Bariera hematoencefalic

Nea-mpratu Mihaela
Facultatea de Medicin General
Anul I, Seria A, Grupa 8
1

Cuprin!

"# $efiniie
%# Itoric
&# Structura 'i funcionarea (arierei hematoencefalice
&#"# Introducere
&#%# Bariera )n*e-lichid cefalorahidian
&#&# Bariera hematoencefalic
&#+# Funcionarea (arierei hematoencefalice
+. Boli care implic (ariera hemato-encefalic
+#"# Menin*it
+#%# ,pilepie
+#&# Sclero-a .n plci
+#+# Boala omnului
+#/# 0eucoencefalopatie multifocal pro*rei1
+#2# Boala Al-heimer

2
"# $efiniie
BARIERA HEMATOENCEFALIC / barriere hemato-encepha-li!e / bloo"-brain barrier
- "en!mire a caracteri#ticilor capilarelor cerebrale care pre$int% o permeabilitate e&trem "e
re#tricti'%( "atorit% c%reia #e pre'ine p%tr!n"erea !nor #!b#tan)e "in #an*e +n creier ,i +n lichi"!l
ce-alorahi"ian. .pre "eo#ebire "e capilarele obi,n!ite( la ni'el!l c%rora cel!lele en"oteli!l!i
capilar pre$int% /onc)i!ni "e#chi#e "e tip *ap( cel!lele en"oteliate ale capilarelor cerebrale
pre$int% /onc)i!ni impermeabile. Ca !rmare( trecerea #!b#tan)elor 0ioni( molec!le1 +n creier e#te
controlat% #trict( "eoarece #e pro"!ce la ni'el!l membranelor cel!lelor en"oteliale. 2n "e-inirea
BHE treb!ie l!ate +n con#i"erare "o!% #tr!ct!ri pericapilare( membranele ba$ale ,i man#on!l "e
cel!le componente ale ne'ro*liei( +n"eo#ebi a#trocitele. 3ermeabilitatea BHE poate cre,te +n
!nele boli. Alteori( acea#ta e#te mo"i-icat% arti-icial pentr! -acilitarea p%tr!n"erii !nor a*en)i
terape!tici. Abre'.4 BHE( BBB 0en*l.1. 567

%# Itoric
3a!l Ehrlich( !n -o#t bacteriolo* #t!"ia colorarea( o proce"!r% !tili$at% +n m!lte #t!"ii
micro#copice pentr! a #pori contra#t!l. 3etele ,i coloran)ii #!nt -rec'ent !tili$a)i +n biolo*ie ,i
me"icin% pentr! a e'i"en)ia #tr!ct!rile "in )e#!t!rile biolo*ice( "e m!lte ori c! a/!tor!l !nor
micro#coape "i-erite. 3etele pot -i !tili$ate pentr! a "e-ini ,i a e&amina ma/oritatea )e#!t!rilor
0e'i"en)iin"( "e e&empl!( -ibrele m!#c!lare #a! )e#!t!l con/!ncti'1( pop!la)iile "e cel!le
0cla#i-ic8n" cel!lele #an*!ine( "e e&empl!1( #a! or*anite +n interior!l cel!lelor in"i'i"!ale. 597
C8n" Ehrlich a in/ectat !nii "intre ace,ti coloran)i 0+n #pecial( coloran)i anilin% care a! -o#t apoi
!tili$a)i pe #car% lar*%1( ace,tia a! p%tat toate or*anele( c! e&cep)ia creier!l!i. La acel timp(
Ehrlich a con#i"erat c% moti'!l pentr! care creier!l n! #e colorea$% e#te pentr! c% n! captea$% la
-el "e m!lt colorant.
C! toate ace#tea( mai t8r$i!( +ntr-!n e&periment( +n 6:6;( E"<in =ol"mann 0!n!l "intre
#t!"en)ii l!i Ehrlich1 a in/ectat colorant "irect +n lichi"!l ce-alorahi"ian "in creier!l animalelor..
El a "e#coperit c%( +n ace#t ca$( creier!l #-a colorat( "ar re#t!l corp!l!i n!. Ace#t l!cr! a
"emon#trat +n mo" clar e&i#ten)a !n!i -el "e compartimentare +ntre cele "o!%. La acea 'reme( #-a
cre$!t c% 'a#ele "e #8n*e +n#ele era! re#pon#abile pentr! barier%( "eoarece nicio membran%
e'i"ent% n! a -o#t *%#it%.. Concept!l "e barier% hemato-ence-alic% a -o#t prop!# "e Lina .tern +n
6:96( "ar n! a -o#t rec!no#c!t% p8n% la intro"!cerea micro#cop!l!i electronic "e #canare +n
"omeniile "e cercetare me"ical%( +n anii 6:>?( c8n" membrana a p!t!t -i ob#er'at% ,i #-a "o'e"it
c% e&i#t%.
.e cre"ea c% e#te mai probabil ca a#trocitele #% -orme$e bariera hematoence-alic% "atorit%
proce#elor "en#e ale ace#tora care +ncon/!ra! cel!lele en"oteliate( "ec8t cel!lele en"oteliale ale
BBB 0bloo"-brain barrier1 +n#ele. 5;7

