0.05).The sucrose favoritism in sucrose consumption test was more decreased in female rats than that in male rats, and the scores of vertical and crossing of open field test in female rats were lower than those in male rats (p<0.05). The level of HSP70 on the hippocampus of female rats detected by Western Blot, RT-PCR and immunohistochemistry was also lower than that of male rats (p<0.05). (2) GGA significantly attenuated depression signs in rats by CMS. The favoritism of sucrose consumption in sucrose preference test and the vertical score, the number of crossings, and the cleaning time in open field test were all significantly reversed by the pretreatment of GGA(p<0.05).(3) We confirmed that CMS in rats caused a reduction in locomotor activity and increases in the levels of monoamine oxidase-A (MAO-A) and caspase-3 in the hippocampus. GGA treatment reversed stress-induced alterations in locomotor activity and levels of MAO-A and caspase-3. In addition, GGA treatment induced heat shock protein 70 (HSP70) expression in the hippocampus.(4) The expression of Trx-1 and CREB was down-regulated in depressive rats compared with control rats, while the decreased expression of Trx-1 and CREB in depressive rats was reversed by treatment with GGA. MAO expression was up-regulated n the frontal cortex of depressive rats compared with control rats, then the increased expression of MAO was obviously suppressed by GGA compared with depressive rats without GGA.(5) The results showed that the expressions of GRP78 and CHOP were increased in depressive rats compared to control rats, and GGA obviously inhibited the level of CHOP. And the expressions of procaspase-3 and procaspase-12 were decreased in depressive rats compared to control rats, and GGA significantly reversed the levels of procaspase-3 and procaspase-12. However, there was no variance in the expressions of procaspase-9 and JNK among depressive rats, depressive rats treated with GGA and control rats.(6) There was no significant deviation in HAMD between before and after treatment (p>0.05). There was no significant deviation in HAMD neither between the strengthening lipid-lowering group and no lipid-lowering group, nor between the standard lipid-lowering group and no lipid-lowering group(p>0.05). There was no significant deviation in HAMD among the strengthening group, the standard group and the no lipid-lowering group (p>0.05).The lipid-lowering in 40 mg groups exceeded the lowering in 20 mg groups (p>0.05). And there was no significant deviation between before and after two kinds of treatments in blood check and HAMD (p>0.05).(7) The peptic ulcer patients with MDD were treated by GGA added in Esomeprazole or by Esomeprazole alone. Four weeks later, there was no difference in the cure rate of the peptic ulcer between the two group ((p>0.05); While the scale of HAMD in GGA group was lower than the control group (p<0.05).In conclusion, this study showed that HSP70 and Trx-1 had the protective effects in major depression disorders. The mechanisms were related to inhibitions of MAO-A, MAO, apoptosis, and endoplasmic reticulum stress. The levels of HSP70 of aged and female rats were lower than those of young and male rats. The depressive symptoms could be reliefed because of the HSP70 expression increasing in longer stress. The inducers of HSP70 and Trx-1 are beneficial and safe for protection against depression. |
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