31.05.

2013 Leptin action on nonneuronal cells in the CNS: potential clinical applications
www.ncbi.nlm.nih.gov/pmc/articles/PMC3407332/ 1/9
Leptin action on nonneuronal cells in the CNS: potential clinical applications
Weihong Pan, Hung Hsuchou, [...], and Abba J Kastin
Abstract
Lept in, an adipocy t e-der iv ed cy t okine, cr osses t he bloodbr ain bar r ier t o act on many r egions of t he
cent r al ner v ous sy st em (CNS). It par t icipat es in t he r egulat ion of ener gy balance, inflammat or y
pr ocesses, immune r egulat ion, sy napt ic for mat ion, memor y condensat ion, and neur ot r ophic
act iv it ies. This r ev iew focuses on t he newly ident ified act ions of lept in on ast r ocy t es. We fir st
summar ize t he dist r ibut ion of lept in r ecept or s in t he br ain, wit h a focus on t he hy pot halamus,
wher e t he lept in r ecept or is known t o mediat e essent ial feeding suppr ession act iv it ies, and on t he
hippocampus, wher e lept in facilit at es memor y , r educes neur odegener at ion, and play s a dual r ole in
seizur es. We will t hen discuss r egulat ion of t he nonneur onal lept in sy st em in obesit y . It s
r elat ionship wit h neur onal lept in signaling is illust r at ed by in vitro assay s in pr imar y ast r ocy t e
cult ur e and by in vivo st udies on mice aft er pr et r eat ment wit h a glial met abolic inhibit or or aft er
cell-specific delet ion of int r acellular signaling lept in r ecept or s. Ov er all, t he glial lept in sy st em
shows r obust r egulat ion and play s an essent ial r ole in obesit y . St r at egies t o manipulat e t his
nonneur onal lept in signaling may hav e major clinical impact .
Keywords: lept in, CNS, obesit y , ast r ocy t es, bloodbr ain bar r ier
Introduction
Obesit y is a global epidemic disor der . In t he Unit ed St at es in 2 01 0, no st at e had a pr ev alence of
obesit y less t han 2 0%, and 1 2 st at es had a pr ev alence of 3 0% or mor e. Lept in is a key adipocy t okine
t hat play s an essent ial r ole in t he r egulat ion of obesit y . It is a 1 6 kDa poly pept ide mainly pr oduced
by adipocy t es in fat t issue. Blood concent r at ions of lept in cor r elat e wit h t he amount of adipocit y .
Lept in lev els ar e also incr eased in inflammat or y sit uat ions. A pr oduct of t he ob gene, lept in has
many cellular t ar get s in differ ent or gans. One of it s major t ar get s is t he cent r al ner v ous sy st em
(CNS). Lept in act s t o r educe feeding behav ior and inhibit obesit y . Aft er administ r at ion of
r ecombinant lept in, it act s dir ect ly on neur onal net wor ks t hat cont r ol feeding and ener gy balance.
Lept in exer t s it s act ions on t he CNS v ia r egionally expr essed lept in r ecept or s (ObR or LepR).
Belonging t o t he cy t okine r ecept or class I super family , t he ObRs consist of fiv e alt er nat iv ely spliced
v ar iant s: a, b, c, d, and e. Among t hem, ObRb has t he longest cy t oplasmic t ail and is r esponsible for
phosphor y lat ion and act iv at ion of signal t r ansducer and act iv at or for t r anscr ipt ion (STAT)-3 . To
exer t it s funct ions in most CNS r egions, lept in must cr oss t he bloodbr ain bar r ier (BBB), which it
does by a unique t r anspor t sy st em; ObRa is t he most abundant isofor m in t he cer ebr al micr ov essels
composing t he BBB. Giv en sufficient lev els of expr ession, as shown in cult ur ed cells ov er expr essing
ObR isofor ms, all of t he membr ane-bound for ms can efficient ly endocy t ose lept in. By cont r ast , t he
soluble r ecept or ObRe may ser v e as an ant agonist not only t o lept in signaling but also t o it s
t r anspor t acr oss t he BBB. In t his r ev iew, we focus on nonneur onal cellular effect s of lept in in t he
CNS and addr ess pat hophy siological implicat ions of t hese findings, not only in obesit y but also in
sev er al CNS disor der s. This ext ends bey ond st udies of t he t r anspor t of lept in acr oss t he BBB.