3
Fi*# " - 3aul ,hrlich
5@7 Fi*# % - ,d4in Goldmann [5]

&# Structura 'i funcionarea (arierei hematoencefalice
&#"# Introducere
Corp!l no#tr! e#te -ormat "in or*ane ,i #i#teme "e or*ane in"i'i"!ale( care nece#it%
con"i)ii "i-erite( "ar con#tante( #% -!nc)ione$eA c!m ar -i4 elemente n!triti'e( hormoni ,i
electroli)i. Toate or*anele corp!l!i #!nt conectate +ntre ele prin #i#tem!l circ!lator. A'8n" +n
'e"ere c% #8n*ele con)ine toate componentele nece#are pentr! a o-eri or*ani#m!l!i ceea ce are
ne'oie ,i pentr! p!ri-icarea proce#elor( #i#temele "e -iltrare treb!ie #% #e a#i*!re c% #!b#tan)ele
nece#are trec prin or*ane ,i c% !nele #!b#tan)e #!nt par)ial oprite. Bnele "intre barierele "e #8n*e
c!no#c!te #!nt4 bariera #8n*e-)e#!t( bariera hemato-hepatic% ( bariera #an*e-lichi"
ce-alorahi"ian(bariera hemato-ence-alic%( bariera lichi"!l ce-alorahi"ian-creier( bariera hemato-
ner'oa#%( bariera hemato-retin%( prec!m ,i bariera placentar%.
Ace#t mecani#m "e -iltrare -!nc)ionea$% c! !n a,a-n!mit e-ect "e barier%( ace#t l!cr!
+n#eamn% c% an!mite #!b#tan)e pot tra'er#a bariera( iar altele #!nt re#tric)ionate( +n ca$!l +n care
#i#tem!l "e or*ane n! are ne'oie "e componente #a! are ne'oie "e ele n!mai +n concentra)ii
mici. Ace#te CbariereD n! #!nt or*ane in"epen"ente( "ar #!nt -ormate "in m!lte cel!le ,i #pa)ii
"intre cel!le care #% permit% *a$elor #an*!ine( n!trien)ilor( prec!m ,i an!mitor #!b#tan)e chimice
#% tra'er#e$e barierele. Ace#tea #!nt con#tit!ite "in pori( care n! permit trecerea
macromolec!lelor( #a! ar p!tea -i membrane lipi"ice #it!ate +n pere)ii 'a#c!lari care a! !n e-ect
"e inhibare a#!pra permeabilit%)ii lipi"elor in#ol!bile +n ap% #a! care a! e-ect!l #electi' "e a l!a
parte +n mo" acti' +n ca"r!l proce#elor "e tran#port capilar. Creier!l!i ,i )e#!t!l ner'o# #!nt
prote/ate prin "o!% #i#teme "e -iltrare( bariera #8n*e-lichi" ce-alorahi"ian ,i bariera hemato-
ence-alic%. 5>7
4

