title: Decreased cerebrovascular brain-derived neurotrophic factor-mediated neuroprotection in the diabetic brain.
abstract: 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.
  
  
  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.
authors.affiliation: Neuroprotection Research Laboratory, Massachusetts GeneralHospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Navaratna
authors.forename: Shu-Zhen
authors.initials: SZ
authors.lastname: Guo
authors.forename: Kazhuhide
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.forename: Chiara
authors.initials: C
authors.lastname: Gerhardinger
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007120:Immunochemistry; D008297:Male; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017127:Glycation End Products, Advanced; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine