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Effect of Daphnetin on the Expression of β-APP after the Ischemia in the Front Brain of the Mouse

Author: OuYangXin
Tutor: YuTingMin
School: Jilin University
Course: Neurology
Keywords: Cerebral ischemia β- amyloid precursor Daphnetin
CLC: R749.1
Type: Master's thesis
Year: 2006
Downloads: 45
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Abstract

Now the incident of the ischemia cerebrovascular disease tend to be up everyyear.Its prevention and cure has been placed high important on by medicalscientists. The pathological change of the ischemia cerebrovascular diseaseincludes:the state of coagulation、hyperviscous and high collection,the reductionof cerebral blood flow, the anoxemia and ischemia ,the energydysmetabolism,the production of oxygen free radical,the participation ofinflammatory cell and its agent and so on.These procedures lead to thedegeneration and death of neurocytes.So it is necessary to find a valid drug totreat the ischemia cerebrovascular disease.The amyloid protein precursor (APP) resides in the multicyst structure、karyolemma、Golgi’s apparatus and rough endoplasmic reticulum. In the state ofnormal physiological function,the large part of β-APP is broken downthrough non-amyloid protein pathway,which can produce soluble amyloidprotein(sAPPα)and the fraction of C83.The function of sAPPα includesneurotrophy 、 promoting the development of neurocytes 、 promoting thegeneration of axis、regeneration of the synapse and protection of neurcytes. APPcan produce β-amyloid protein(Aβ) through amyloid protein pathway. Aβmay spread the survival time of cultivated mouse neurons at low concentrationwhile it is characteristic of cytotoxicity at high concentration.It hasbeen reported that β-APP and Aβ are related with the progression of ADlong before.It is proved that Aβ takes part in the pathology process ofcerebral ischemia lesion. So interference in the processing of the expression ofβ-APP may impossible be one of the elements in curing the cerbralinfarction. Some attraction from the traditional Chinese medicine such as flavonoidssaponins of panax natoginseng and coumarin can improve circulation forincreasing cerebral blood flow and anti-assembly of platelet anti-coagulationanti-inflammation cleaning out oxidant and adjusting serum lipids. Thesefunctions have non-substitutive action in treating ischemic cerebrovasculardisease. Daphnetin, the derivative of coumarin , is used for treating ischemicheart disease thromboangitis obliterans and precauting atherosclerosis because itcan expand blood vessel strengthen cardiac muscleanti-coagulation(anti-vimentinK) anti-assembly of platelet bearing hypoxiadecreasing total cholesterol increasing high dencity lipoprotein cholesterol, thatit is little toxicity and side effect, it is metabolized and drained quickly.Daphnetin is central restrain ,simultaneously it can get across blood brain barrierso we hypothesize it has same function in central nercous system,namelycerebral protection. But we didn’t find clinical and experimental report aboutdaphnetin for treating ischemic cerebrovascular disease.The wistar mousse is divides into sham operation group、control group andtherapy group in this experiment.The mouses in the sham operation group arestripped out the double sides of common carotid artery which aren’t ligated;theprocessing steps of the control group:First sripping out the double sides ofcommon carotid artery,second occlusing them for fifteen minutes,thirdreperfusing for 1 hour,forth occlusing them for fifteen minutes,fifthreperfusing ,lavaging the same Sodium Chloride as daphnetin after operation;theprocessing steps of the therapy :the operation is the same as the controlgroup,but lavaging daphnetin.Kill the mouse respectively at 2nd week、4thweek、6th week,then take out the brain,fixture,make cut sheets,observe the cellquantity and shape of HE stained sheets and β-APP stained sheets taken fromthe hippocamp CA1 domain and frontal lobe domain through light microscope.The display of results: the normal shape of brain tissue、the integratedand dintint formation of neurocytes and gliacytes、normal interstitiumcan been seen from the HE-stained sheets of the mouse in the sham operationgroup at every designed spot of time. After the damage due to brain ischemiareperfusion , cell interstitial edema 、thickly stained nucelus pyknosis 、theshorten neurons and the lessened blood capillaries can be seen at thehippocamp CA1 and frontal domain.As time being extended, interstitial edemais obviously lessened ,but the reduction of nerve cells is obvious ,andgliosis can been seen in the control group.But the change above ismore little in the therapy group by daphnetin than in the controlgroup.The result of β-APP immunohistochemistry: β-APP positivereactant as brown particle disposition around cellular membrane andendochylema like ring circellus can be seen from β-APP-stained sheets at thesame domain. β-APP positive cells are evidently in the control group morethan in the sham operated group at all the designed time-spots after brainischemia reperfusion. At the designed spot of 2th and 4th week, theexpression of β-APP has been deceased in the therapy group than in thecontrol group, as are similar by statistics. At the designed spot of 6th week,the expression of β-APP is obviously lower in the therapy group than inthe control group and similar with the sham operated group by statistics(P>0.05). It is suggested that daphnetin can protect from the damage aftercerebral ischemia reperfusion through the effects on the expression of β-APP .It should be administered more than 6 weeks at least.Daphnetin may probably make an influence on the expression of β-APPby many means.(1)Maintain the integrality of the cellular membrane.Therejective function on lipid peroxidation can refrain from spallation of theauxiliary fibers and microtubule and profluvium of β-APP. It can protectthe cholinergic neurons and relieve the inflammatory reaction that theoxygen free radical lead to.(2)Prevent the formation of βlamellarstructure.Daphnetin improves the circulation,prevents thrombogenesis anddecrease the blood fat, which can maintain the homoeostasis and preventβlamellar structure. (3)The function of anti-inflammatory.Depressing theinflammatory reaction can lessen the expression of APP and diminish thetoxicity of Aβ.Lessen the quantity of the active gitter cells,so prevent theexpression of APP. (4)Winter daphne radix can diminish the excitatory aminoacids content ,especially glumatic acid and aminosuccinic acid, simultaneouswhich can raise rejective amino acids content, such as aminobutyric acid. (5)Lowering the cholesterol can lessen the deposition of the Aβ. (6)Increasethe metabolism of monamine media 5-HT. 5-HT can increase the α-secretaseprocessing through the excitement of the 5-HT2A receptor,which canpruduce sAPPα and lessen the formation of Aβ.To sum up, daphnetin can lessen the change of pathology morphologic andinterfere with the expression of β-APP through many elements after cerebralischemia damage.It is suggested that daphnetin can function as protection aftercerebral ischemia. One of the mechanisms of action may impossible be theinterference with the expression of β-APP.

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