ObR distribution in the brain
In t he init ial st udy wit h nonr adioact iv e in situ hy br idizat ion (ISH) of ObR mRNA in t he br ain of C5 7
mice, Huang et al. showed t hat t he ar eas wit h t he highest lev el of expr ession include t he ar cuat e
nucleus and median eminence of t he hy pot halamus. The dent at e gy r us and CA1 r egion of t he
hippocampus ar e t he second most abundant . Low lev els ar e also seen in t he pir ifor m cor t ex and t he
medial mar gin of t he medial habenular nucleus. Most of t he ISH signals appear t o be pr esent in
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neur ons, such as t hose pr oducing neur opept ide Y. This was confir med by an independent st udy ,
which also showed t he pr esence of ObR mRNA in t he chor oid plexus. In t he obese ob/ob mouse
dev oid of lept in pr oduct ion, ObR mRNA is incr eased in t hese hy pot halamic r egions, pir ifor m and
olfact or y cor t ices, and t he medial habenular nucleus in compar ison wit h lean mice. Alt hough t he
cont r ol condit ions may not be ideal, it appear s t hat upr egulat ion of ObR has r egional specificit y and
may be dependent on t he inducing fact or s, such as obesit y , fast ing, ischemia, or inflammat ion.
ISH wit h isofor m-specific pr obes showed t hat ObRa and ObRb ar e abundant in t he hy pot halamus,
wher eas ObRa, ObRc, and ObRf, but not ObRb, ar e pr ominent in t he chor oid plexus. Besides br ain
r egions descr ibed in t he pr eceding par agr aph, t he t halamus, subst ant ia nigr a, and gr anular cell
lay er of t he cer ebellum also show int ense ObR signals. When r elat iv e lev els of ObR isofor ms ar e
compar ed wit h t hose measur ed by r ev er se t r anscr ipt asepoly mer ase chain r eact ion (RT-PCR), t he
ObRb t o ObRa mRNA r at io is highest in t he hy pot halamus of t he nor mal adult mouse br ain. Shioda
et al. fir st showed t he pr ot ein expr ession of ObR by immunohist ochemist r y (IHC) and west er n
blot t ing (WB) in r at br ain. ObR immunor eact iv it y was seen in t he ar cuat e, par av ent r icular , and
v ent r omedial nuclei of t he hy pot halamus, lat er al hy pot halamus, olfact or y bulb, neocor t ex,
cer ebellar cor t ex, dor sal r aphe nucleus, infer ior oliv e, nucleus of t he solit ar y t r act , and dor sal
mot or nucleus of t he v agus ner v e, wit h WB showing a molecular weight cor r esponding t o t he 1 2 0
kDa major band. The lev els of pr ot ein and mRNA expr ession ar e congr uous. In human aut opsy
samples, ObR immunor eact iv it y is seen in chor oid plexus epit helium, ependy mal lining, neur ons of
t he hy pot halamic nuclei (ar cuat e, supr achiasmat ic, mamillar y , par av ent r icular , dor somedial,
supr aopt ic, and post er ior ), nucleus basalis of Mey ner t , infer ior oliv ar y nuclei, and cer ebellar
Pur kinje cells. The molecular weight s ar e 97 kDa and 1 2 5 kDa. Howev er , t her e was no significant
r egulat or y change by obesit y and diabet es in compar ison wit h lean subject s. Mor e r ecent ly ,
adv ances in t r ansgenic t echnology enabled a nov el appr oach t o gener at e a LepRb-IRES-Cr e EYFP
r epor t er mouse line. These mice hav e high lev els of ObRb mRNA/EYFP coexpr ession, including in
ar eas pr ev iously not shown t o hav e abundant ObR, such as t he dor somedial nucleus of t he
hy pot halamus, v ent r al pr emammillar y nucleus, v ent r al t egment al ar ea, par abr achial nucleus,
t he dor sal v agal complex, insular cor t ex, lat er al sept al nucleus, medial pr eopt ic ar ea, r ost r al linear
nucleus, t he Edinger West phal nucleus, and midbr ain. The t r ansgenic mice ar e t hus useful t o
locat e ObRb cells and st udy t heir r egulat or y changes.
