w w w . r b o . o r g . b r
Review
Article
The
role
of
pharmacotherapy
in
modifying
the
neurological
status
of
patients
with
spinal
and
spinal
cord
injuries
夽
Renato
Carlos
do
Vale
Ramos
∗,
Nuno
Alegrete
SchoolofMedicine,UniversidadedoPorto,Porto,Portugal
a
r
t
i
c
l
e
i
n
f
o
Articlehistory: Received17July2014 Accepted2September2014 Availableonline1October2015
Keywords:
Spinalcordinjuries Methylprednisolone G(M1)ganglioside Apoptosis Calpain Naloxone
a
b
s
t
r
a
c
t
The aim here was to conduct a review of the literature on pharmacological thera-pies for modifying the neurological status of patients with spinal cord injuries. The PubMed database was searched for articles with the terms “spinal cord injury AND methylprednisolone/GM1/apoptosisinhibitor/calpaininhibitor/naloxone/tempol/tirilazad”, inPortugueseorinEnglish,publishedoverthelastfiveyears.Olderstudieswereincluded becauseoftheirhistoricalimportance.Thepharmacologicalgroupsweredividedaccording totheircapacitytointerferewiththephysiopathologicalmechanismsofsecondaryinjuries. Use of methylprednisoloneneeds tobe carefullyweighed up: other anti-inflammatory agentshaveshownbenefitsinhumansorinanimals.GM1doesnotseemtohavegreater efficacythanmethylprednisolone,butlonger-termstudiesareneeded.Manyinhibitorsof apoptosishaveshownbenefitsininvitrostudiesorinanimals.Naloxonehasnotshown benefits.Tempolinhibitsthemainconsequencesofoxidationatthelevelofthespinalcord andotherantioxidantdrugsseemtohaveaneffectsuperiortothatofmethylprednisolone. Thereisanurgentneedtofindnewtreatmentsthatimprovetheneurologicalstatusof patientswithspinalcordinjuries.Thebenefitsfromtreatmentwithmethylprednisolone havebeenquestioned,withconcernsregardingitssafety.Otherdrugshavebeenstudied, andsomeofthesemayprovidepromisingalternatives.Additionalstudiesareneededin ordertoreachconclusionsregardingthebenefitsoftheseagentsinclinicalpractice.
©2014SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditora Ltda.Allrightsreserved.
O
papel
da
farmacoterapia
na
modificac¸ão
do
estado
neurológico
de
traumatizados
vértebro-medulares
Palavras-chave:
Traumatismosdamedulaespinal Metilprednisolona
r
e
s
u
m
o
Oobjetivodestetrabalhofoifazerumarevisãodaliteraturasobreaterapia farmacológ-icaparaa modificac¸ãodoestadoneurológicode traumatizadosvértebro-medulares.Foi feitaumanabasededadosPubmedporartigoscomostermos“spinalcordinjuryAND
夽
WorkperformedattheSchoolofMedicine,UniversidadedoPorto,Porto,Portugal. ∗ Correspondingauthor.
E-mail:mimed08243@med.up.pt(R.C.doValeRamos). http://dx.doi.org/10.1016/j.rboe.2015.09.001
GangliosídeoG(M1) Apoptose
Calpaína Naloxona
methylprednisolone/GM1/apoptosisinhibitor/calpaininhibitor/naloxone/tempol/tirilazad”, emportuguês oueminglês,publicadosnosúltimoscincoanos.Trabalhosmaisantigos foramincluídospelasuaimportânciahistórica.Osgruposfarmacológicosforamdivididos em func¸ãodasua capacidadeparainterferirnosmecanismosfisiopatológicos da lesão secundária. O uso de metilprednisolona deve ser cuidadosamente ponderado. Outros anti-inflamatóriosmostrarambenefíciosemhumanosouemanimais.OGM1nãoaparenta termaioreficáciadoqueaMP,masestudosemmaislongoprazosãonecessários.Muitos inibidoresdaapoptosetêmmostradobenefícioemestudosinvitroouemanimais.A nalox-onanãodeumostrasdebenefício.Otempolinibeasprincipaisconsequênciasdaoxidac¸ão nonível damedulaeoutros fármacosantioxidantesaparentamterum efeitosuperior aodametilprednisolona.Éurgenteencontrarnovostratamentosquemelhoremoestado neurológico dos traumatizados vértebro-medulares. Os benefícios do tratamento com metilprednisolonatêmsidoquestionados,hápreocupac¸õesemrelac¸ãoàsuaseguranc¸a. Outrosfármacostêmsidoestudados,podemalgunsdelesseropc¸õespromissoras.Estudos adicionaissãonecessáriosparatirarconclusõessobreobenefíciodessesagentesnaprática clínica.
