| BACKGROUNDChronic psychological stress can damage the central nervous system,and induce high incidence of many mental diseases such as depression. As a result, to study the preventive measures of stress-induced damages is necessary and of great significance for the protection of human's physical and mental health.Most of the existing anti-depressant drugs target to increase the function of 5-HT and NE system,but the efficiency of clinical effect is only 30% with obvious side-effects and expensive cost. So, exploring effective medicine to protect central nervous system has become one of the hotspots in the prevention research of chronic stress damage recently.Curcumin, a kind of polyphenols found in plants, can prevent cancer, bacteria, inflammation and oxidation with less side-effect. Recent researches show curcumin can improve cognitive function, protect brain and treat Alzheimer's disease and Parkinson.PURPOSETo study the neuron protective function of Curcumin in chronic psychological stress induced by chronic psychological stress and discuss its related mechanisms.METHODPART 1 The protective effect of curcumin on hippocampus damages in rats induced by chronic psychological stress. The chronic psychological stress model of rats was established by CUMS and isolated raising. Wistar rats were divided into six groups: control group, chronic stress group, curcumin treatment group (subgroup into low, medium and high dose) and fluoxetine treatment group.All the rats were involved in the following detection experiments: the test of behavioral indictors , serum glucocorticoid level by ELISA, amount of monoamine neurotransmitters in hippocampus by HPLC,LTP in fascia dentata by stereotaxie apparatus,histology analysis by HE staining and immunohistochemistry. Western blot was used to determine the expression of brain-derived neurotrophic detector (BDNF) in hippocampus , micro tubule associatedprotein 2(MAP-2) and the expression of the mRNA of BDNF and MAP-2,so as to evaluate the protective function of curcuimin on hippocampus damages in rats induced by chronic psychological stress.PART 2 The protective effect of curcumin on the hippocampal neuron damages induced by glucocorticoid(GCs)The stress damaged cell model was established by GCs. The primary cultured neuron cultured for 7-8 days were divided into three groups: control group, stress damaged group, curcumin group and curcumin/stress group. The morphology of neurons were observed by optical microscope and inverted phase-contrast microscope, the purity of neuron was determined by Nissl's staining, the survival rate of the neuron was detected by CCK-8,the neuron was determined by immunofluorescence. Western blot was used to determine the expression of brain-derived neurotrophic factor (BDNF) in the primary cultured neuron , microtubule associated protein 2(MAP-2) and the expression of the mRNA of BDNF and MAP-2,in order to evaluate the protective function of curcumin on the hippocampal neuron damages induced by the GCs.RESULTSPART 1 The chronic psychological stress led to the lente increase of the weight of the rats, decrease of the ingest of julep,and the sensitivity of the rats towards the reward as a incentive;the inhibition of the excitation and reactivity of rats in openfield test;besides it also induced the weakened abilities of exploration and memory in water maze(P<0.05).After HFS, the increasing extent of the PS peak to peak value was notablely lower than the normal rats(P<0.05), The chronic psychological stress influenced the synaptic transmission and the ability of learning and memory, brought about the weakened functions of the hippocampus,the marked elevation of the level of the GCs in serum(P<0.01), the disorder of the function of HPA,the marked decrease of the content of 5-HT, the exhaustion of synaptic cleft monoamines, the decrease of the expression of mRNA and proteins of MAP-2(P<0.01) and BDNF(P<0.01), the damage to the stability of cytoskeleton and the neural plasticity, it also impacted the regeneration capacity of neural plasticity; the LSAB results of the stress group indicated that the expression of the MAP-2 and BDNF in the hippocampus increased a lot .Curcumin could relieve the damages induced by chronic psychological stress in rats notablely. It could help the rats gain weight significantly(P<0.05), increase the preference of the rats to the julep(P<0.05), reverse the anhedonia induced by chronic stress, significantly improve the reactivity in openfield test,the number of the checks scrambled (P<0.05) and the time (P<0.05) erected by the rats in the openfield increased a lot, improve the learning ability of the hippocampus, promote the formation of LTP in hippocampal fascia dentate, after HFS, the increasing extent of the PS peak to peak value of the curcumin treatment group was notablely higher than the stressed rats (P<0.05), curcumin decreased the level of the GCs in serum(P<0.01), regulated the axis function of HPA, medium dose of curcumin increased the content of the 5-HT, slowed down the exhaustion of synaptic cleft monoamines induced by chronic psychological stress. Curcumin enhanced the protein expression of the BNDF and MAP-2mRNA, reversed impaction of the chronic psychological stress to the function of neural and structural plasticity.The protective effect of the curcumin on the hippocampal stress damage was in accordance with the effect of the classical antidepressant drug fluoxetine.In comparison, fluoxetine would induce serious enteric reaction, as a result affected the weight and reactiveness of the rats, compared with the stress groups, fluoxetine improved the expression of the BDNF mRNA and the proteins notabley(P<0.01), however, it had no significant impact on the the expression of the protein and the mRNA of the neural skeleton protein MAP-2mRNA (P<0.05).GCs at 10-5mol/L would lead to damage on hippocampal neuron,induced the change of the hippocampal neural shape,reduction of the synapse and the cell survival rate(P<0.01),decrease of the protein expression of the BDNF(P<0.01) and MAP-2(P<0.01), curcumin at terminal concentration 1umol/L could prevent the decrease of the cell survival rate induced by GCs(P<0.01), and reverse the suppression of the expression of BDNF and MAP-2 induced by GCs(P<0.01).The results showed that curcumin have direct protective effect on the hippocampal neuron.CONCLUSION Chronic psychological stress can injure function of hippocampus which can be declined by curcumin. Our research indicated that curcumin can enhance the function of 5-HT system , regulate HPA axis hypoglycemia,at the same time reverse the decline of the expression of BDNF and MAP-2, promote the formation of the neuron,improve the function of neural plasticity of the hippocampus, consequently curcumin can protect the central nervus.We first discovered that curcumin regulate neural and structural plasticity through the improvement of expression of the relative microtubule associated protein MAP-2, so as to lessen the hippocampal damage induced by chronic psychological stress,and consequently protect the central nervus.Our research indicated that curcumin probably had direct protective effect on the hippocampal neuron.Without activation of the 5-HT system, curcumin had direct protective effect through the regulation on neurotrophic factor-BDNF and the neural plasticity.The functional pathways need further investigation. |
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