&#% Bariera )n*e-lichid cefalorahidian
0ichidul cefalorahidian 50C67, cerebrospinalis Liquor, e#te !n lichi" clar care oc!p%
#pa)i!l #!barachnoi" ,i #i#tem!l 'entric!lar +n /!r!l ,i +n interior!l creier!l!i. 2n e#en)%( creier!l
Epl!te#teE +n el. 5F7


Fi*. ;. LCR e#te pro"!# +n interior!l 'entric!lilor( a"8nc +n creier. LCR circ!l% +n interior!l
creier!l!i ,i al m%"!'ei #pin%rii ,i apoi +n a-ar%( c%tre #pa)i!l #!barachnoi". Frec'ente #ite-!ri "e
ob#tr!c)ie4 61 "in -oramen Monro( 91 "in ape"!ct .Gl'i!#( ,i ;1 obe&. 5H7


2n timp!l pro"!cerii "e lichi" ce-alorahi"ian( ca ,i at!nci c8n" #!b#tan)ele trec "in #8n*e
+n -l!i"( a! loc -iltrarea( "i-!$ia ,i tran#-er!l acti' "e "io&i" "e carbon( *l!co$% ,i aminoaci$i.
Ace#t #chimb "e #!b#tan)e e#te re*lat "e bariera #8n*e-lichi" ce-alorahi"ian( care #e -ormea$% "in
cel!lele en"oteliale ale capilarelor ,i #!pra-a)a creier!l!i ,i poate -i +nt8lnit +ntre 'a#ele "e #8n*e
,i #pa)i!l lichi"!l!i ce-alorahi"ian. Ii-eritele concentra)ii "e *l!co$%( proteine ,i electroli)i +n
#8n*e ,i +n LCR #!nt re*late "e ace#te -!nc)ii "e -iltrare +n #cop!l "e a men)ine concentra)iile
optime +n creier. 5>7
5

Fi*. @. Locali$area
barierei hematoence-alice ,i a #tr8n#ei /onc)i!ni +ntre cel!lele en"oteliale 5:7

&#& Bariera hematoencefalic
2n ca"r!l #i#tem!l!i ner'o# central #pa)i!l "intre ne!roni e#te aproape complet !mpl!t
c! cel!le *liale ,i prel!n*irile lor. Metaboli#m!l!i +ntre*ii cel!le ner'oa#e are loc prin
interme"i!l ace#tor cel!le *liale - #a! cel!le en"oteliale( al c%ror #cop e#te "e a in#tala cel!lele ,i
-ibrele ner'oa#e( prec!m ,i "e a le hr%ni ,i i$ola.
Bn tip "e cel!le *liale #!nt a#trocitele. Bn tip "e a#trocite are n!meroa#e rami-ica)ii ale
prel!n*irilor care a"er% la pere)ii capilarelor ,i !n alt tip acoper% capilarele pe toate lat!rile(
c%pt!,in" cel!lele en"oteliale. Ace#te cel!le en"oteliale #!nt !nite prin elemente con/!ncti'e( #a!
/onc)i!ni #tr8n#e 0a #e 'e"ea "ia*rama1 ,i #!nt echipate c! o #!b#tan)% c! permeabilitate #electi'%
care permite trecerea n!mai a partic!lelor c! !n "iametr! mai mic "e 9?nm.5>7
6
Fi*. J. - Repre$entarea #chematic% a barierei hematoence-alice4 a. #pa)ial%( b. tran#'er#al% -
#!r#%4 Ieet/en/.pecKmann( 3hG#iolo*G 9
n"
printin*( Brban L .ch<ar$enb!r*( 6::@ 5>7
2n ace#t -el( +ntre*!l metaboli#m al cel!lei ner'oa#e are loc prin interme"i!l ace#tei re)ele
en"oteliale( a#t-el +nc8t at!nci c8n" #!b#tan)ele nece#are #e *%#e#c +n #8n*e #!nt ime"iat trec!te
printr-!n -iltr! biolo*ic. C! toate ace#tea( orice #!b#tan)e care pot a-ecta -!nc)ionarea creier!l!i
#!nt )in!te "eparte "e #i#tem!l ner'o#.5>7