Wit h r egar d t o t he cellular dist r ibut ion of ObR in t he br ain, chor oid plexus epit helia show a
het er ogeneous dist r ibut ion of st r ong immunor eact iv it y . This populat ion is pr obably r esponsible for
lept in t r anspor t acr oss t he bloodcer ebr ospinal fluid bar r ier . ObR mRNA is also seen in meninges
and blood v essels. Among CNS par enchy mal cells, neur ons ar e t he most st udied t ar get ; indeed,
lept in-induced immediat e ear ly gene c-Fos act iv at ion mainly r esides in neur ons, as seen in a st udy
focusing on hy pot halamus and br ainst em. Howev er , ObR mRNA is also seen in ast r ocy t es, as
fluor escent ISH wit h double-labeling immunost aining of glial fibr illar y acidic pr ot ein (GFAP) may
be colocalized in nor mal r at hy pot halamus. In t he ar cuat e nucleus of t he hy pot halamus, about
2 0% of ObR immunor eact iv it y is seen in GFAP ast r ocy t es, and t his is fur t her incr eased in mice
wit h adult -onset obesit y (Fig. 1 , modified fr om Ref. ), as will be fur t her discussed in t his r ev iew.
Young showed t hat ast r ocy t es hav e a specific anat omical r elat ionship wit h lept in-sensit iv e
neur ons. Lat er , t he dist r ibut ion and upr egulat ion of ast r ocy t ic ObR was shown in mouse models of
adult onset obesit y . Lept in can at t enuat e oligodendr ocy t e dev elopment embr y onically ,
pr omot e neur ospher e self-r enewal, incr ease angiogenesis aft er st r oke, and show r obust effect s
on micr oglial cy t okine pr oduct ion.
Fi gur e 1
Obesi ty changes the number of ObR cel l ty pes i n hy pothal ami c r egi ons. Upper panel : some ObR
cel l s ar e al so GFAP , shown by conf ocal i mages i n the ar cuate nucl eus of a B6 mal e mouse. Lower
panel : counti ng of demar cated r egi ons f r om i ndependent secti ons ...
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Extrahypothalamic actions of leptin in the brain
Besides it s effect on neur oendor ine r egulat ion of feeding, t he ext r ahy pot halamic act ions of lept in ar e
becoming incr easingly r ecognized. One major sit e of act ion is t he hippocampus. Lept in act iv at es
lar ge conduct ance Ca -act iv at ed K channels in t he hippocampus and pr omot es long-t er m
depr ession of excit at or y sy napt ic t r ansmission. Lept in may be neur ot ophic and pr omot e
neur ogenesis, and lept in deficient ob/ob mice show r educt ion of br ain size and neur on
number s as well as defect iv e glial and sy napt ic pr ot eins. Lept in also act s t hr ough ObR and
mit ogen-act iv at ed pr ot ein kinase (MAPK) t o facilit at e N-met hy l-D-aspar t at e (NMDA) r ecept or -
mediat ed Ca influx. This suggest s a pot ent ially delet er ious r ole of lept in signaling dur ing excess
excit at ion as seen in epilepsy .
Bot h ant i- and pr oconv ulsiv e r oles of lept in hav e been shown by sev er al gr oups. The ant iepilept ic
effect of lept in is seen in ob/ob mice, which hav e incr eased seizur e suscept ibilit y , and in t he
effect iv eness of int r anasal lept in t o decr ease seizur es. The pr oepilept ic effect is also well
char act er ized. Aft er int r acer ebr ov ent r icular inject ion, lept in has dose-dependent effect s t o
pot ent iat e penicillin-induced conv ulsion; lower doses (1 or 2 g) ar e most effect iv e, seen 90 min
aft er deliv er y t o t he r at , wher eas a high dose (1 0 g) has no effect . The pr oconv ulsiv e effect of
lept in appear s t o be mediat ed by t he NMDA r ecept or . The NMDA r ecept or mediat es t he lept in-
induced excit at or y effect by incr easing int r acellular calcium lev els and sy napt ic t r ansmission in
r at hippocampal slices and cell cult ur e. Nonet heless, t he same gr oup of r esear cher s showed t hat
lept in can also act t hr ough PI3 K and BK channels t o inhibit epilept ifor m-like act iv it y in neur ons.
These cont r adict or y findings for lept in may be r elat ed t o differ ent cellular effect s upon act iv at ion of
ast r ocy t es, micr oglia, or neur ons, as all t hr ee cell t y pes expr ess lept in r ecept or s.
