Interaction Of FGF2and VEGF In Animal Model Of CUMS

Depression is a high incidence, easy relapse, harms big mental disorders, with ongoingdepression and cognitive dysfunction as the main clinical features. In recent years, withincreasing incidence of depression caused widespread concern, but the pathogenesis arecomplex and have not yet fully elucidated.Research found that brain neurotrophic factor (neurotrophic factor, NTFs), plasticitychange with the occurrence of factors such as depression and outcome closely related. Itreveals the pathogenesis of depression and for its and providing the new ideas and new ways.Neurotrophic factor is a kind of active protein, mainly by neural control target organization orglial cells to produce, can promote central and peripheral nerve differentiation, growth andsurvival and the central and peripheral nervous system are nutritional role. This smallmolecule protein has55%~65%of the same amino acid sequence and in the development ofthe nervous system and maintains normal physiological function plays an important role.Scholars in2006put forward "depression nerve nutrition hypothesis"(Neurotrophichypothesis of depression). This hypothesis, neurotrophic factors to promote growth, maintainsynaptic neuron survival role, if prefrontal, such as the hippocampus brain regions lackneurotrophic factor is the corresponding brain function will be crimped eventually lead todepression; And antidepressant drugs is through the increase in the brain neurotrophic factorcontent and to improve synaptic plasticity and promote the survival of neurons to exert itsdepression effect. Namely neurotrophic factor expression level by the depression in somepathophysiological process.In the depression candidate genes study, FGF2and VEGF and nerve regeneration,nutrition and change the phenomenon such as neural plasticity relationship exists, so widelyattention. FGF2fibroblast growth factor is a member of the family, has simulative nervetissue damage repair, nerve protection and neural nutritional role. In the adult brain to FGF2can promote neurons grew, in the early of neurogenesis played a certain role. Research showsthat FGF2closely related with depression, basically have the following aspects:(1) the basisof foreign corpse solution research shows that: patients with depression prefrontal cortex and the hippocampus FGF2m RNA expression lower total (in CA1area, CA4area express belowthe dentate gyros), and FGF2neurons in the hippocampus decrease.(2) The antidepressantdrug research: study has confirmed that the use of antidepressant drug therapy, the FGF2expression was increased.(3) The animal study: Perez, etc. FGF2through testing the mice,found that FGF2level of high and low and mice is directly related to the degree of depression,and strengthen the environment can reduce the degree of depression. The above research toshow that depression affected by FGF2which may be involved in a variety of physiological.VEGF called angiogenesis factor, can effectively promote the regeneration of theendothelial cells and blood vessels proliferation. Foreign scholars study showed that patientswith depression acute episode, the level of VEGF increased. Not only such, can stimulateregeneration through blood vessels VEGF, protect ischemic and degeneration of neurons,caused adult brain neurons regenerate, thereby affecting the depression. The main basis forthe following aspects:(1) gene polymorphism related research:2010years Vikki of VEGFgenetic polymorphism and the relationship between the antidepressant treatment, theyselected the119production by electricity seizures therapy, eight subjects used the fiveserotonin reuptake inhibit (serotonin selective reuptake inhibitors, SSRI) therapy. The resultsfound VEGF2578C/A site in two treatments are change after expression.(2) theantidepressant drug research: the study used a variety of antidepressant drugs to evaluate itseffect, found in the lateral ventricle injection VEGF increase big rat hippocampal the dentategyros neural happen at the same time, can produce antidepressant sample behavior; Andinjection VEGF receptor antagonist SU5416can offset VEGF mediated the hippocampus cellproliferation reaction and antidepressant effect.(3) The animal study: VEGF can stimulate theSGZ cell proliferation and in animal models of behavior evaluation have similarantidepressant effect; block VEGF, this kind of effect is restrained. The research shows that,VEGF antidepressants may be related to.In conclusion, FGF2and VEGF, there are certain and depression is connected, thebiological function of both also has similarities, so whether both can joint mediateddepression? Depression and neural plasticity hypothesis nutrition hypothesis occurred in theprocess of recovery and depression in the hippocampus and the brain structure will significantfunction and change shape. Stress or depression will lead to the hippocampus, prefrontal andthe amygdala, edge is shrinking and cell loss neurons, and cause neurotrophic factor expression down; The use of antidepressant drugs can promote adult hippocampal nerveregeneration and neurotrophic factor expression was increased, and the correspondingincrease in the hippocampus adult neural accident and neurotrophic factors can produce theexpression of antidepressants. The present study results showed that patients with depressionbrain structure and function change mainly in the prefrontal cortex, hippocampus, theamygdala and other major target organ, is the main stress sexual response regulating center ofneural plasticity and brain regions. Comprehensive analysis of antidepressant mechanism, thekey lies in whether can induce adult may occur in the hippocampus and nerve neurotrophicfactor expression was increased, similar to the antidepressant drug treatment function.Accordingly, can theoretically through regulation corresponding nervous factor expression