©2014SociedadeBrasileiradeOrtopediaeTraumatologia.PublicadoporElsevier EditoraLtda.Todososdireitosreservados.
Introduction
Spinal and spinal cord injuries are among the most
dev-astating traumaticsituations and are responsible for high
morbidity and mortality rates. The consequences of these
injuriesincludereductionofmotorandsensorycapacityand perturbationsofintestinal,urinaryandsexualfunctioning.1
The impact of these problems becomes greater through
absenceofsatisfactorytherapyformodifyingthesepatients’ neurologicalstatus.1
Thepathogenesisofspinal cordinjuriescan bedivided intotwophases.Theprimaryinjuryoccursimmediately,and is characterized by compression, bruising or, rarely,
com-plete breakage of the spinal cord. The secondary lesions
arise overthe course ofseveraldays and involvea variety ofprocesses,suchasinflammation,edema,ischemia, hem-orrhage,electrolyticimbalances,releaseofarachidonicacid, excitotoxicityduetoglutamate,apoptosis andlipid
peroxi-dation.Thesephenomenaleadtoexpansionoftheprimary
lesion and cavitation of the spinal cord.1,2
Pharmacologi-cal therapies for spinal and spinal cord injuries have the aimofinhibitingtheseprocessesorstimulatingspinalcord regeneration.
Methylprednisolone(MP),whichisfrequentlyusedin treat-ing acutespinalcord injuries,showed evidenceofbenefits intheNational AcuteSpinalCordInjurySurvey(NASCIS)II
andNASCISIIIstudies.3,4 However,thesefindings havenot
beenreproducedinotherstudiesanduseofMPisbecoming
increasingly controversial, because of the risk of
poten-tiallyseriouscomplications,incomparisonwiththemodest benefits.1Thishasledtoeffortstowarddevelopingnewdrugs
thatmightimproveneurologicalfunctioningincasesofthese diseases.1
Theobjectiveofthisstudywastoconductareviewofthe literatureon pharmacologicaltherapy forspinaland spinal cordinjuries.
Materials
and
methods
A search for articles was conducted in the PubMed
database,usingtheterms“spinalcordinjuryAND methylp-rednisolone/GM1/apoptosis inhibitor/calpain inhibitor/nalo-xone/tempol/tirilazad”,inPortugueseorinEnglish,published overthelastfiveyears.Someolderstudieswerealsoincluded becauseoftheirhistoricalimportance.
The pharmacological groups were divided according to
theircapacityforinterferinginthephysiopathological mech-anismsofsecondarylesions.
Drugs
that
inhibit
inflammation
Subsequenttospinalandspinalcordinjury,inflammationand hydrolysisoccurinthespinalcord,whichresultsin destruc-tionofneuronsandmicrovessels.4Themainfunctionofthese
drugsistoinhibitormodifythelocalinflammatoryresponse.
Methylprednisolone
MP isthebest knownand moststudiedanti-inflammatory
drugforattemptingtoblockthisprocess,andthusformsthe paradigm.
