【doc】脑损伤后早期前列腺素的变化及消炎痛的干预作用
脑损伤后早期前列腺素的变化及消炎痛的
干预作用
Changesofprostaglandininearlybraininjuryand
therapeuticeffectofindomethacin?
TanYuan—fu.DepartmentofNeurosurgery.FirstAmliatedHospitalof
GuangxiMedicalUniversity,Nanning53002l,GuangxiZhuangAu—
tonomousRegion,China
LiYao—hua,DepartmentofBrainSurgery,ZhongdaHospital,MedicalCollege
ofSoutheastUniversity,Nanjing210000,JiangsuProvince,China
TanYuan—fu?.Male.HanNationality,Bornin1963inZhuzhouCountv,
HunanProvince,China,GraduatedfromHunanMedicalUniversityin1999,
Doctor,Professor.Researchdirection:traumaticbraininjury.
tyful69@sohu.eom
Telephone:+86—77l一5356506
Received:2004—09—04Accepted:2004—11—11(04/SMl
Abstract
BACKGRoUND:Traumaticbraininjurygeneratesacascadeofarachidonic
acidmetaboliceventsthatmainlypresentedbytheincrementofprostaglandin
andoxygenfreeradicals.1ndomethacincanpotentlyinhibittheactivitv0f
cyclooxygenase,decreasethesynthesisofprostaglandins,andmaydecrease
theproductionofoxygenfreeradical,andthusmayattenuatethepathological
changesofbraininjury.
OBJECTIVE:Toobservethechangesofprostaglandininearlybraininjury
andafterindomethacinintervention,soastoexplorethepharmaeologieal
mechanismofindomethacin.
DESIGN:Arandomizedandcontrolledtrialbasedonexperimentalanimals.
SETTING:Departmentofneurosurgeryanddepartmentofcerebralsurgery
inauniversityhospital.
MATERIALS:ThisstudywascarriedoutattheLaboratory0fNeurosurgery
Department,MedicalCollegeofSoutheastUniversitybetweenMarchand
September2000.Thirty—sixhybridcatswererandomlydividedint0nornqal
controlgroup,braininjurygroupandindomethacininterventiongroup,with
12catsineachgroup.
INTERVENTIoNS:Braininjurywassimulatedaccordingt0previouslvre—
portedgradingmechanicaltraumaticanimalmodelestablishment;catswith
mediumbraininjurywereenrolledinthisstudy.Theultimateeoneentrations
ofprostaeyelin(PGl2)andthromboxaneA(TXA2)to6一ket0一
prostadandinFl
alpha(6一
keto—PGF~ot)andthromboxaneB2(TXB2)inbrainveinblood.as
wellastotalbrainsuperoxidedismutase(SOD)andcerebralwatercontent
weremeasured6hoursaftertrauma.
MAINOUTCOMEMEASURES:6-keto—PGFIot,TXB2.SOD,andcereb
ral
watercontent.
RESULTS:Both6一
keto—PGFlotandTXB2inbrainveinb100dremarkablv
increasedinearlybraininjury[from(0.0574-0.010)g/Lt0(0.264
4-0.126)g/L,from(O.0604-0.012)g/Lto(0.1344-0.048)g/Lrespec.
tively】,withtheincrementoftheformerhigherthanthelatter.therati00f
TXBJ6一
keto—PGF~otdecreasedfrom1.0524-0.145to0.5454-0.184.and
cerebralwatercontentincreasedfrom(77.394-0.36)%to(78.06
4-0.41)%;meanwhile.totalbrainSODsignificantlydecreasedfrom
(94.8694-5.418)~kat/gto(54.3684-3.417)~kat/g(P<0.011.In
contrasttobraininjurygroup,theconcentrationsof6一
keto.PGFIotandTXB2
inindomethacininterventiongroupsignificantlydecreased.
whichweresimilar
tothoseofcontrolgroup.butthetotalSODsignificantlyincreasedfrom
(54.3684-3.417)p.kat/gto(81.4334-7.268)Ixkat/g(P<0.
01),and
watercontentlightlydecreasedwithoutstatisticalsignificance(P>0.1).
CONCLUSION:PGl2andTXA2increaseinearlybraininj”ryinexDeri.
mentalcatmodel,accompaniedbyfreeradicalsynthesis.resultinginthe
exacerbationofbraininjury.Indomethacinmaybehelpfult0relievepost.
traumaticsecondarybraininjurybyregulatingtheimbalanceofPGT2/TXA2
anddecreasingtheproductionoffreeradical.