ofdepression, but FGF2and VEGF are molecules, its effect is difficult to separate the bloodbrain barrier directly affect neural happen. And FGF2and VEGF role of depression whenalone can only part of the explanation to the physiological mechanism. VEGF has increasedand the influence angiogenesis of neurogenesis role, FGF2also through nerve protection orincrease angiogenesis role to improve the function of nervous system. So when the jointaction of both whether through angiogenesis and may increase the role of nerve regeneration?Although FGF2, VEGF biological function different, but complementary functions evenoverlap, may be common control downstream of signal transmission and gene transcriptionprocess, in the antidepressant process plays an important role. Therefore, this study researchedexpression of FGF2and VEGF by molecular and protein level in the hippocampus and theprefrontal cortex layer, and explored interaction between them in the hippocampus.Method：1．20male Sprague-Dawley rats of180-220g were randomly divided into two groups and10rats in2groups: normal control group, model group. The depressed model was reduced bysingle feed combined with CUMS. After twenty-one days, behavior changes in rats weredetected through open-field test, sugar consumption test and body weight,to detected themodel was successfully established.2．Model was successfully established, the expressive levels of FGF2and VEGF in thehippocampus and PFC of SD were verified by using q RT-PCR and western-blot technique.3．To explore the interaction of FGF2and VEGF:64rats were randomly divided into8groups： A control group; B CUMS group; C SU5416group; D SU5402group; E CUMS+SU5416group; F CUMS+SU5402group; G CUMS+SU5402+SU5416group; HCUMS+SU5416+SU5402group; Immunohistochemistry was used for measuring levels ofFGF2and VEGF, Open-field test, Sucrose preference test, Forced-swim test was used forobservation of animal behavior test.Result：1．After chronic unpredietable mild stress by28days, behavior changes in rats weredetected through open-field test, sugar consumption test and body weight. Data analysisshowed that compared with the control group, the CUMS group began to exhibit asignificantly lower gain in body weight compared with the control group（P<0.05）. In thesucrose preference test, the total water consumed was the same in the two groups (controls:79.41±11.2ml, CUMS:73.22±14.3ml, p<0.05); however, rats undergoing CUMS showed adecreased sucrose preference following the stress period as compared with the control rats.After21days of stress, the CUMS rats exhibited a similar locomotor activity to the controlrats (control:104.67±23.7, CUMS:58.61±19.8, p<0.05). Specifically, in comparison withcontrol rats, rats treated with CUMS exhibited a significant decrease also in rearing (p <0.05)and grooming (p <0.05). Our current protocol of a21-day CUMS appears to be able toinduce a rat model of depression characterized by depression-like behavioral changes thatmay mimic anhedonia, loss of interests, weight loss, psychomotor retardation and recurrentthoughts in depressed patients.2．The levels of FGF2and VEGF gene protein expression in the the hippocampus andPFC of model group were significantly lower than control group. And the levels of FGF2andVEGF gene mRNA expression in the hippocampus and PFC of model group weresignificantly lower than control group. The less of FGF2and VEGF expression in thehippocampus and PFC may be one of the important pathophysiological bases for depression.3．Biology results: After treatment, the SU5402/SU5416-injected animals exhibitedsignificantly lower levels of FGF2/VEGF mRNA in hippocampus than the controls (p<0.05).Interestingly, there were no significant differences in the expression of FGF2/VEGF in thehippocampus between the two groups of injection sequence. In the present study, we providedthe first evidence that injections of the FGF2inhibitor (SU5402) and the VEGFinhibitor(SU5416) into one side of the hippocampus significantly increased depression-likebehavioral changes induced by CUMS, including a marked suppressed in the amount of sucrose intake, body weight, locomotor activity, rearing and grooming in open field test, and asignificant increased in immobility time in forced swimming test.Conclusion：1．The animal models were established by applying chronic unpredictable mild stress torats raised alone. Open field test, sugar consumption test and body weight demonstrated thatthe models well simulated many of human depression symptoms,suggesting that the modelswere psychomotor retardation and recurrent thoughts in depressed patients. And easy ofoperation can be repeated, ideal for depression and animal models.2．In this study, we focused on the FGF2and VEGF level was decreased in CUMSmodels of depression in comparison with their respective controls. There is substantialevidence that disregulation of the FGF2and VEGF system is involved in depression. Thereason for this is likely that, since depression is a developmental disease, early disruption of asystem may be causal to the disease even if when the disease symptoms are expressedcompensation has occurred. What is clear is that alteration in the FGF2and VEGF system canplay a role in depression.3．FGF2and VEGF may shown to interact with depression in development of thehippocampus in mouse. These results support the idea that inhibition of hippocampal FGF2and VEGF may increased the development of CUMS model of depression. Consistent withthis result, it is well known that FGF2can stimulate the production of angiogenic growthfactors (such as VEGF) as well as neurogenic growth factors from endothelial cells, astrocytes,and neurons. In this regard, the localization of receptors for FGF2and VEGF on neuroblastsraises the possibility that these neurotrophic factors could work both independently and/orcooperatively to influence specific stages of neurogenesis.