&#+# Funcionarea (arierei hematoencefalice
Acea#t% re)ea en"otelial% ,i cel!lele en"oteliale care acoper% capilarele ca o membran%
ba$al%( #!nt "e#emnate ca -iin" bariera hematoence-alic%. O&i*en!l( "io&i"!l "e carbon( I-
*l!co$a( I-He&o$a( !nii L-aminoaci$i ,i lipi"ele #ol!bile +n ap% pot p%tr!n"e BBB 0bloo"-brain
barrier1( toate -iin" nece#are pentr! b!na -!nc)ionare a creier!l!i . 2n ace#t mo" componentele
"e*ra"ante #!nt( "e a#emenea( tran#mi#e +n #8n*e. 3rel!n*irile ,i rami-ica)iile a#trocitelor
repre$int% o barier% pentr! an!mi)i hormoni( lipi"ele in#ol!bile( #ol!bile +n ap% ,i n!meroa#e alte
#!b#tan)e chimice(iar ace#t l!cr! a#i*!r% -apt!l c% e#te men)in!t !n me"i! con#tant pentr!
ne!roni ,i pentr! #i#tem!l ner'o#.5>7
7
&#/# $ifuncionalitile (arierei hematoencefalice
.tr!ct!ra cel!lar% a a#trocitelor e#te at8t "e re$i#tent% +nc8t e#te capabil% #% con#tr!ia#c%
!n a"e'%rat #c!t +mpotri'a celor mai mari #!b#tan)e molec!lare ,i or*ani#me. C ! toate ace#tea(
+n con"i)ii normale n! e#te complet #i*ilat%( a,a c% !nele partic!le a! po#ibilitatea "e a tra'er#a
bariera. 2n ca$!ri "e in-ec)ie( tra!me( in-lama)ie( otr%'ire( hipo&ie( -ebr% ,i +n ca$!ri "e t!mori(
/onc)i!nile #tr8mte "intre cel!lele en"oteliale "e'in +ntin#e "in ca!$a !m-l%rii a#trocitelor ,i
a#t-el bariera hematoence-alic% "e'ine mai permeabil% pentr! alte #!b#tan)e. Mo"i-ic%rile le*ate
"e l%)imea "e#chi"erilor #e "atorea$% ,i !m-l%rii ,i "e$!m-l%rii cel!lelor en"oteliale. Nici chiar
membrana capilar% ba$al% n! e#te #i*ilat%. Iac% e&i#t% #a! n! #!nt pori +n membran%( care /oac%
!n rol acti' +n #chimb!l "e #!b#tan)e( "epin"e "e "en#itatea re)elei "e -ibre. .i#temele 'a#c!lare
ale t!morilor patolo*ice n! "e$'olt% nicio barier% hematoence-alic%.
Ieoarece ace#t -apt era c!no#c!t( a -o#t !tili$at +n proce"!rile "e "ia*no#ticare. Bn me"i!
"e contra#t e#te a"mini#trat +n #i#tem!l 'a#c!lar pentr! a 'eri-ica "ac% r%m8ne +n #i#tem!l
'a#c!lar #a! "ac% trece +n t!mor%. C! m!lt +nainte "e !tili$area antibioticelor( me"icii cre,tea!
permeabilitatea barierei hematoence-alice prin in"!cerea "e !nei -ebre arti-iciale( #imilar% c! cea
pro"!#% +n timp!l !nei boli in-ec)ioa#e. Ace#t tip "e tratament a -o#t !tili$at pentr! a trata #i-ili#!l
+n #i#tem!l ner'o# central ,i pentr! terapia c! ,oc +n "omeni!l "e 3#ihiatrie( c! ace#t tip "e
tratament( me"icamenta)ia p!tea -i a"mini#trat% "irect la creier. 2n ca$!l +n care con"i)iile care a!
pro"!# cre,terea temporar% a permeabilit%)ii barierei hematoence-alic%( #!nt oprite( acea#ta
re'ine la #tarea ini)ial%.5>7


