PMID- 22886392
OWN - NLM
STAT- MEDLINE
DCOM- 20130517
LR  - 20211021
IS  - 1573-4919 (Electronic)
IS  - 0300-8177 (Print)
IS  - 0300-8177 (Linking)
VI  - 371
IP  - 1-2
DP  - 2012 Dec
TI  - Homocysteine alters cerebral microvascular integrity and causes remodeling by 
      antagonizing GABA-A receptor.
PG  - 89-96
LID - 10.1007/s11010-012-1425-5 [doi]
AB  - High levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), are 
      associated with cerebrovascular diseases, such as vascular dementia, stroke, and 
      Alzheimer's disease. The gamma-amino butyric acid (GABA) is an inhibitory 
      neurotransmitter and a ligand of GABA-A receptor. By inhibiting excitatory 
      response, it may decrease complications associated with vascular dementia and 
      stroke. Hcy specifically competes with the GABA-A receptors and acts as an 
      excitotoxic neurotransmitter. Previously, we have shown that Hcy increases levels 
      of NADPH oxidase and reactive oxygen species (ROS), and decreases levels of 
      thioredoxin and peroxiredoxin by antagonizing the GABA-A receptor. Hcy treatment 
      leads to activation of matrix metalloproteinases (MMPs) in cerebral circulation 
      by inducing redox stress and ROS. The hypothesis is that Hcy induces MMPs and 
      suppresses tissue inhibitors of metalloproteinase (TIMPs), in part, by inhibiting 
      the GABA-A receptor. This leads to degradation of the matrix and disruption of 
      the blood brain barrier. The brain cortex of transgenic mouse model of HHcy 
      (cystathionine beta-synthase, CBS-/+) and GABA-A receptor null mice treated with and 
      without muscimol (GABA-A receptor agonist) was analysed. The mRNA levels were 
      measured by Q-RT-PCR. Levels of MMP-2, -9, -13, and TIMP-1, -2, -3, and -4 were 
      evaluated by in situ labeling and PCR-gene arrays. Pial venular permeability to 
      fluorescence-labeled albumin was assessed with intravital fluorescence 
      microscopy. We found that Hcy increases metalloproteinase activity and decreases 
      TIMP-4 by antagonizing the GABA-A receptor. The results demonstrate a novel 
      mechanism in which brain microvascular permeability changes during HHcy and 
      vascular dementias, and have therapeutic ramifications for microvascular disease 
      in Alzheimer's patients.
FAU - Lominadze, David
AU  - Lominadze D
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Bldg. A, Room 1115, 500 South Preston Street, Louisville, KY 40202, 
      USA. david.lominadze@louisville.edu
FAU - Tyagi, Neetu
AU  - Tyagi N
FAU - Sen, Utpal
AU  - Sen U
FAU - Ovechkin, Alexander
AU  - Ovechkin A
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - HL-80394/HL/NHLBI NIH HHS/United States
GR  - R01 HL080394/HL/NHLBI NIH HHS/United States
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - R01 NS051568/NS/NINDS NIH HHS/United States
GR  - NS-51568/NS/NINDS NIH HHS/United States
GR  - HL-71010/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120812
PL  - Netherlands
TA  - Mol Cell Biochem
JT  - Molecular and cellular biochemistry
JID - 0364456
RN  - 0 (GABA-A Receptor Agonists)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 2763-96-4 (Muscimol)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
MH  - Animals
MH  - Blood-Brain Barrier/metabolism
MH  - *Capillary Permeability
MH  - Cerebrovascular Circulation/physiology
MH  - Cystathionine beta-Synthase/metabolism
MH  - GABA-A Receptor Agonists
MH  - Homocysteine/*metabolism/pharmacology
MH  - Hyperhomocysteinemia/metabolism
MH  - Matrix Metalloproteinases/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Muscimol/pharmacology
MH  - Receptors, GABA-A/*metabolism
MH  - Tissue Inhibitor of Metalloproteinases/metabolism
PMC - PMC3484206
MID - NIHMS400373
EDAT- 2012/08/14 06:00
MHDA- 2013/05/18 06:00
PMCR- 2013/12/01
CRDT- 2012/08/14 06:00
PHST- 2012/04/05 00:00 [received]
PHST- 2012/08/01 00:00 [accepted]
PHST- 2012/08/14 06:00 [entrez]
PHST- 2012/08/14 06:00 [pubmed]
PHST- 2013/05/18 06:00 [medline]
PHST- 2013/12/01 00:00 [pmc-release]
AID - 10.1007/s11010-012-1425-5 [doi]
PST - ppublish
SO  - Mol Cell Biochem. 2012 Dec;371(1-2):89-96. doi: 10.1007/s11010-012-1425-5. Epub 
      2012 Aug 12.