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Evaluationofantiinflammatoryeffectofstatinsinchronicperiodontitis

IndianJPharmacol.2013JulAug45(4):391394.

PMCID:PMC3757610

doi:10.4103/02537613.115017

Evaluationofantiinflammatoryeffectofstatinsinchronicperiodontitis
SnophiaSuresh,SatyaNarayana,P.Jayakumar,UmaSudhakar,andV.Pramod1
DepartmentofPeriodontology,ThaimoogambigaiDentalCollegeandHospital,Chennai,India
1
DepartmentofPeriodontology,NewHorizonDentalCollege,Bilaspur,Chattisgarh,India
Correspondenceto:Dr.SnophiaSuresh,Email:suresh_sno@yahoo.com
Received2013Jan21Revised2013Feb18Accepted2013Apr23.
Copyright:IndianJournalofPharmacology
ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNoncommercialShareAlike3.0Unported,whichpermits
unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract
Objectives:
Statinsarethegroupoflipidloweringdrugscommonlyusedtocontrolcardiovascularandcerebrovascular
diseases.Statinshavepotentialantiinflammatoryeffectbyblockingtheintermediatemetabolitesofthemevalonate
pathway.Theobjectiveofthisstudywastoevaluatetheantiinflammatoryeffectofstatinmedicationinchronic
periodontitispatients.
MaterialsandMethods:
Thirtypatientsofagegroupbetween40and60yearswereselectedfromtheoutpatientpoolofDepartmentof
Periodontics,ThaimoogambigaiDentalCollegeandHospital,Chennai.Thirtypatientsselectedweregroupedinto
twogroups,GroupIconsistsofpatientswithgeneralizedchronicperiodontitisandonstatinmedicationandGroup
IIconsistsofpatientswithgeneralizedchronicperiodontitis.Clinicalparameterswererecordedandgingival
crevicularfluid(GCF)sampleswereanalyzedforinterleukin(IL)1usingcommerciallyavailableenzymelinked
immunosorbentassay.
Results:
ThemeanGCFIL1levelsingeneralizedchronicperiodontitispatientswhoareonstatinmedication(GroupI)
werelowerthanthegeneralizedchronicperiodontitispatientswithoutstatinmedication(GroupII).
Conclusion:
ReductionofGCFIL1levelsinstatinusersindicatethatstatinshaveantiinflammatoryeffectonperiodontal
disease.
KEYWORDS:Chronicperiodontitis,gingivalcrevicularfluid,interleukin1,statins

Introduction
Periodontitisisamultifactorialchronicinflammatorydiseasecharacterizedbydestructionoftoothsupporting
tissues.Theprogressionofperiodontaldestructioninvolvescomplexinteractionbetweenperiodontalbacteriaand
cellsofimmunesystem.[1]Thecomplexcytokinenetworkthatmediatestheimmuneresponseincludes
proinflammatorycytokines,antiinflammatorycytokines,andspecificcytokinereceptors.[2]Cytokinesplayan
importantroleintheinitiation,progression,andthehostmodulationofperiodontaldisease.[3]
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Statins,3hydroxy3methylglutarylcoenzymeA(HMGCoA)reductaseinhibitors,prescribedtoprevent
cardiovascularandcerebrovasculardiseases.Theeffectivenessofstatinmedicationisbasedontheircapacityto
reduceserumcholesterollevels,primarilylowdensitylipoprotein(LDL)cholesterol.StatinsinhibitHMGCoA
reductaseanddecreasetheproductionofmevalonate,geranylpyrophosphate,andfarnesylpyrophosphate,and
subsequentproductsonthewaytoconstructionofthecholesterolmolecule.Thus,statinscouldinhibit
inflammation,byinhibitionofthecholesterolpathwayandintracellularlyinterferingwithRassuperfamilyprotein
function.[4]
Interleukin(IL)1isfoundintwoactiveforms,IL1andIL1encodedbyseparategenes.Botharepotent
proinflammatorymoleculesandarethemainconstituentsofwhatwasoncecalledosteoclastactivatingfactor.The
proinflammatoryeffectsofIL1includestimulationofendothelialcellstoexpressselectinsthatfacilitaterecruitment
ofleukocytesandinductionofprostaglandinE2bymacrophagesandgingivalfibroblasts.[5]
Gingivalcrevicularfluid(GCF)providesanoninvasivemeansofstudyingthehostresponsefactorbychangeof
constituentsinthefluid.Theinflammatoryexudatefromgingivalmicrocirculationcrossesinflamedperiodontal
tissueandenroutecollectsmoleculesofpotentialinterestfromthelocalinflammatoryreaction.Therefore,thefluid
offersagreatpotentialsourceoffactorslikeinflammatorymediators,tissuebreakdownproducts,andhostderived
enzymesthatmaybeassociatedwithtissuedestruction.[6]IncreaseinthelevelsofinflammatorymediatorsinGCF
maybeofdiagnosticvalueinevaluatingperiodontaldiseasestatus.[7]AlthoughGCFIL1levelsinperiodontal
diseasehavebeenstudiedextensively,[8,9]ourscouldbethefirststudycarriedouttoknowtheinfluenceofstatin
medicationontheinflammatorymediatorespeciallyIL1.Statinsalsohaveshowntohaveantiinflammatory
effect.[10]TheaimofourstudywastoknowtheeffectofstatinmedicationontheinflammatorymediatorGCFIL
1levelsinchronicperiodontitissubjects.