Fi*. >. 3arte a !nei re)ele "e capilare ce hrane,te cel!lele creier!l!i 5;7
8
+. Boli care implic (ariera hemato-encefalic
+#"# Menin*it
Menin*ita e#te o in-lama)ie a membranelor care +ncon/oar% creier!l ,i m%"!'a #pin%rii
0ace#te membrane #!nt( "e a#emenea( c!no#c!t ca menin*e7. Menin*ita e#te cel mai -rec'ent
ca!$at% "e in-ec)ii c! a*eni pato*eni "i-eri)i( ale c%ror e&emple #!nt Streptococcus pneumoniae
,i Haemophilus influenza. 2n ca$!l +n care menin*ele e#te in-lamat( bariera hematoence-alic%
poate -i pert!rbat%. Acea#ta poate cre,te p%tr!n"erea "i'er#elor #!b#tan)e 0incl!#i' to8ine #a!
antibiotice1 +n creier. Antibioticele -olo#ite pentr! a trata menin*ita ar p!tea a*ra'a r%#p!n#!l
in-lamatori! al #i#tem!l!i ner'o# central( prin eliberarea "e ne!roto&ine "e la pere)ii cel!lelor ale
bacteriilor-c!m ar -i lipopolG#acchari"e 0L3.1.56?7 Tratament!l c! *eneraia a treia au
*eneraia a patra de cefaloporine e#te pre-erat "e obicei.
+#%# ,pilepia
,pilepia e#te o boal% com!n% ne!rolo*ic%( caracteri$at% prin con'!l#ii rec!rente ,i(
!neori( netratabile. Mai m!lte "ate clinice #i e&perimentale a! implicat e,ec!l -!nc)ion%rii
barierei hematoence-alice +n "eclan,area cri$elor ac!te #a! cronice 5;7( !nele #t!"ii implic%
interac)i!nile "intre o protein% com!n% a #8n*el!i - alb!mina ,i atrocite.5667 Ace#te "e#coperiri
a! "emon#trat c% ac!tele cri$ele #!nt o con#ecin)% pre'i$ibil% "e pert!rbare a BBB 0bloo"-brain
barrier1 -ie prin mecani#me arti-iciale #a! in-lamatorii. 2n pl!#( e&pre#ia re$i#ten)ei molec!lelor
la me"icament ,i a tran#portatorilor la BBB e#te !n mecani#m important "e re$i#ten)% la
me"icamentele -rec'ent !tili$ate anti-epileptice.5697
+#&# Sclero-a .n plci 5SM7
Sclero-a multipla 0.M1 e#te con#i"erat% a -i o t!lb!rare a!to-im!n% ,i
neurode*enerati1, +n care itemul imunitar atac% mielina care prote/ea$% ,i i$olea$% electric
ne!ronii "in #i#tem!l ner'o# central ,i periferic. 2n mo" normal( #i#tem!l ner'o# al !nei
per#oane ar -i inacce#ibil pentr! cel!lele albe "in #8n*e( "atorit% barierei hemato-ence-alice. C!
toate ace#tea( #-a "emon#trat c! a/!tor!l IRM c% at!nci c8n" o per#oan% e#te +n c!r# "e !n atac
.M( bariera hematoence-alic% #e "e#comp!ne +ntr-o #ec)i!ne a creier!l!i #a! a m%"!'ei #pin%rii(
permi)8n" *lo(ulelor al(e n!mite limfocite 9 #% tra'er#e$e pe#te ,i #% atace mielina# A -o#t
!neori #!*erat -apt!l c%( .M e#te mai probabil o boal% a barierei hematoence-alice( "ec8t !na a
#i#tem!l!i im!nitar.56;7 C! toate ace#tea( "o'e$ile ,tiin)i-ice act!ale #!nt necon'in*%toare.
E&i#t% in'e#ti*a)ii acti'e +n pre$ent +n ceea ce pri'e,te tratamentele pentr! a e'ita
compromiterea barierei hematoence-alice# .e cre"e c% treul o8idati1 /oac% !n rol important +n
"e#comp!nerea barierei. Anti-o&i"anti( c!m ar -i acidul lipoic pot -i capabili "e a o #tabili$a.56@7