Using a mouse model of epilepsy induced by pilocar pine, we det ect ed r obust upr egulat ion of ObR in
t he r eact iv e ast r ocy t es (Fig. 2 ). By cont r ast , neur onal ObR in t he hippocampus was only incr eased
wit h sev er e seizur es, as seen by high Racine scale scor es. In t he ast r ocy t e-specific lept in r ecept or
knockout (ALKO) mice gener at ed in our labor at or y , high-dose pilocar pine-induced seizur es had a
milder pr esent at ion, and t he acut e mor t alit y immediat ely aft er seizur e induct ion was r educed in
compar ison wit h t he wildt y pe lit t er mat es (Fig. 3 ). Bet t er sur v iv al and less sev er e seizur es in t he
ALKO mice in r esponse t o a high dose of pilocar pine suggest t hat ast r ocy t ic ObR is det r iment al t o
epilepsy .
Fi gur e 2
In the hi ppocampus of a mouse 6 weeks af ter pi l ocar pi ne-i nduced epi l epsy (l ower panel ), ther e i s
i ncr eased GFAP (r ed) and ObR (gr een) i mmunor eacti v i ty . Conf ocal col ocal i zati on shows that most
ObR i s pr esent i n astr ocy tes i n contr ol mi ce (upper panel ) ...
Fi gur e 3
Sei zur es wer e i nduced i n f emal e ALKO and l i tter mate contr ol s wi th a hi gh dose of pi l ocar pi ne
(350 mg/kg i .p., sev enf ol d mor e than the usual dose), 30 mi n af ter pr etr eatment wi th scopol ami ne
(1 mg/kg i .p.) to r educe per i pher al chol i ner gi c ef f ects. The ...
Wit h r egar d t o spat ial lear ning and cognit iv e funct ions, int r ahippocampal lept in administ er ed
immediat ely aft er t r aining impr ov es subsequent r et ent ion of T-maze foot shock av oidance and st ep-
down inhibit or y av oidance behav ior in nor mal CD1 mice, and has a beneficial effect on memor y
pr ocessing of t he SAMP8 mice wit h t heir spont aneously acceler at ed aging and elev at ed cer ebr al
amy loid pr ot ein. This is consist ent wit h a dose-dependent facilit at or y r ole of lept in in
hippocampal long-t er m pot ent iat ion. It r emains t o be det er mined how ast r ocy t ic and neur onal
lept in signaling int er act wit h each ot her in t he execut ion of nor mal and pat hophy siological
funct ions in t he hippocampus.
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Astrocytic leptin signaling in the brain regulates the development of obesity
It is now clear t hat adult -onset obesit y is associat ed wit h r egion-specific upr egulat ion of ast r ocy t ic
ObR, shown in bot h agout i v iable y ellow (A ) mice t hat hav e a genet ic mut at ion wit h const it ut iv e
pr oduct ion of a r ev er se melanocor t in r ecept or ant agonist and r educed appar ent influx of lept in
fr om blood t o t he br ain, and in cont r ol C5 7 mice wit h adult -onset obesit y . When ast r ocy t ic
act iv it y is inhibit ed by pr et r eat ment of t he A mice wit h fluor ocit r at e, int r acer ebr ov ent r icular
lept in-induced STAT3 act iv at ion is incr eased in neur ons, concur r ent wit h a higher signal int ensit y
of fluor escent ly conjugat ed lept in t aken up by per iv ent r icular neur ons. Ther e ar e a few
possibilit ies explaining how ObR ast r ocy t es may affect neur onal lept in signaling: (1 ) lev els of ObR
in ast r ocy t es affect lept in per meat ion acr oss t he BBB; (2 ) once lept in cr osses t he BBB, it r eaches
ast r ocy t es fir st but has a longer diffusion dist ance t o neur ons. Ast r ocy t ic ObR might compet e wit h
neur onal ObR for lept in endocy t osis, and (3 ) ast r ocy t es gener at e secondar y signals in r esponse t o
lept in, which, in t ur n, modulat es neur onal r esponses (t o lept in and t o ot her st imuli, Fig. 4).
Gliov ascular coupling (bet ween ast r ocy t es and BBB micr ov essels) and met abolic coupling (bet ween
ast r ocy t es and neur ons) ar e dy namic pr ocesses r esponsible for r egulat ion of cer ebr al blood flow and
met abolism. Lept in is not a v asoact iv e poly pept ide but pr obably can par t icipat e indir ect ly in t hese
pr ocesses.
