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Probucol Intervention Effect and Possible Mechanism of Experimental Autoimmune Encephalomyelitis Rat Blood-brain Barrier

Author: RenGuoYong
Tutor: TanGuoJun
School: Hebei Medical University
Course: Neurology
Keywords: Probucol Experimental Autoimmune Encephalomyelitis Multiple Sclerosis ZO-1 IL-23 MDA
CLC: R965
Type: Master's thesis
Year: 2013
Downloads: 18
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Objective: Multiple sclerosis (MS) is a common autoimmune demyelina-ting disease of the central nervous system(CNS), its exact etiology andpathogenesis is unclear. Complete blood-brain barrier (BBB) is an importantprerequisite for the normal functioning of the nerve tissue. The inflammatorycells must be through the BBB before it invading the CNS in ms onset, oncethe BBB destruction cannot maintain a homeostatic state of the CNS, whichmay be the basis of MS pathogenesis. Experimental autoimmune encephalo-myelitis (EAE) and MS in the clinical, immunological and pathologicalaspects have the same characteristics, EAE is internationally recognized as anideal animal model of MS.Tight junction(TJ) constitutes the first barrier of the BBB. TJ consists ofthe transmembrane protein(occludin),hecytoplasm attachment protein(ZO)and the cytoskeletal proteins(actin). ZO plays a role as a bridge in connectionoccludin and actin,The ZO1distributes in zonula occludens of a variety ofepithelial and endothelial cells, which is sensitive to reaction barriers damagedin pathological case.It is a good indicator to detect the endothelial cell barrierof the structure and function.Immunological factors and oxidative stress play a key role in MSpathogenesis. In recently years, with the in-depth study of the Th17cells, itwas found that the imbalance of oxidative stress and IL-23/IL-17inflammat-ory axis play a more important role in MS. Probucol is an antioxidantsubstances which can enrich in LDL and easy access to the arterial intima.Itmainly used for lipid-lowering, but at the same time it was able to adjust theinflammatory factors and play an anti-inflammatory effect.It has not beenreported that Probucol as antioxidants can affect the incidence of MS. The experiment proposes to see whether it has a protective effect for EAE and toprovide new ideas for the clinical treatment of MS by concepting theblood-brain barrier damage index changes and detecting immunological andoxidative stress indicators corresponding changes in EAE rats.Methods:(1) The group of experiment,120female,6-8weeks old,about200g Wistar rats were randomly divided into normal control group,EAE group, probucol-EAE group (500mg/kg/d), prednisone-EAE group(5mg/kg/d),30in each group. Each group was randomly divided into sixsubgroups by6points(0,3,7,10,14,21days),5in each subgroup.(2) Establishanimal model, We take the whole spinal cord of SPF female guinea pig.Theweight of spinal cord and the volume of brine ice is1:10,is made for guineapig spinal cord homogenate.Then it is mixed with the complete Freud`sadjuvant with6mg/ml of bcg vaccine.It is made of oil-in-water emulsion inthe ice,then each rat is0.5ml for limbs footpad and subcutaneous,establishEAE mode.Drug treatment groups give the appropriate dose of the drugsorally once a day in model prepared, until the animals were killed.(3) Theneurological score, To observe the state of the animals spirits,activities,weighed and the neurological score everyday after the immuniza-tion. Assessed with the international common Kono scores.