The NASCISstudies proposed toadminister MPat high
doses(loadingdoseof30mg/kgofweightandmaintenance
doseof5.4mg/kg/h),for24hifthetreatmentwasstartednot more than 3h afterthe injury, orfor48hif it was started between3and8haftertheinjury.3,4
In victims of complete cervical rupture, increased lev-els ofinterleukin (IL) 6, IL-8, macrophage chemoattractant protein-1,neutrophilactivatingpeptide-2,intercellular adhe-sion molecule-1 (ICAM-1), soluble Fas, tissue inhibitors of
metalloproteinase-1andmatrixmetalloproteinases(MMP)2
cord injury has been found to result in significant reduc-tion in the activity of caspases 3, 6, 8and 9 for a period of up to seven days after the occurrence of the injury.6
MP inducesinteraction ofthe glucocorticoid receptor with HIF-1␣,whichresultsintransactivationoferythropoietinin
oligodendrocytes, but not in cortical neurons, which may
explainitsefficacy inlesionsofthewhite matterand inef-ficacyinlesions ofthegraymatter.7 MPinhibitsthe death
ofoligodendrocytesinducedby␣ -amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid(AMPA)inamannerdependenton thesignaltransducerandactivationoftranscription(STAT)5 gene.8Ontheotherhand,theneuralgrowthfactorincreases
inpatientstreatedwithMP.5
However,otherexperimentalstudieshavefoundnegative effectsfromMP.Invitro,significantinhibitionofthe prolifer-ationofneuronprogenitorcellsthatwereincubatedwithMP foratleastfivedayswasobserved,alongwithalterationsto theexpressionof143genes,amongwhichsomeareinvolved inregulatingcellproliferationandapoptosis.9
MPwasfoundtochronicallyreduceproliferationand
acti-vation of microglia and macrophages and the number of
oligodendrocyteprogenitorcells,andtoinhibitproliferation ofneuronprogenitorcellsofthehippocampusandmedulla.10
InanimalstreatedwithMP,asignificantreductionin cil-iary neurotrophic factor (a neuroprotective molecule) was observed12and24hafterspinalcordinjury.Atsix,48and 72h,nostatisticallysignificantdifferenceswerefound.11
In therapeuticterms, rats treated with MPhave shown
significant improvements in neurological function, with
reducedlatencyandthresholdandincreasedevokedmotor
potential.12Inanotheranimalstudy,nosignificant
improve-mentinneurologicalrecoveryorinthequantityofinjured tissuewasobservedthroughtreatmentwithMP.13Areview
evaluatedthevalidityofanimaltrialsforstudyingtreatments for spinal cord injuries. Among the studies included, 34% foundthatMPhadbeneficialeffects,58%didnotfindanysuch effectsand8%hadmixedresults,andtherewereinconsistent resultsbetweenspeciesandwithineachspecies.Thisreview concludedthattherewasaneedtodevelopvalidatedmethods foranalyzingthesetreatments.14
Inhumans,theresultshavebeen contradictory: accord-ingtoAndrade,therewasnorelationshipbetweenapplication oftheNASCISIIprotocolandthepatients’evolution.15
How-ever,amongpatientstreatedusingMPandsurgery,therewas
greater motor recovery than among patients who did not
undergothistreatment.16
Ameta-analysisonthreestudiesonhumansindicatedthat treatmentwithMPthatwasstartednotmorethan8hafterthe injurysignificantlyimprovedneurologicalfunctioning.Oneof thesestudiesconcludedthattreatmentwithMPfor48h pro-videdadditionalbenefit,especiallyifthetreatmentwasonly startedbeyondthefirst3h.17
Althoughevidenceofgreaterincidenceofcomplicationsor mortalitythroughtreatmentwithMPisnotalwaysreported,17