MaterialsandMethods
ThepresentobservationalcrosssectionalstudywascarriedoutafterapprovalfromDr.MGREducationaland
ResearchUniversity'sethicalcommittee.Allthevolunteerswereinformedabouttheaimandthemethodsofthe
presentstudyandgavewrittenconsenttoparticipate.SubjectswereenrolledinthestudyfromJuly2012to
September2012.
Thirtypatientsofagegroupbetween40and60yearswereselectedfromtheoutpatientpoolofDepartmentof
Periodontics,ThaimoogambigaiDentalCollegeandHospital,Chennai.Theselectedsubjectsweregroupedinto
twoGroupIconsistsofsubjectswithgeneralizedchronicperiodontitisandonstatinmedicationandGroupII
consistsofsubjectswithgeneralizedchronicperiodontitis.Generalizedchronicperiodontitisisdefinedbyhaving
thefollowingcriteria,subjectswithclinicalattachmentlossof35mmsinmorethan30%ofsites.Otherinclusion
criteriaweresubjectswithminimumnumberof15teeth,plaqueindexandgingivalindexscoresof23forboththe
groups.GroupIsubjectswereonatorvastatinmedicationwiththedosageof20mg/dayforaminimumperiodof6
months.Exclusioncriteriaincludeddiabetesmellitus,smokers,andsubjectsonlongtermsteroidmedicationsand
underwentperiodontaltreatmentinthepast6months.Afullmouthperiodontalexaminationwascarriedoutwhich
includedplaqueindex,gingivalindex,andclinicalattachmentlevel(CAL).
GCFCollection

AllGCFsampleswerecollectedfromthesitewithmaximumCALintheforenoonatthesametimeoftheday,to
allowforcircadianvariationseeninGCFvolume.Acalibratedvolumetricpipetteof5Lcapacitywasplaced
extracellularlyforcollectionofGCF[Figure1].Thesampleof2Lcapacitywascollectedfor20min.The
collectedsamplewasthentransferredtoasterilizedplasticvialwiththehelpofairspray.Thesamplewas
transportedtolabandthevialwasstoredat71C.
Figure1
MicropipetteforcollectingGCF

BiochemicalAnalysis

GCFsampleswereanalyzedforIL1usingcommerciallyavailableenzymelinkedimmunosorbentassay(ELISA)
(AvibionhumanILELISAKit,AniBiotech).Analyseswereperformedaccordingtothemanufacturer'sprotocol
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[Figure2].TheGCFIL1valueswereobtainedfromELISAreader[Figure3].Resultswerecalculatedusingthe
standardcurvescreatedineachassay.ThetotalamountofcytokinesinGCFwasexpressedaspictogram(pg/ml).
Figure2
Microtitreplates

Figure3
ELISAreader

StatisticalAnalysis

Datawereexpressedasmeanandstandarddeviations.DataanalysiswascarriedoutusingSPSSassoftwarefor
statistics.IndependentsamplettestwasdoneforintergroupcomparisonofclinicalparametersandGCFIL1
levels.