Fi gur e 4
Possi bi l i ti es of how obesi ty acts thr ough the astr ocy ti c l epti n sy stem to modul ate neur onal
l epti n si gnal i ng. Metabol i c f actor s, i ncl udi ng l epti n i tsel f , may i nduce r eacti v e astr ogl i osi s and
i ncr ease astr ocy ti c ObR. Lepti n uptake and/or si gnal i ng by astr ocy tes ...
Ast r ocy t es expr ess sev er al ObR splice v ar iant s, including ObRa, ObRb, ObRc, and ObRe. The
pr esence of lept in signaling in ast r ocy t es is shown by an incr ease of calcium influx in pr imar y
ast r ocy t es aft er lept in super fusion dur ing r eal-t ime calcium imaging. To det er mine whet her t he
lev el and isofor ms of ObR in ast r ocy t es affect lept in per meat ion acr oss t he BBB, C6 ast r ocy t oma cells
wer e t r ansfect ed wit h differ ent ObR isofor ms befor e t hey wer e cocult ur ed wit h hCMEC/D3 cer ebr al
endot helial cells in a Tr answell sy st em. The apical-t o-basolat er al per meat ion of lept in in t he in vitro
BBB sy st em was unchanged when t he C6 cells ov er expr essed ObRa, but it was incr eased in C6 cells
ov er expr essing ObRb or ObRe. This appear s t o indicat e t hat alt er ed ast r ocy t ic lept in signaling
facilit at es lept in t r anspor t acr oss t he BBB. Howev er , new pr eliminar y dat a suggest t hat ObRa is t he
major for m of upr egulat ed ast r ocy t ic lept in r ecept or . Opposit ely , r emov al of ast r ocy t ic lept in
signaling does not hav e a significant effect on baseline t r anspor t of lept in acr oss t he BBB, since t he
newly gener at ed ALKO mice do not show a r educt ion of lept in t r anspor t acr oss t he BBB in
compar ison wit h t heir wildt y pe lit t er mat es. Of cour se, ALKO mice hav e an embr y onic absence of
ast r ocy t ic lept in r ecept or s, so t hat compensat or y mechanisms could hav e emer ged.
It is y et t o be det er mined whet her ast r ocy t ic lept in r ecept or expr ession or signaling compr omise t he
av ailabilit y of lept in t o ObR neur ons, or whet her secondar y signals fr om lept in modulat e neur onal
lept in act iv it ies. This can be achiev ed by use of a gene knockdown appr oach befor e cocult ur e of
ast r ocy t es and neur ons, or by compar ison of ast r ocy t es fr om ALKO or wild-t y pe mice on t heir effect s
on cocult ur ed neur ons. Nonet heless, in vivo inhibit ion of ast r ocy t ic met abolic act iv it y by
fluor ocit r at e has shown an incr ease of neur onal upt ake of lept in aft er int r acer ebr ov ent r icular
inject ion, accompanied by an elev at ion of STAT3 act iv at ion.
The bor der bet ween t he ar ea post r ema and nucleus t r act us solit ar ius and dor sal v agal complex in
t he caudal br ainst em consist s mainly of pallisading ast r ocy t es. The columnar cells compose a
cont inuous monolay er and ar e immunoposit iv e for bot h t he t ight junct ion pr ot ein zona occludin-1
and t he ast r ocy t e mar ker GFAP. These cells also expr ess ObRa and ObRf as well as ObRb in r at s;
t hey not only const it ut e a diffusion bar r ier t o fluor escent dy es aft er int r av enous or
int r acer ebr ov ent r icular inject ion, but also show upr egulat ion of t he ObR shor t for ms. This r eflect s
vy
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r egulat or y changes of lept in t r anspor t fr om blood t o t he medulla and per haps also ot her par t s of t he
br ainst em dur ing ener gy insufficiency . This impor t ant set of dat a is complement ar y t o t he r esult s
ident ify ing lept in r ecept or s in select iv e br ain r egions in mice wit h adult -onset obesit y , and
illust r at es an impor t ant r ole of ObR ast r ocy t es in t he blood-t o-CNS t r anspor t of lept in.
In t he nucleus t r act us solit ar ius, lept in play s an impor t ant r ole in r egulat ing aut onomic ner v ous
sy st em act iv it ies, including feeding, gast r ic mot ilit y , and t he hy per capnic v ent ilat or r esponse.