thecomplicationsresultingfromitsusehavegenerallybeen duetoimmunosuppressanteffects(infections)andmetabolic effects(hyperglycemia).1,18Astatisticallysignificantlygreater
numberofcomplicationswasobservedamongpatientswith
complete ruptures.16 Asignificantly greater riskof
compli-cations in general was seen among patients treated with
highdosesofMP(>5000mg),alongwithsignificantlygreater incidenceofulcersorgastrichemorrhage.Nosignificant
dif-ferences in intrahospital mortality were found between a
groupthatreceivedhighdosesofMPandacontrolgroup.19
Among patients hospitalized in intensive care, it was
seen thatthe riskofinfection (especiallyrespiratory
infec-tion) and hyperglycemia was significantly greater among
patients treatedwithMP.Therewasno statistically signifi-cantdifferenceinmortalityandnodifferencesinneurological functioningwere seenatthe timeofrelease fromhospital, betweentreatedanduntreatedpatients.18
BenefitsfromtreatmentwithMPwerethusonlyobserved intheNASCISstudiesandinoneortwootherstudies,andit wasseenthattreatmentwithhighdosesofMPincreasedthe riskofinfectionandconsequentlylengthenedhospitalization anddependenceonmechanicalventilation.Itwasconcluded thatuntiltherewasmoreevidence,useofsteroidsfortreating spinalcordinjuriesshouldbesuspended,2consideringthat
thebenefitsfromthetreatmentmightnotcompensateforthe adverseeffectsassociatedwiththis.20
Inanarticleonfirst-aidmeasuresandtreatmentforspinal andspinalcordinjurieswithfracturing,theauthorsreported thattheywerecurrentlyonlyusingMP(usingtheNASCISII protocol)amongpatientswithincompletespinalcordinjuries, withinthefirst8haftertheinjury,giventhattheyhadnot observedanybenefitsfromthistherapyamongpatientswith completerupture.21
Areviewconductedin2013concludedthatMPcouldnot beconsidered tobeastandardtreatmentforpatientswho hadsufferedspinalorspinalcordinjuries,butthatitshould bekeptasanoptionuntilnewtreatmentsofprovenefficacy emerged.1
Tirilazad
Tirilazadisa21-aminosteroidthatactsinamannersimilar tocorticoids,withinhibitionoflipidperoxidationbutwithout immunosuppressantormetaboliceffects.22
Areviewreportedthattirilazadhad beneficialeffectsin theNASCISstudies,butemphasizedthattherewasaneedto developnewantioxidanttherapiesthatweresaferandmore effective.22
Drugs
that
interfere
with
edema,
ischemia
and
membrane
equilibrium
Afterinjury,edema,ischemiaandalteredequilibriumofthe cellmembranesofthespinalcordareobserved.
GM1
GM1 is a ganglioside that intervenes in these processes,
throughraisingtheneurotrophicfactorlevelsandreducing neurondestruction.23
improvedmotorfunctionbutinalessmarkedmannerthan seenwithMPalone.23
Inhumans,noevidenceofreducedmortalitythrough treat-mentwithGM1hasbeenfound.24
Apoptosis
inhibitors
Apoptosis is an importantcomponent of secondary spinal
cordlesions,whichcontributestowardlossofneuronsand oligodendrocytes.25 Several drugsinhibit apoptosisthrough
a variety of mechanisms, and these include inhibition
of caspases,25 inhibition of several intracellular signaling
routes26,27 andreductionofoxidativestress.28 Avastgroup
ofdrugsinhibitscalpain,anendoproteasethatpromotes apo-ptosisinseveraltypesofcellsthroughproteolysisofproteins inthecytoskeleton,membraneandmyelin.29
Caspaseinhibitors
Afterexperimentalinjuryinrats,itwasfoundthatcaspases 3,8and9becameactivated,especiallyinneuronsand oligo-dendrocytes.IntrathecalinjectionofBoc-d-fmk,anonspecific inhibitorofcaspases,resultedinimprovementofmotor func-tionobservedonthe21stand28thdaysaftertheexperimental spinalcordinjury.Useofz-DEVD-fmk,aselectiveinhibitor