TanYF,LiYHChangesofprostaglandininearlybraininjuryandtherapeutice”ecf0f
indomethacinZhongguoLinchuangKangfu2005;9f5l:232—4fChinal
【?,?zglckfcam]
?qTRoDUCTIoN
Recentresearcheshaveshownthataseriesofpathophysiolo西cal
metabolicchangesfollowingtraumaticbraininjurymightplayan
importantroleinsecondarybraindamage.Specifically,trau—
ma—inducedcascadeofarachidonicacidmetabolicevents,mainly
presentedbytheincrementofprostaglandinandoxygenfreeradi—
cals.-maybeextremelyimportantll一”.Thisstudywasdesignedto
indirectlyobservetheposttraumaticchangesofprostacyclin(PGl2)
andthromboxaneA(TXA2)inbrainveinblood,aswellasoxygen
freeradicals【theresidualofsuperoxidedismutasefSOD)after
assumption】,inordertoinvestigatetheeffectofcyclooxygenase
inhibitor—indomethacinontraumaticbraininjury.
MATERIALSANDMETHoDS
Materials
ThisstudywascarriedoutatthelaboratoryofNeurosurgeryDe—
partment.MedicalCollegeofEast—SouthUniversitybetweenMarch
andSeptember2000.Totally36hybridcats,weighedfrom2.5to
3.5kgwithoutsexlimitation【providedbyJiangshuExperimental
AnimalCenter,certificationNo:SCXX(Su)2000—00311wereran—
domlydividedintonormalcontrolgroup,braininjurygroupand
indomethacininterventiongroup,with12catsineach
group.Medianextra?durainjurywassimulatedonexperimentalcats
ofinjurygroupandindomethacingroupwithgradingmechanical
traumaticdevicef4..
Methods
Theanimalswereanaesthetizedbyintramuscularinjectionofke—
tamineby30mg/kg,followedbyarterialcatheterandheadfixation,
thencranialwindowwasopenedatparietaltoinsertconcussivede.
vice.Catswithnormalbreath,BP,intra—cranialpressure,cornearetiex
andthenarreflexweregivenconcussiveinsults.Traumaticpeakpres—
sureof(0.65-i-0.05)kg/cm.andmorphologicalvarianceof3.5mm
wereadoptedtomakeinjuryatleftparietallobereachingtothedeep
hemisphere.Intracranialpressure,meanarterialpressure.aswellas
breathandnervereflexesweremonitored.CatsininterventiongrouD
receivedintravenousinjectionofindomethacin(3mg/kg)atpost.
traumatic30minutes,andadditionalhalfdosewereadded3hours
laterandthencontinuouslymonitoredfor6hours.Noconcussive
insultsweregiveninthenormalcontrolgroupinwhichtheratsre-
ceivedtheshamoperations.
Specimencollection
6-keto—prostaglandinF1alpha(6-keto.PGFIct)andthromboxaneB2
(TXB2)measurement:2mLbrainveinbloodwasrecruitedfrom
theuppersagittalsinus30minutesbeforefinishingexperiment.and
thenimmediatelycentrifugedat2000rperminutefor5minutes
inasilicictube(bothinjectorandtubewererinsedwithheparin
indomethacin).Supernatantswerepreservedat一80?forfol—
lowingexaminations.
StablecatabolicproductsofPGl2andTXA2:6-keto—PGFlqand
TXB2weremeasuredwithIRA.TotalSODdetermination:0.4g
braintissuesattheinsultedregionwereobtainedbeforethecats
werekilledandthenthesetissueswerepreservedat一30?for
theexaminationoftotalSODcontentwithhydroxylamine
method.Cerebralwatercontent:Afterexperiment,animalswere
killedbylettingbloodfromabdominalartery,soonafterthatthe
injuredhemispherewastakenouttomeasurethewetweightwithin
3minuteswiththeaidofanalysisscaleof10thousandDrecision
andtheconstantweightafterdesiccationinovenof(105?1)oC
for24hours,andthusthecerebralwatercontentcouldbecalcu—
wetmethods. latedbydry—
Statisticalanalysis:AlldatawerepresentedbyMean?SD.andt-test
wasusedforcomparison.P<0.05denotedstatisticalsignificance.
Mr.YinfromthestatisticsdepartmentofMedicalC011ege0fEast—S0uth
UniversitymadestatisticalanalysiswithSPSS9.