Results
Atotalof30patientswereincludedinthisstudy.Ofthese,16weremalesand14werefemales.Independent
samplettestwasdoneforintergroupcomparisonofclinicalparametersandGCFIL1levels.
ThemeanscoresofGCFIL1levelsinGroupIandGroupIIwere180.7332.15and308.2027.73pg/ml,
respectively.OncomparisonofmeanGCFIL1levelsofGroupsIandII,GCFIL1levelsingeneralized
chronicperiodontitissubjectswhowereonstatinmedication(GroupI)werelower(180.7332.15)thanthe
generalizedchronicperiodontitissubjects(308.2027.73)withoutstatinmedication(GroupII).Thedifference
wasstatisticallysignificant(P<0.001)[Table1andFigure4].Themeanvaluesofplaqueindexandgingivalindex
scoresofGroupIandGroupIIwere2.6and2.6and2.5and2.6,respectively.ThemeanvaluesofCALsof
GroupIandGroupIIwere4.1and3.9mms,respectively.Oncomparisonofmeanvaluesofplaqueindexscore,
gingivalindexscoreandCALsofGroupIandGroupII,thedifferencewasstatisticallynonsignificant,[Tables2
and3].GroupIandGroupIIsubjectswereselectedinsuchawaythatbothgroupshavesimilaramountofclinical
parameterslikegingivalinflammatorystatus,plaquescore,andclinicalattachmentloss.
Table1
MeanGCFinterleukin1levelsinpatientsofchronicperiodontitis
Figure4
MeanGCFIL1blevelsinGroupsIandII

Table2
Meanplaqueindexscoresinpatientsofchronicperiodontitis
Table3
Meangingivalindexscoresofpatientsofchronicperiodontitis

Discussion
Periodontaldiseaseprocessissitespecificandhasmultifactorialoriginwhereperiodontalpathogens,hostresponse,
genetic,systemic,andbehavioralriskfactorsinterplaytodevelopthediseaseprocess.Hence,variousmeasures
havebeentakentoincludemicrobial,immunologic,systemic,andgeneticfactors,inadditiontotraditionalclinical
andradiographicparameters,forassessingpatient'speriodontalstatus.Inflammatorymediatorlevelswithinthe
GCFhavebeenconsideredassubclinicalmarkerofprogressionandseverityofperiodontitis.[11]