(4) Take thetissues arounding2mm of optic chiasma,making paraffin mass.The expressionof ZO-1is measured by immunohistochemistry.It is detected the levels ofIL-23and MDA with ELISA kit.Results:(1) The observation of incidence, There are no morbidity in7days after the induction of antigen.The EAE groups gradually appearlistlessness, loss of appetite, weight loss, fur unsmooth about11days.Theincidence reached a high peak at12~14days,17~21days the symptomsgradually eased. Compared with the EAE group,the time of onset are delayedin Probucol-EAE group and Prednisone-EAE group(13.20±0.84vs11.89±0.06,14.50±0.58vs11.89±0.06;P<0.05),the neurological score are smallerin Probucol-EAE group and Prednisone-EAE group(1.00±1.15vs2.80±1.40,0.80±1.14vs2.80±1.40;P<0.05).Normal control group has no rats incidence.(2) The changes of histopathology, At the same time, select thelumbar enlargement of the spinal cord from the control group,the EAEgroup,the probucol-EAE group and the prednisone-EAE group and stain itwith HE, observe the changes of pathological in the light microscope. Wefound that in EAE rats the inflammatory cell infiltration has been occured inthe7th day, the spinal cord inflammatory cell infiltration is the most obviousin the14th day. There is "cuff-like" cell infiltration in the perivascular. TheProbucol-EAE and prednisone-EAE group also have inflammatory cellinfiltration, but the degree of infiltration is significantly reduced compared tothe EAE group.(3) The results of immunohistochemistry, The ZO-1positivecells of EAE group is decreased and then increased,it is significantlydecreased in the7th day,reached a peak in the14th day, slowly rised in the21th.The symptoms is heaviest when the ZO-1decline reach a peak,Clinicaland pathological results are consistent,which is indicated neurological deficitbefore the paroxysm.The EAE group of7th day compared with the third dayhas declined obviously (1770±0.0354vs0.2562±0.0133,P<0.05), the10th daycompared with the7th day has no significant decline(0.1517±0.0158vs0.1770±0.0354,P>0.05),the10thday compared with the3rdday has declinedobviously(0.1517±0.0158vs0.2562±0.0133,P<0.05);The EAE group of14thcompared with the third day,7th day,10th day,21th day haddeclinedobviously(P<0.05);The group of probucol-EAE, prednisone-EAEcompared with EAE at14th day,21th day has declined obviously (P <0.05).(4) The EAE group compared with the control group in the day of10,14,21,the level of IL-23is higher,(161.99±56.25pg/m1vs77.98±10.41pg/m1,195.04±88.52pg/m1vs81.11±16.49pg/m1,127.19±26.02pg/m1vs79.17±14.14pg/m1,P<0.05).The levels of IL-23, The IL-23of EAE group inthe day of10is significantly higher, compared with the10thday the14thday isstill elevated but has no statistically significant. The Probucol-EAE group,prednisone-EAE group compared with the control group in the day of10,14,21, there is little changes (P>0.05);The Probucol-EAE group comparedwith prednisone-EAE group at each time,there is little changes(P>0.05).(5) The levels of MDA, The EAE group compared with the control group in theday of10,14,21,the level of MDA is higher,(6.63±0.39nmol/mlvs4.84±0.06nmol/ml,9.34±0.40nmol/mlvs4.82±0.07nmol/ml,5.20±0.13nmol/mlvs4.82±0.11nmol/ml,P<0.05).The EAE group compared with the controlgroup in the day of0,3,7, there is little changes (4.80±0.20nmol/ml vs4.79±0.78nmol/ml,4.84±0.13nmol/mlvs4.78±0.11nmol/ml,4.93±0.14nmol/mlvs4.82±0.08nmol/ml, P>0.05).The Probucol-EAE group compared with theprednisone-EAE group in the day of10,14, there is littlechanges(P>0.05);There is significant differences among other groups(P<0.05).Conclusion:1There is destruction of the blood-brain barrier in EAE rats before theonset.2When the peak of EAE,ZO-1decreased the most obvious.Raising theespression of ZO-1,thereby protecting the blood-brain barrier may be one ofthe mechanisms of probucol.3Probucol can delay the time of onset of EAE rats, to alleviate thedamage of diseases to the nervous system function.4Probucol can suppress the levels of IL-23and MDA in EAE rats,whichsuggesting that the mechanism for the treatment of MS may be related.5Compared with Prednisone, Probucol has safer and better tolerated,although it is worse in delaying the disease.

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