Study On Geranylgeranylacetone Against Depression Induced By Acute Stress

Depression is mood disorder, which mainly caused by various psychological pressure, social pressure, and major accidents. Its main clinical features is the low mood, lack or disorder of emotion, and the cognitive disorder, more seriously, most of patients with depression have suicidal motivation. Nowadays, the depression has become a social problem. The mechanism of depression is very complicated. Beside the monoamine hypothesis and the HPA (hypothalamus-pituitary-adrenal) hypothesis, oxidative stress and various kinds of neurotrophic factors are closely related to the pathogenesis and development. In addition, the damage of memory and cognitive function are associated with depression. The synaptic plasticity is the mechanism of learning and memory, and it is closely related with the development of depression. The synaptic plasticity are regulated by glutamate receptors, N-methyl-D-aspartic acid(NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid(AMPA). In the model of depression, the activity of NR2B receptor, one of the subtypes of NMDA receptor was decreased, as well as AMPA receptor.Thioredoxin (Trx) has been determined to have the functions of regulating the redox balance and promoting cell growth. Trx has become a new good drug which can trea various diseases induced by oxidative stress, aging and inflammation. Thus, inducers and targeted tissues become the direction of medicine development.Heat shock protein70(Hsp70) is a protein of molecular weight70kDa. Both in prokaryotic or eukaryotic cells, Hsp70expression can be detected. When the cells was subjected to emergency response, Hsp70firstly response and prevent cell damage. Beside the effect of the maintaining normal biological function, Hsp70can also inhibit cell apoptosis, cell necrosis and inflammatory reaction.Geranylgeranylacetone (GGA) has been widely used and the main application is the disease of ulcer in the gastrointestinal tract in clinical. Studies in recent years show that GGA may induce the expressions of Trx and Hsp70in the neurons, liver cells, and retinal cells, as well as in ischemic brain, in renal failure, in light-caused damage and protect the cell from injury. However, the effect of GGA for the treatment and prevention of depression has not been reported. This project is to study the mechanism on GGA resisting acute stress-induced depression by using mouse model of acute stress-induced depression, to explore the the mechanism on GGA regulating behavioral changes and the expression of related proteins in animal models.The main results as followings:1. The GGA treatment mice resisted acute stress, the immobility time was significantly lower than the stress group in the tail suspension and forced swim test. This suggests GGA has the role in resisting stress-induced depression.2. GGA increased expressions of Trx and Hsp70in brain tissue, and played roles in inhibiting oxidative stress, protecting neurons. This suggests GGA inhibits cell damage by inducing expressions of Trx and Hsp70.3. GGA induced phosphorylation of cAMP-response element binding protein (CREB) and increased expression of glycogen synthase kinase3β(GSK3β). This suggests GGA induced Trx expression by increasing the expressions of p-CREB and GSK3β.4. GGA regulated molecules related to synaptic plasticity in animal models, played antidepressant role. The expressions of CaMKII and NR2B involved in synaptic plasticity changed. This suggests CaMKII and NR2B are associated with GGA role.In conclusion, GGA induced expressions of Trx and Hsp70through GSK3β pathways and inducing phosphorylation of CREB and played protective roles in suppressing acute stress-induced depression in mice. As well as GGA regulated synaptic plasticity to resist depression. This study may provide a theoretical basis and a new target for preventing and treating acute stress-induced depression.