of caspase 3, led to functional improvement only on the
21stdayaftertheinjury.25Inanotherstudy,useof
z-DEVD-fmk resulted in a lower degree of histological alterations seen 24hafter theinjury, withreduced apoptosis and sig-nificantimprovementofmotorfunction.30Inacomparison
betweentreatmentwithmagnesiumsulfate,anantagonistof N-methyl-d-aspartate(NMDA)receptors,anduseof
z-LEDH-fmk,along withcombined treatmentwithbothofthese, a
histological but nonfunctional improvement was seen. No
statisticallysignificant differences were identified between thesetwodrugs.31AgroupstudiedtheeffectsofM50054,an
inhibitorofcaspase-3,infishwiththecapacitytoregenerate thecentralnervoussystem.Asignificantreductionin
apopto-siswasobservedoverthemediumtolongterm,amongthe
existingneurons,recentlyformedcellsandrecently differen-tiatedneurons,inassociationwithfasterfunctionalrecovery amongthetreatedfish.32
Calpaininhibitors
The calpain inhibitor MDL28170 improved the survival of
Schwanncells,bothinvitro,afterexposuretohydrogen per-oxide,andinvivo,aftertransplantationintheinjuredspinal cord.33Treatmentwithasingleintravenousdoseofthisagent,
orwithadailydoseadministeredintraperitoneally,resulted inimprovementofmotorfunction,butnotoftheextentof thelesion.Combinationofthesetwoformsofadministration improvedbothofthevariables.29Removalofcalciumfromthe
mediumorinhibitionofcalpainusingMDL28170avoidedthe myelinretractioninducedbyexposuretoglutamate.34
Othercalpaininhibitorshavealsobeenstudied.SJA6017 significantlyreducedthedegreeoftissuedamageand apo-ptosisand significantlyimproved motorfunction.35 Inrats,
administration of calpain inhibitors led to formation of
abnormal axon extremities that were swollen and did not
presentmicrotubules.Thissuggeststhatactivationofcalpain isnecessaryforeffectiveregeneration.36
Drugsthatinterferewithotherroutes
Spinal cord injury activates autophagia and apoptosis in
neurons and astrocytes. Inhibition of autophagia using
3-methyladeninehasbeenfoundtoresultinworsened
neu-rologicalfunction,whileitsstimulationwithrapamycinhas theoppositeeffect.Theseresultssuggestthatstimulationof autophagiahasanti-apoptoticandneuroprotectiveeffects.37
Treatmentwithaminoguanidine,aninhibitorofinducible
nitric oxide synthase (iNOS), has been found to lead to
improvement ofmotor function of the hind limbs ofrats,
reduce mortalityand reduceneuronalmorphological
alter-ations. This treatment has also been shown to lead to
reductionofdephosphorylationofthepro-apoptotic phospho-rylatedBcl-2-associateddeathpromoter(p-BAD)proteinand reductionofiNOSexpression,whichresultsinlowerrelease ofcytochromecandmitochondriaandreducesthedegreeof apoptosis.38
Treatment withbuteinhas beenfound toattenuatethe
expressionofproteinp65ofthenuclearfactorB(NF-B)and toincreasethe phosphorylationofthe ␣inhibitorofNF-B (I-B␣).Therewasalsoareductioninmyeloperoxidase activ-ity,whichtranslatedaslowerneutrophilinfiltrationandless expressionofactivatedcaspase-3.Fromthis,itcouldbe con-cludedthattherewasadecreaseinapoptosis.39
Inanother study,use ofBMS-345541,aninhibitorofthe kinasepathwayofI-B␣(IKK)/NF-B,avoidedneutrophil infil-trationthroughreductionoftheexpressionoftheadhesion moleculeICAM-1andhadanti-apoptoticeffectsthrough inhi-bitionofcaspase3andmodulationoftheexpressionofBcl-2 andBax.40