0statisticalsoftware.
RESULTS
Quantitativeanalysisoftheexperimentalanimals
Thirty—sixoutoftotal41catsenteredthefinalanalysis.
The0ther
fivecatswereexcludedforincompleteinformation0r0thersDeci矗c
reasons.
Changesofposttraumatic6-keto.PGFlOtandTXB2(Table1)
Both6-keto—PGF~ctandTXB2inbrainveinb100dremarkablvincreased
after6-hourbraininjury,especiallytheincreaseof6-keto—PGFlq.
whichcontributingtothereversalofTXPn/6一keto—PGFlq(P<0.01).
Both6-keto—PGF~ctandTXB2inindomethacingroupsignificantlv
decreasedincontrasttoinjurygroup(P<0.01),similartothos.
ofcontrolgroup.However,6-keto—PGFlqwasfoundevenslightlv
lowerthancontrolgroup,resultingintheincreasedratioofTXB2/
6-keto—PGF~ct,whichwashigherthannormalcontr01sbutwithoutsta—
tisticalsignificance(P>0.05),indicatingthatthelevels0fPGl2
andTXA2increased6hoursfollowingbraininj”rywithPGl2in
particular,whichcouldbemarkedlyinhibitedbvindomethain.
ChangesofcerebralSODaftercerebralinjury
TotalcerebralSODsignificantlydecreased6hoursaftertraumafP
<0.01).ThelevelofSODinindomethacininterventiongr(Jupwas
slightlylowerthanthatofcontrolgroup,butsignificantlyhigherthan
thatofinjurygroup(P<0.01),indicatingthatmanvfreeradicals
.Pp..”d”posttraumaticbrain.whichcanbeattenuatedbyin—
domethacin(Table1).
Changesofcerebralwatercontent
Brainwatercontentoftraumaticside(injurygroup)increasedat6
hours(P<0.01).Itwasslightlylowerinindomethacinintervention
groupwhencomparedwiththatofinjurygroup,butnosignificant
differencewasfound(P>0.1),indicatingthathydrocephalus0c.
curredaftertraumaandcouldnotbeattenuatedbyindomethaci”
(Table1).
Changesofintracranialpressure,breathandnerverenexes
followingbraininjury
Atthemediuminjurylevelinthisstudy,incrementofintracranial
pressurewithsignificantdifferencecouldnotbeobservedexceDtfbr
„nstantIncrementatposttraumatic15S.Thetimeoftemporarybreath
standstillrangedfrom60to120swithreflexinhibltingtime1ess
than10minutes.
Nosignificantdifferencewasfoundbetweeninjury
groupandindomethacininterventiongroup(P>0.5).
DISCUSSION
PGl2,synthesizedinvascularendotheliumduet0thestipulation0f
„
ischemiaandmechanicalforce,haspotentdiastoliceffect0nlocal
microvessels.TXA2,synthesizedbyplateletsattributingt0collage—
nousfiber,ischemiaandplatletscoagulation,ispotentconstrictor0f
localvasculature.BothPGl2andTXA!aresynthesizedbvtheacti—
vationofcyclooxygenasepathwayofphopholipid—phopholipase
A2一arachidonicacidmetabolism,whichisaccompaniedbvfreerad—
icalproduction”引.Normally,theratioofPGl2/TXA2keeDsata
relativelystablelevelandcanbeadjustedtoregulatelocalcircula—
tionthatfitforcerebr~metabolism.Acascade0fAA—+PGs
metaboliceventsaregeneratedinbraininjuryduetoactivatedmi—
crovascularendothelium,inadditionwithprimary
,injuryofner_vous
tissueandcleavageofcellularwallphospholipidintoAA.Because0f
differentinducementandsynthesizingsites,inequableproduction0f
PGl2andTXA2mayleadtotheimbalanceofPGl2/TXA2atlocal
cerebraandsubsequentlylocalbloodflowdisorder.
Bloodf10wmav
IncreaseduetothediastoliceffectofPGl2ifPGl2ishigherthan
TXA2…,butifbloodflowexceedsthedemand0fcerebral
metabolism,suchsecondaryoverperfusionmay:Q)induceandag—
gravatefreeradicalimpairment;?causeover—perfusionalinjurv:?
