title: Endothelial nitric oxide synthase protects neurons against ischemic injury through regulation of brain-derived neurotrophic factor expression.
abstract: OBJECTIVE
  Several lines of evidence demonstrated that endothelial nitric oxide synthase (eNOS) confers protective effects during cerebral ischemia. In this study, we explored the underlying cellular and molecular mechanisms of neuroprotection by eNOS.
  
  
  METHODS
  A series of in vivo and in vitro ischemic models were employed to study the role of eNOS in maintaining neuronal survival and to identify the downstream factors.
  
  
  RESULTS
  The current data showed that pretreatment with a specific eNOS inhibitor, L-N5-(1-iminoethyl) ornithine (L-NIO), aggravated the neuronal loss in the rat cerebral ischemic model, accompanied by reduction in brain-derived neurotrophic factor (BDNF) level, which was consistent with the findings in an oxygen-glucose deprivation model (OGD) with two neuronal cells: primary rat cortical neurons and human neuroblastoma SH-SY5Y cells. Furthermore, the extensive neuronal loss induced by L-NIO was totally abolished by exogenous BDNF in both in vitro and in vivo models. On the other hand, eNOS overexpression through an adenoviral vector exerted a prominent protective effect on the neuronal cells subject to OGD, and the protective effect was totally abrogated by a neutralizing anti-BDNF antibody.
  
  
  CONCLUSIONS
  Collectively, our results indicate that the neuroprotection of neuron-derived eNOS against the cerebral ischemia was mediated through the regulation of BDNF secretion. In conclusion, our discovery provides a novel explanation for the neuroprotective effect of eNOS under pathological ischemic conditions such as stroke.
authors.affiliation: Department of Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Shi-Ting
authors.initials: ST
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.forename: Xu-Ming
authors.initials: XM
authors.lastname: Hua
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Sa
authors.initials: S
authors.lastname: Shen
authors.forename: Jia-Fu
authors.initials: JF
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Bang-Bao
authors.initials: BB
authors.lastname: Tao
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Ge
authors.forename: Xu-Hui
authors.initials: XH
authors.lastname: Wang
authors.forename: Juan-Hong
authors.initials: JH
authors.lastname: Shi
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000276:immunology / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D006801:Humans; D000860:Hypoxia / Q000473:pathology / Q000517:prevention & control; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000276:immunology / Q000378:metabolism*; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000906:Antibodies; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; C065027:N(G)-iminoethylornithine; D009952:Ornithine; D052250:Nitric Oxide Synthase Type III; D053148:Caspase 3; D005947:Glucose
keywords: Brain-derived neurotrophic factor; Endothelial nitric oxide synthase; Ischemia/reperfusion; Nitric oxide