Astudy on ratscomparedthe effectsoftreatmentwith
ginkgolide B with the effects of methylprednisolone and
AG490, aninhibitor ofthe Januskinase (JAK)/Statpathway. TheanimalstreatedwithginkgolideBorwithMPpresented significantlybettermotorfunctionthanthoseofthecontrol
group.ThetreatmentwithginkgolideBandAG490reduced
theactivationoftheJAK/Statpathwayandincreasedthe Bcl-2/Baxratio,whichresultedinananti-apoptoticeffect,with lowerexpressionofcaspase-3andreductionofthenumberof TUNEL-positivecells.ThetreatmentwithginkgolideBandMP alsoresultedingreaterneuronpreservation.27
Inhibitionofcyclin-dependentkinase-1(CDK1)usingCR8
or roscovitine resulted in reduction of apoptosis among
culturedcorticalneurons,especiallyusingCR8.Invivo, admin-istrationofCR8resultedequallyingreaterneuronsurvival.26
oxidativeand inflammatorydamage).Decreasedexpression ofFasligandsandBaxandincreasedexpressionofBcl-2have alsobeenobserved.Inthespinalcordofanimalstreatedwith fasudil,noapoptoticcellshavebeendetected.28
Inrats,treatmentwith17-estradiolwasfoundtoreduce apoptosis ofoligodendrocytes, lossofaxonsand activation
ofcaspases 3and 9,homologue A ofRas(RhoA),c-Jun
N-terminalkinase (JNK)3 andphosphorylated c-Jun (p-c-Jun) levels, independentlyofthe estrogenreceptor. Administra-tionofPEP-1-C3,afusionproteinthatinhibitsRhoA,wasalso foundto reduceapoptosis ofoligodendrocytes, JNK3 activ-ityandp-c-Junlevel,whichconfirmedthatthisroutehasa roleininducingapoptosis.4117-estradiolreducedthe
phos-phorylation of JNK and apoptosis of spinal neurons after
spinalcordinjuryinrats andreduced thephosphorylation ofJNKandtheexcitotoxicityinducedbyglutamateinvitro.42
An in vitro study tested the effects of estrogen and of an agonistofestrogenreceptor(ER) ␣ (PPT)and an agonistof ER(DPN)onmotorneuronsexposedtoTNF-␣.Allofthese ledtoreductionofapoptosis,inductionofphosphorylation ofextracellular-sign-regulated kinases (ERK)and increased expressionoftherespectivereceptors,withgreaterexpression ofanti-apoptotic proteins.The agonists ofestrogen recep-torsinhibitedboththeintrinsicandtheextrinsicpathwayof apoptosis.43
Chickenembryoshavethecapacitytoregeneratethespinal cord until the 13th day of the embryonic period. Peptidy-larginine deiminase 3is a calcium-dependent proteinthat hasbeenimplicatedinlossofthiscapacity.Treatmentwith Cl-amidine,acalciumchelant,hasbeenfoundtoreduce apo-ptosisandtheextentofspinalcordinjuryinchickenembryos untiltheir15thdayofdevelopment.44
Inastudyonmice,apocynin,aninhibitorofreduced nic-otinamideadeninedinucleotidephosphate(NADPH)oxidase, gaverisetoreducedinflammation,extentofspinalcord dam-age,infiltrating neutrophils, adhesionmoleculeexpression, NF-Bexpression,nitrotyrosineandpoly-ADP-ribose forma-tion,pro-inflammatorycytokinelevels,MAPKactivationand apoptosis.Animprovementinmotorfunctionwasalsoseen.45
Pretreatment withU0126, an inhibitor ofMAPK kinases
(MEK),wasfoundtoleadtoinhibitionofphosphorylationof ERK1/2,reductionofapoptosis andgreaterneuronsurvival. InhibitionofMEKinduced phosphorylationofI-B,favored
binding ofNF-Bto AND and increased the expression of
apoptosis-inhibitingcellularprotein-2. Astatistically
signif-icant improvementofmotor functionwas observed inthe
limbsaffected.46
SP600125, an inhibitor of JNK, was found to produce
increased levels of p-BAD and the dimer BAD/14-3-3,
decreased dimerization ofBAD with Bcl-XL and Bcl-2, and
