PMID- 21562076
OWN - NLM
STAT- MEDLINE
DCOM- 20110711
LR  - 20211020
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 60
IP  - 6
DP  - 2011 Jun
TI  - Decreased cerebrovascular brain-derived neurotrophic factor-mediated 
      neuroprotection in the diabetic brain.
PG  - 1789-96
LID - 10.2337/db10-1371 [doi]
AB  - OBJECTIVE: Diabetes is an independent risk factor for stroke. However, the 
      underlying mechanism of how diabetes confers that this risk is not fully 
      understood. We hypothesize that secretion of neurotrophic factors by the cerebral 
      endothelium, such as brain-derived neurotrophic factor (BDNF), is suppressed in 
      diabetes. Consequently, such accrued neuroprotective deficits make neurons more 
      vulnerable to injury. RESEARCH DESIGN AND METHODS: We examined BDNF protein 
      levels in a streptozotocin-induced rat model of diabetes by Western blotting and 
      immunohistochemistry. Levels of total and secreted BDNF protein were quantified 
      in human brain microvascular endothelial cells after exposure to advanced 
      glycation end product (AGE)-BSA by enzyme-linked immunosorbent assay and 
      immunocytochemistry. In media transfer experiments, the neuroprotective efficacy 
      of conditioned media from normal healthy endothelial cells was compared with 
      AGE-treated endothelial cells in an in vitro hypoxic injury model. RESULTS: 
      Cerebrovascular BDNF protein was reduced in the cortical endothelium in 6-month 
      diabetic rats. Immunohistochemical analysis of 6-week diabetic brain sections 
      showed that the reduction of BDNF occurs early after induction of diabetes. 
      Treatment of brain microvascular endothelial cells with AGE caused a similar 
      reduction in BDNF protein and secretion in an extracellular signal-related 
      kinase-dependent manner. In media transfer experiments, conditioned media from 
      AGE-treated endothelial cells were less neuroprotective against hypoxic injury 
      because of a decrease in secreted BDNF. CONCLUSIONS: Taken together, our findings 
      suggest that a progressive depletion of microvascular neuroprotection in diabetes 
      elevates the risk of neuronal injury for a variety of central nervous system 
      diseases, including stroke and neurodegeneration.
FAU - Navaratna, Deepti
AU  - Navaratna D
AD  - Neuroprotection Research Laboratory, Massachusetts GeneralHospital, Harvard 
      Medical School, Charlestown, Massachusetts, USA.
FAU - Guo, Shu-Zhen
AU  - Guo SZ
FAU - Hayakawa, Kazhuhide
AU  - Hayakawa K
FAU - Wang, Xiaoying
AU  - Wang X
FAU - Gerhardinger, Chiara
AU  - Gerhardinger C
FAU - Lo, Eng H
AU  - Lo EH
LA  - eng
GR  - R01-NS-56530/NS/NINDS NIH HHS/United States
GR  - RC2-NS-69335/NS/NINDS NIH HHS/United States
GR  - R37 NS037074/NS/NINDS NIH HHS/United States
GR  - P01-NS-55014/NS/NINDS NIH HHS/United States
GR  - RC2 NS069335/NS/NINDS NIH HHS/United States
GR  - R37-NS-37074/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110511
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Glycation End Products, Advanced)
RN  - 0 (advanced glycation end products-bovine serum albumin)
RN  - 27432CM55Q (Serum Albumin, Bovine)
SB  - IM
MH  - Animals
MH  - Brain/drug effects/*metabolism
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Experimental/*metabolism
MH  - Endothelium/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Glycation End Products, Advanced/pharmacology
MH  - Humans
MH  - Immunoblotting
MH  - Immunochemistry
MH  - Male
MH  - Rats
MH  - Serum Albumin, Bovine/pharmacology
MH  - Signal Transduction/drug effects
PMC - PMC3114398
EDAT- 2011/05/13 06:00
MHDA- 2011/07/12 06:00
PMCR- 2012/06/01
CRDT- 2011/05/13 06:00
PHST- 2011/05/13 06:00 [entrez]
PHST- 2011/05/13 06:00 [pubmed]
PHST- 2011/07/12 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - db10-1371 [pii]
AID - 1371 [pii]
AID - 10.2337/db10-1371 [doi]
PST - ppublish
SO  - Diabetes. 2011 Jun;60(6):1789-96. doi: 10.2337/db10-1371. Epub 2011 May 11.