Lept in is closely associat ed wit h obst r uct iv e sleep apnea sy ndr ome, wher eas cont inuous posit iv e
air way pr essur e t r eat ment for 8 weeks r educes t he concent r at ion of lept in as well as t ot al
cholest er ol and low-densit y lipopr ot ein. It is int er est ing t o not e t hat obesit y at t enuat es t he clock
genes Bmal1 and Rev-erbalpha and upr egulat es per oxisome pr olifer at or -act iv at ed r ecept or alpha in
t his ar ea. Consist ent wit h t his, t her e is a cir cadian r hy t hm of lept in concent r at ion and lept in
t r anspor t acr oss t he BBB and bloodspinal cor d bar r ier , despit e par t ial sat ur at ion (Fig. 5 ). This
might be associat ed wit h a r ole of lept in in sleep r egulat ion, as lept in-deficient mice hav e impair ed
sleep wit h mor e ar ousals and shor t er sleep bout s despit e an incr ease in t he t ot al amount of nonr apid
ey e mov ement sleep.
Fi gur e 5
Lepti n pr oducti on and bl ood concentr ati on show a 24-h r hy thm that has a peak i n the ear l y
mor ni ng and nadi r i n l ate af ter noon i n mal e CD1 mi ce that al so show r hy thmi ci ty i n bl oodspi nal
cor d bar r i er tr anspor t but not bl oodbr ai n bar r i er ...
Ast r ocy t es ar e well posit ioned t o r egulat e sy napt ic t r ansmission and t he neur ov ascular net wor k. In
ast r ocy t es, gly cogen is met abolized int o lact at e, which is subsequent ly t r anspor t ed int o neur ons t o
ser v e as a st or ehouse for glucose for neur ons. Cholest er ol is also t r anspor t ed fr om ast r ocy t es t o
neur ons wher e it aids in sy napt ogenesis. Ast r ocy t ic act iv at ion induces t he accumulat ion of
ar achidonic acid and r elease of t he gliot r ansmit t er s glut amat e and adenosine-5 -t r iphosphat e
(ATP). The r ole of ast r ocy t es in met abolic coupling has been r ev iewed ext ensiv ely . In t he near
fut ur e, we shall hav e a bet t er under st anding of how lept in signaling cont r ibut es t o ast r ocy t e
neur onal communicat ion.
Summary
Though one of t he best known funct ions of lept in is r egulat ion of feeding behav ior , lept in also play s
essent ial r oles in t he r egulat ion of cer ebr al blood flow and met abolism, cell differ ent iat ion, cognit ion
and lear ning, and neur odegener at ion, wher e it may play dual r oles in st r oke or epilepsy . The
ext r ahy pot halamic dist r ibut ion and nonneur onal cellular dist r ibut ion of lept in for m a st r uct ur al
basis for it s pleiot r opic act ions. By illust r at ing how ast r ocy t ic lept in signaling facilit at es lept in
t r anspor t acr oss t he in vitro BBB and at t enuat es t he dev elopment of diet -induced obesit y in mice, we
hav e deduced a nov el r ole for t he ast r ocy t ic lept in sy st em in gliov ascular and met abolic coupling.
The ObR ast r ocy t es show dy namic changes in neur ological and met abolic disor der s, and ar e
int r icat ely linked t o CNS funct ions.
Acknowledgments
We t hank many past and cur r ent member s of t he BloodBr ain Bar r ier Gr oup in t he dev elopment of
ast r ocy t ic and endot helial lept in signaling pr oject s. This wor k was suppor t ed in par t by NIH Gr ant s
DK5 4880, DK92 2 45 , and NS62 2 91 .
Conflicts of interest
The aut hor s r epor t no conflict s of int er est .
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Article information
Ann N Y Acad Sci. 2012 August; 1264(1): 6471.
Published online 2012 April 24. doi: 10.1111/j.1749-6632.2012.06472.x
PMCID: PMC3407332
NIHMSID: NIHMS357925
Weihong Pan, Hung Hsuchou, Bhavaani Jayaram, Reas S Khan, Eagle Yi-Kung Huang, Xiaojun Wu, Chu Chen, and Abba J Kastin
Blood-Brain Barrier Group, Pennington Biomedical Research Center, Baton Rouge, Lousiana
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, Republic of China
Neuroscience Center of Excellence, Louisiana State University Health Science Center, New Orleans, Lousiana
Address for correspondence: Weihong Pan, M.D., Ph.D., Blood-Brain Barrier Group, Pennington Biomedical Research Center, 6400 Perkins Road, Baton
Rouge, LA 70808. Email: panw/at/pbrc.edu
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Copyright 2012 New York Academy of Sciences.
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