reduced release of cytochrome c. There was also greater
preservation of the morphology of the mitochondria and
diminishedapoptosis.47
Rolipram,aninhibitorofphosphodiesterase-4,wasfound toinducegrowthofneuritesand axonregeneration,unlike MP,but it didnotreduceneuron deathin vitro,or the lev-elsofchondroitinsulfateproteoglycans,whichwasobserved withMP.Combinedtreatmenthadaneffectonthesevariables thatwasmoreintensethanmonotherapy.Bothofthesedrugs significantlydiminishedthe volumeofthelesion,and this
wasmoremarkedlysoincombination.Onlythetreatment
withbothoftheseagentsresultedinasignificantfunctional improvement.48
Naloxone
DynorphinA,anendogenousopioidthatshowsincreased lev-elsafterspinalcordinjury,hasneurotoxiceffectsandreduces thearterialflow.Naloxone,anantagonistofopioids,hasbeen usedinsomestudiestocounteracttheseeffects.3However,in
theNASCISIIstudy,naloxonedidnotshowany neuroprotec-tiveeffect.3
Antioxidant
drugs
Oxidativedamagecausedbyreactiveoxygenand
peroxyni-trite speciesis an importantprocess in secondarylesions. Itleadstoperturbationofionichomeostasis,mitochondrial dysfunction,potentiationofexcitotoxicityandmicrovascular lesions.22
Tempolisanantioxidantthatreducesthelevelsofthese
substancesanddiminishesinflammationthroughinhibiting
COX-2.49
In several studies, tempol has been shown to reduce
the oxidative damage mediated by peroxynitrite and the
mitochondrialrespiratorydysfunction.50,51Reductionsinthe
degradationofcytoskeletonproteinshavealsobeenobserved whentreatmentwasadministeredwithinthefirsthourafter theinjury,50alongwithreductionofCOX-2expression.49The
areaofthespinalcordthatwasirreversiblydamagedwasalso seentobereducedthroughusingtempol.49
In astudy inwhichthe effect oftempolwascompared
withthatoftheuncouplingprotein2,4-dinitrophenol,the
lat-ter preserved the functioning ofsynaptic and nonsynaptic
mitochondria,whereastempolonlyhadaneffecton
nonsy-napticmitochondria.52
Another antioxidant,edaravone,wascomparedwithMP
inatrialusingrats.ItwasfoundthatMPhadgreatereffect regardingmotorrecoverythanedaravonewhenthetreatment
was administered within eighthours afterthe spinalcord
injury,whiletheoppositewasseenwhenthetreatmentwas givenmorethaneighthoursafterwards.Therewasgreater
expression ofBcl-XL in the group treated with edaravone,
independentofthetimingofthetreatment.Whenthe
treat-ment wasadministered within8hofthe injury, therewas
greater reductionoftheexpressionofcaspase-3inthe ani-malstreatedwithMP,whilebeyond8h,onlyedaravonegave risetoasignificantreduction.53
AninvivoandinvitrostudyevaluatedtheeffectofMPand MnTBAP(anantioxidant)ontheproductionofreactive oxy-gen species.Invivo, bothagentsgaverisetodiminutionof hydrogenperoxideproduction,butonlyMnTBAPsignificantly reducedthequantityofsuperoxide.Invitro,MnTBAPrevealed acapacity tocapturebothreactiveoxygen species,but MP
did nothaveany effectoneither ofthem.Treatmentwith
neurologicalfunctioning,andthiswasmoremarkedlysowith MnTBAP.54
Other
drugs
A study on mice evaluated the effect of cocaine and
amphetamine-regulatedtranscript(CART)peptides,aloneor
in combination with MP. It was found that both of these
drugsimprovedmotorfunction.TheeffectofMPwasboosted throughconcomitantadministrationofCART,evenatadose
thatwould besub-effectiveasmonotherapy. CARTand MP
alsoreducedthenumbersofastrocyteswithpositivemarking forGFAPandastrocytichypertrophy.Histological abnormal-itieswerereducedinsimilarmannersbyCART,MPandthe combinedtreatment.55
