PMID- 22331300
OWN - NLM
STAT- MEDLINE
DCOM- 20120913
LR  - 20211021
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 21
IP  - 10
DP  - 2012 May 15
TI  - The blood-brain barrier is disrupted in a mouse model of infantile neuronal 
      ceroid lipofuscinosis: amelioration by resveratrol.
PG  - 2233-44
LID - 10.1093/hmg/dds038 [doi]
AB  - Disruption of the blood-brain barrier (BBB) is a serious complication frequently 
      encountered in neurodegenerative disorders. Infantile neuronal ceroid 
      lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal 
      storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It 
      remains unclear whether BBB is disrupted in INCL and if so, what might be the 
      molecular mechanism(s) of this complication. We previously reported that the 
      Ppt1-knockout (Ppt1-KO) mice that mimic INCL manifest high levels of oxidative 
      stress and neuroinflammation. Recently, it has been reported that CD4(+) T-helper 
      17 (T(H)17) lymphocytes may mediate BBB disruption and neuroinflammation, 
      although the precise molecular mechanism(s) remain unclear. We sought to 
      determine: (i) whether the BBB is disrupted in Ppt1-KO mice, (ii) if so, do 
      T(H)17-lymphocytes underlie this complication, and (iii) how might T(H)17 
      lymphocytes breach the BBB. Here, we report that the BBB is disrupted in Ppt1-KO 
      mice and that T(H)17 lymphocytes producing IL-17A mediate disruption of the BBB 
      by stimulating production of matrix metalloproteinases (MMPs), which degrade the 
      tight junction proteins essential for maintaining BBB integrity. Importantly, 
      dietary supplementation of resveratrol (RSV), a naturally occurring 
      antioxidant/anti-inflammatory polyphenol, markedly reduced the levels of T(H)17 
      cells, IL-17A and MMPs, and elevated the levels of tight junction proteins, which 
      improved the BBB integrity in Ppt1-KO mice. Intriguingly, we found that RSV 
      suppressed the differentiation of CD4(+) T lymphocytes to IL-17A-positive T(H)17 
      cells. Our findings uncover a mechanism by which T(H)17 lymphocytes mediate BBB 
      disruption and suggest that small molecules such as RSV that suppress T(H)17 
      differentiation are therapeutic targets for neurodegenerative disorders such as 
      INCL.
FAU - Saha, Arjun
AU  - Saha A
AD  - Section on Developmental Genetics, Program on Endocrinology and Genetics, Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development, 
      Bethesda, MD 20892-1830, USA.
FAU - Sarkar, Chinmoy
AU  - Sarkar C
FAU - Singh, Satya P
AU  - Singh SP
FAU - Zhang, Zhongjian
AU  - Zhang Z
FAU - Munasinghe, Jeeva
AU  - Munasinghe J
FAU - Peng, Shiyong
AU  - Peng S
FAU - Chandra, Goutam
AU  - Chandra G
FAU - Kong, Eryan
AU  - Kong E
FAU - Mukherjee, Anil B
AU  - Mukherjee AB
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20120213
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Stilbenes)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
RN  - Q369O8926L (Resveratrol)
SB  - IM
MH  - Animals
MH  - Blood-Brain Barrier/*metabolism
MH  - Brain/metabolism/pathology
MH  - Disease Models, Animal
MH  - Enzyme Inhibitors/*pharmacology
MH  - *Mice
MH  - Mice, Knockout
MH  - Neuronal Ceroid-Lipofuscinoses/enzymology/*metabolism
MH  - Resveratrol
MH  - Stilbenes/*pharmacology
MH  - Thiolester Hydrolases/*genetics/metabolism
PMC - PMC3335311
EDAT- 2012/02/15 06:00
MHDA- 2012/09/14 06:00
PMCR- 2013/05/15
CRDT- 2012/02/15 06:00
PHST- 2012/02/15 06:00 [entrez]
PHST- 2012/02/15 06:00 [pubmed]
PHST- 2012/09/14 06:00 [medline]
PHST- 2013/05/15 00:00 [pmc-release]
AID - dds038 [pii]
AID - 10.1093/hmg/dds038 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2012 May 15;21(10):2233-44. doi: 10.1093/hmg/dds038. Epub 2012 Feb 
      13.