9
+#+# Boala omnului
Boala omnului, e#te o a-ec)i!ne +n care TrGpano#oma 0proto$oar1 #e *%#e,te +n )e#!t!l
cerebral. N! e#te +nc% c!no#c!t mo"!l +n care para$i)ii in-ectea$% creier!l "in #8n*e( "ar #e
#!#pectea$% c% trec prin interme"i!l ple8ului coroid, !n or*an circ!m'entric!lar. 5;7
+#/# 0eucoencefalopatia multifocal pro*rei1 50M37
0eucoencefalopatia multifocal pro*rei1 0LM31 e#te o boal% "emielini$ant% a
#i#tem!l!i ner'o# central( ca!$at% "e reacti'area !nei in-ec)ii c! !n papo1a1iru latent
5pol:oma1iru ;C7, care poate tra'er#a BBB. Acea#ta a-ectea$% pacien)ii compromi,i "in p!nct
"e 'e"ere im!n ,i "e obicei e#te +nt8lnit% la pacien)ii care #!-er% "e SI$A# 5;7
+#2# Boala Al-heimer
Bnele noi "o'e$i in"ic% -apt!l c% pert!rbarea barierei hemato-ence-alice la pacien)ii c!
Boala Al-heimer permite pla#mei care con)ine (eta-amiloid 0AM1 #% intre +n creier(!n"e AM
a"er% pre-eren)ial la #!pra-a)a atrocitelor# Ace#te con#tat%ri a! con"!# la ipote$ele c% 061
"e#comp!nerea barierei hematoence-alice permite acce#!l a!toanticorpilorce 0#e lea*% "e
ne!roni1 ,i a AM@9 #ol!bil e&o*en c%tre ne!roni ,i 091 c% le*area a!toanticorpilor "e ne!roni
"eclan,ea$% ,i / #a! -acilitea$% internali$area ,i ac!m!larea "e AM@9 +n ne!ronii '!lnerabili( prin
ten"in)a lor nat!ral% "e a e'ac!a a!toanticorpii( prin interme"i!l endocito-ei# 2n cele "in !rm%
a#trocit!l e#te cople,it( moare( e#te r!pt ,i #e "e$inte*rea$%( l%#8n" +n !rm% placa AM@9
in#ol!bile. A#t-el( la !nii pacien)i( boala Al$heimer poate -i ca!$at% 0#a! mai probabil( a*ra'at%1
"e c%tre o "i#r!p)ie a barierei hemato-ence-alice# 56J7
Nir!#!l herpe# pro"!ce beta-amiloi"!l 0AM1( iar ace#t 'ir!# a -o#t "o'e"it a -i a*ent!l
pato*en re#pon#abil pentr! o ca!$% ma/or% a bolii.56>7
2n !rma !n!i #t!"i! reali$at pe iep!ri( c%rora li #-a "at $ilnic echi'alent!l +n co-eina al
!nei ce,ti "e ca-ea ,i a! -o#t hr%ni)i c! o "iet% bo*at% +n cole#terol pentr! 69 #%pt%m8ni( #-a
"emon#trat c% ace,tia a! #!-erit o a-ectare relati' mai mic% a barierei hematoence-alice. Co-eina
o-er% #e pare o oarecare protec)ie a/!t8n" proteinelor #% men)in% le*%t!ra #tr8n#% +ntre cel!lele
care -ormea$% bariera hematoence-alic%( oprin" +n ace#t -el molec!lele ne"orite #% p%tr!n"% +n
#i#tem!l ner'o# central. Ie#coperirile con-irm% #t!"iile anterioare care ar%ta! c!m co-eina
prote/ea$% +mpotri'a pier"erilor "e memorie "in mala"ia Al$heimer.56F7

10
Bi(lio*rafie!
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