Inastudyonrats,theeffectsofMPandmagnesiumwere
evaluated.Administrationofmagnesiumwithineighthours
aftertheinjuryresultedinasignificantimprovementinmotor function,inrelationtotheplacebogroupandtogroupsthat receivedmagnesiumafter12or24hours.MP,magnesiumand theircombinationsignificantlyreducedthelossofwhite mat-ter,butthecombinationwasnotshowntobebetterthanthe separatetreatment.Noneofthetreatmentshadany signifi-canteffectonthemyelinindex.56
The Nogo-66 receptor is activated by three myelin
moleculesanditinhibitsthegrowthofneurites.Astudyin
whichcombinedtreatmentconsistingofMPandNEP1-40(an
antagonistofNogo-66)wasusedresultedinagreaterincrease insurvivalofneuronsandoligodendrocytesandsignificantly bettermotorrecoverythanamonganimalstreatedwithonly oneofthesedrugs.57
Inaretrospectivestudyonhumans,itwasfoundthatthere wasamoresignificantimprovementinautonomyinrelation toactivitiesofdailylivingthroughcombinedtreatment con-sistingofMPanderythropoietinthanwithMPalone.58
In a study on rats that evaluated the effects of MP
and dexmedetomidine, both of these treatments
signifi-cantlyreducedthelevelsofTNF-␣andIL-6,along withthe infiltration of neutrophils.59 In another study,
dexmedeto-midine caused greater elevation of paraoxonase and IL-6,
alongwithgreater reductionofhemorrhage,thanMP.Both
of these agents reduced edema and necrosis to equal
degrees.60
Discussion
TheevidencerelatingtotheefficacyofMPiscontradictory, whileevidenceregardingitsnegativeeffectshasbeen accu-mulating.Inthelightofthepresentknowledge,useofMPfor treatingspinalandspinalcordinjuriesneedstobecarefully weighedup.Otheranti-inflammatoryagentshaveshown ben-efitsforhumansoranimals,butfurtherstudiesarerequiredin ordertocometoconclusionsregardingitsefficacyandsafety inclinicalpractice.
GM1doesnotseemtohavegreaterefficacythanMP.Given thattheeffectsofthisdrugmayonlybeshownlateron, long-termstudiesare neededinordertoidentifythe benefitsof GM1.23
Apoptosis is acomplex process, withmany intervening
factors,andthus,drugsthatinhibititthroughvarious mecha-nismshavebeendeveloped.Theonesthathavebeenstudied mostseem tobecaspase inhibitorsand calpain inhibitors. Many ofthesedrugshaveshownbenefitsininvitrostudies orinanimalmodels.
Naloxonedidnotshowanyneuroprotectiveeffectinthe NASCISIIstudy.
In the studies that have been conducted, tempol was
showntoinhibitthemainconsequencesofoxidationatthe spinalcordleveland isapromisingformoftherapy. Other antioxidantsseemtohaveeffectsthataresuperiortothatof MP,butfurtherstudiesareneededinordertoconfirmtheir efficacy.
Final
remarks
Inordertoaddresstheenormousimpactofspinalcordinjuries and the lackofeffectivetherapeuticoptions forsecondary lesions,thereisanurgentneedtofindnewtreatmentsthat makeitpossibletoimprovetheneurologicalstatusofpatients with spinaland spinal cordinjuries. Thebenefitsof
treat-ment with methylprednisolone have been questioned, and
thereareconcernsregardingitssafety.Otherdrugsthat
inter-veneininflammationorthathaveothermechanismshave
beenstudied.Someofthesemaybepromisingalternativesto methylprednisolone.Additionalstudiesare neededinorder toreachconclusionsregardingthebenefitoftheseagentsin clinicalpractice.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
r
e
f
e
r
e
n
c
e
s
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