Increaseintracranlalpressureduetohighercerebralbl【J(Jdf10w:?
aggravatecerebralangioedemaduetohighermicrovascularDeiTne—
ability?Unthecontrary,ifTXA2exceedsPGl2duetoalargenumber
ofendotheliumcellsbreakageinprimaryorsecondaryinjury.mi—
c.0Vascularcontractionandintra—vascularmlcrothrombusformation
mayOCCUrandresultlnsevereischemicinjury.Inthisstudy.we
foundthatbothPGl2andTXA2remarkabllyincreasedattheearlv
braininjurywithPGl2higherthanTXA2,totalSODdecreased.
free
.0dicalincreased,andbrainedemaaggravated.
A1lthesefurther
demonstratedthatpost—traumaticAA?PGsmetabolicdisorderwasan
importantsecondarypathologicalchangeinbraininjury.
1ndomethacin1soneofnon—steroidanti—inflammatory.Itcanpotentlv
inhibittheactivityofcyclooxygenaseandconsequentlvreducethe
synthesisofPGs.RecentresearchesprovedthatitcoulddecreaseAA
productionbydirectlyinhibitingphopholipaseA2actlvitv,andcould
alsoreducemembranemobilitybyinhibitinglipidperoxidationl3l”.It
hasbeenreportedthatindomethacinrelatedbrainedemaandlow
pertusionfollowingischemiawereimprovedafterbeingpretreated
withindomethacininexperimentalcats,whichwassimilart00xvgen
freeradicalsclearingsubstancef6】inreducingischemiaextentand
alleviatingincompleteischemlcbrainedema”】.
Furthermore,Dre—
treatmentwithindomethacincandecreasethemortalitv0fratswith
braininjury.引.ManycurrentreportsindicatedthatI?.?indomethacin
hasrapidreducingintracranialhypertensionandantifebrilePropertv
withoutobviousi~ffluenceonCBFandoxygenmetabolismifapplied
tOrtreatingintractableintracranialhypertensionandhyperthermia
„.lJowingseverebraininjury,suggestingthatindomethacinhasa
certaineffectonimprovingcerebralmicrocirculationand
metabolism,andmayimprovetheprognosisofbraininiury.Its
pharmacologicalmechanismmaybeexplainedasfollows[„】:firstlv.
“domethacinhasdirectvasoconstrictiveeffectpresentedbyreducing
CBFandintracranialpressure;secondly
,rati00fTXB,/
6-keto—PGF~otincreasesbyinhibittingAA.PGsmetabolicpathwav
,
whichresultsinmicrovascularconstriction,decreasedCBFandin-
tracranialpressure.Inourstudyweobservedthatsynthesis0fPGI,
andTXA2wasremarkablyattenuatedbyindomethacinappliancefor
braininjuryincats,resultinginthechangeofTXB2/6一keto—PGFlct
anddecreasedfreeradicalproduction,suggestingthatindomethacin
exertildluenceonsecondaryinjuryandhasacertaintheraDeutic
effectonbraininjurybyregulatingtheimbalanceofPGl2andTXA,.
„mprovingcerebrMmicrocirculation,
anddecreasingfreeradicals
production.
Inconclusion,PGl2andTXA2remarkablyincreaseatearlvbraln
injurywithPGl2higherthanTXA2.Inaddition,freeradicaIincn?ses
234ISSN1671—5926CN21—1470/R/[com中国临床康复2005笙旦!
旦笙!鲞笙塑
andbrainedemaOccurs,restulinginseverebrainin?
jury.Indomethacincansignificantlyattenuatethepost—traumatic
productionofPGI2andTXA2,regulatetheimbalanceofPG%/TX.
A2,decreasefreeradicalproduction,andthereforeplayabeneficial
roleinimprovingtheoutcomeofthesecondarybraininjury.
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脑损伤后早期前列腺素的变化及消炎痛的
干预作用?
谭源福r,李耀华(r广西医科大学第一附属医院神经外科,广西壮族自
治区南宁市530021;东南大学医学院附属中大医院脑外科,江苏省
南京市210000)
谭源福?男,1963年生湖南省株洲县人,汉族,1999年湖南医科大学
毕业,博士,教授,主要从事创伤性脑损伤的研究.
摘要
背景:颅脑损伤诱发的花生四烯酸代谢瀑布过程中产生的前列腺素类
和氧自由基的增加是其重要的一方面,消炎痛能强烈抑制环氧化酶
活
性,减少前列腺素类合成,并可能减少氧自由基的增加,从而可能具有
减轻脑损伤作用.