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Inourstudy,weusedmicropipetteofknowninternaldiameterforcollectionofGCF.GCFinthecrevicemigrates
intothetubebycapillaryactionandbecausetheinternaldiameterisknownthevolumeoffluidcollectedcanbe
accuratelydeterminedbymeasuringthedistancetheGCFhasmigrated.Advantageofthistechniqueisthatit
providesundilutedsampleofnativeGCFwhosevolumecanbeaccuratelyassessedasgivenbyGriffiths.[12]
Inourstudy,GroupIandGroupIIsubjectswereselectedinsuchawaythatbothgroupshavesimilaramountof
clinicalparameterslikegingivalinflammatorystatus,plaquescore,andclinicalattachmentloss,andtheirmean
valuesbetweentwogroupswerestatisticallynonsignificant.
Inthisstudy,themeanGCFIL1levelswerelowerinchronicperiodontitispatientsonstatinmedicationthan
chronicperiodontitispatientswithoutstatinmedicationwhichissimilartostudyreportedbySakodaetal.,[10]who
foundthatsimvastatinreducesIL1mediatedproductionofinflammatorymediatorsIL6andIL8incultured
humanepithelialcelllines.OurstudycouldbethefirststudytoassesstheGCFIL1levelsinchronicperiodontitis
patientswhoareonstatinmedication.
Antiinflammatoryeffectofstatinshasbeenprovedfromourstudy.Numerousreasonshavebeenquotedtothis
effectofstatins.Onereasoncouldbethatstatinsdepletetheisoprenoids,whichinhibitthesignallingpathwayfor
IL1andIL6mediatedinflammationasstatedbyOmoiguietal.[13]Isoprenoidprecursorsarenecessaryforthe
posttranslationallipidmodification(prenylation)andareneededforthefunctionofRasandguanosine
triphosphatases(GTPases).TheseGTPaseproteinssuchasRas,Rho,Rac,andRab(particularlyRho)are
intracellularsignallingproteinswhich,whenactivated,areinvolvedinreceptorcoupledtransductionofsignals
fromextracellularstimulitocytoplasmandthenucleus.Blockagesofisoprenoidsbystatinsaffectthecellsignalling
pathwaytherebyreducingcytokineexpression.[14]
Anotherreasonfortheantiinflammatoryeffectofstatinscouldbeduetothebeneficialeffectsofstatinswhichis
mediatedthroughtheloweredLDLcholesterollevels,whichhasbeensuggestedtohaveantiinflammatory
propertiesasgivenbyMatsuuraetal.[15]Sangwanetal.,[16]inhisstudyfoundthathyperlipidemicpatientsare
morepronetoperiodontaldiseaseandstatinshavepositiveimpactonperiodontalhealth.
Periodontitisiswidelyacceptedasariskfactorforcardiovasculardiseaseduetoelevatedinflammatorymediators
inperiodontallesionsandconsequentlyincreasedserumlevels.[17]Theadministrationofstatinstocardiovascular
patientsmayhaveadditionalbenefitsthroughinhibitionofinflammationinoraltissues.Meiseletal.,[18]described
statinsaseffectmodifiersintherelationshipbetweenperiodontitisanditsinflammatorycounterpartsinthesystemic
circulation.Statinscouldattenuatetheinflammationrelatedsystemiceffects.
Numerousstudieshaveshowedtheprotectiveeffectofstatinsonperiodontalinfections.Lindyetal.,[19]reported
thatpatientsonstatinmedicationexhibitedfewersignsofperiodontalinjurythansubjectswithoutstatinregimen
andCunhaCruzetal.,[20]showedtheassociationofstatinusewithreducedtoothlossrateinchronicperiodontitis
patients.Thesefindingindicatethatstatinsmighthavebeneficialeffectnotonlyinperiodontaldiseasebutalsoin
cardiovasculardisease.
Simvastatinandatorvastatin,asalocaldrugdelivery,haveshowntohaveseveraladvantagesinthetreatmentof
periodontaldiseases.[21,22]Theantioxidantandantiinflammatorypropertiesoflocallydeliveredstatinscould
furtherfacilitatehealingofperiodontalintrabonydefects.However,longtermclinicalstudiesinhumansubjectsare
requiredtoevaluatethepotentialbenefitsofstatinsinperiodontalregenerativetherapy.

Conclusion
Statinsarenowamongthefrequentlyprescribedmedicationandarecurrentlyusedbyabout25millionpeople
worldwide.Thesafetyandtolerabilityofstatinssupporttheiruseasafirstlinetreatmentforhypercholesterolemia.
Myopathyanditsseriouscomplicationrhabdomyolysisarethepotentialeffectoftherapywiththeavailablestatins,
butoccurveryrarely.Thepopulationtreatedwithstatinsislikelytoincreasedramaticallyinnearfuture,because
theyarenowrecommendedalsoforpeoplewithlowornormalcholesterollevel,especiallyasasecondary
prevention.Theresultsofourstudyprovedtheantiinflammatoryeffectofstatinsonchronicperiodontitis.Patients
ofchronicperiodontitisreceivingstatinswouldhaveadditionalbenefits,iftheantiinflammatoryeffectofstatinsis
confirmedthroughlongitudinalfurtherstudies.

Footnotes
SourceofSupport:Nil
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ConflictofInterest:Nonedeclared

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