目的:观察脑损伤后早期前列腺素的变化及消炎痛对其的干预作用,探
讨其作用机制.
:以实验动物为研究对象,随机对照实验研究
单位:一所大学医院的神经外科和一所大学医院的脑外科.
材料:实验于2000—03/09在东南大学医学院神经外科实验室完成.将
36只杂种猫,随机分为正常对照组,脑损伤组和消炎痛干预组3组,每
组12只.
干预:脑创伤按分级机械脑损伤实验动物模型制作,取中度脑损伤水平
进行研究.伤后6h测定脑静脉血中前列腺环素(PGI:)和血栓素(TXA)
的最终分解产物6一酮一前列腺素FIa(6一keto—PGF.”)和血栓烷素B2
(TXB),脑组织总超氧化物歧化酶(SOD)及脑含水量.
主要观察指标:6.keto.PGF.0l,TXB!,SOD含量和脑含水量测定
结果:猫脑损伤后早期脑静脉中6-keto.PGF.”和TXB_,均明显增加[由
(0.057?0.010)g/L增至(0.264?0.126)g/L,由(0.060?0.012)g/L
增至(0.134?0.048)g/L,6.keto.PGF1”增幅大于TXB,TXB/
6-keto.PGF.”比值下降(由1.052?0.145降为0.545?0.184),脑含水量
增加[由(77.39?0.36)%增至(78.06?0.4l%)],同时脑组织总SOD明
显降低[由(94.869?5.418)Ixkat/g降至(54.368?3.417)Ixkat/g](P
<0.01);消炎痛干预组与脑损伤组比较,6-keto.PGF?”和TXB!明显降
低,与正常对照组接近,而总SOD则有增加[(54.368?3.417)Ixkat/g
增至(81.433?7.268)Ixkat/g】(P<0.O1),脑含水量略降低,但无统
计学意义(P>0.1).
结论:猫脑损伤后早期PGIz和TXA!增加,并伴随自由基产生,由此加
重脑损害.消炎痛通过调节脑损伤后PGT/TXAz失衡,减少自由基产
生,有助于减轻脑创伤后继发性脑损害.
主题词:脑损伤;前列腺素;自由基;脑水肿;吲哚美辛;猫
中图分类号:R743文献标识码:A文章编号:1671—5926(2005)05—0232—03
谭源福,李耀华.脑损伤后早期前列腺素的变化及消炎痛的干预作用IJI中国
临床康复,2005,9(5l:232—41wwwzglckfcornl
(EditedbyGuLJ/SunSG/JiH/XiaoXL)
?
BAslCREsEARCH?
Relationshipbetween(TTTTA)ngenepolymorphisminthe
ap0lip0pr0tein(a)5?controlregionandatherosclerotic
cerebralinfarctioninHannationalityofHubeiarea?
HuBo,ZhouXin,LiZhao—xia,HongOuo?qiang,LuoMin—qi.ZhuZhen—
yu
HuBO,I.iZhao—xia,HongGuo—qiang,LuoMin—qi,DepartmentofClini
cal
Laboratory,ThirdAffiliatedHospitalofSunYat—senUniversity.Guangzho
u
5l0630.GuangdongProvince.China
ZhouXin,DepartmentofClinicalLaboratory.CentralSouthHospita1.Wuhan
University,Wuchang43007l,HubeiProvince,China
ZhuZhen—yu,DepartmentofBiochemistry,BasicMedicalCollege,
Sun
Yat—senUniversity,Guangzhou510089,GuangdongProvince,China
HuBO?,Male,HanNationality.Borninl970inWuhanCitv.Hubei
Province,China,StudyinginSunYat—senUniversityfordoctorate.Attending
physician.Researchdirection:lipoproteinandcardiovasculardisease.
hubo—bo@2lan.COB
Telephone:+86—20—85516867Ext.3057
Suppor~dby:ScientificResearchStartingFoundationofSunYat..senU.
nlversityofMedicalScience.No.A503
Received:2004一O7—28Accepted:2004一II一16f09/SL)
Abstract
BACKGROUND:Apolipoprotein(a)[Apo(a)]playssomeroleinpromot—
ingtheformationofatheroscleroticplaque,andcontainspentanucleotide
repeats(PNR),whichhasakeyvalueingenicresearchandinforecaston
theincreasedriskofearlyatherosclerosiscerebralinfarction(ACI).Butthe
relationshipbetweenACIandApo(a)PNRindifferentracesneedstobe
furtheri?