title: Chelating intracellularly accumulated zinc decreased ischemic brain injury through reducing neuronal apoptotic death.
abstract: OBJECTIVE
  Zinc has been reported to possess both neurotoxic and neuroprotective capabilities. The effects of elevated intracellular zinc accumulation following transient focal cerebral ischemia remain to be fully elucidated. Here, we investigated whether removing zinc with the membrane-permeable zinc chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), would decrease the intracellular levels of zinc in the ischemic tissue, leading to reduced brain damage and improved neurological outcomes.
  
  
  METHODS
  Rats were pretreated with TPEN or vehicle before or after a 90-minute middle cerebral artery occlusion. Cerebral infarct volume, neurological functions, neuronal apoptosis, poly(ADP-ribose) polymerase activity, and cytosolic labile zinc were assessed after ischemia and reperfusion.
  
  
  RESULTS
  Cerebral ischemia caused a dramatic cytosolic labile zinc accumulation in the ischemic tissue, which was decreased markedly by TPEN (15 mg/kg) pretreatment. Chelating zinc lead to reduced infarct volume compared with vehicle-treated middle cerebral artery occlusion rats, accompanied by much improved neurological assessment and motor function, which were sustained for 14 days after reperfusion. We also determined that reducing zinc accumulation rescued neurons from ischemia-induced apoptotic death by reducing poly(ADP-ribose) polymerase-1 activation.
  
  
  CONCLUSIONS
  Ischemia-induced high accumulation of intracellular zinc significantly contributed to ischemic brain damage through promotion of neuronal apoptotic death. Removing zinc may be an effective and novel approach to reduce ischemic brain injury.
authors.affiliation: From the Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China (Y.Z., S.L., Y.L., F.Y., J.Y., Z.Q., Y.Y., X.J.); Beijing Geriatric Medical Research Center, Beijing, China (Y.Z., S.L., Y.L., F.Y., Z.Q., Y.Y., X.J.); Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China (Y.Z., Y.L., F.Y., J.Y., Z.Q., X.J.); Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (Y.Z., Y.L., F.Y., J.Y., Z.Q., X.J.); and Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque (R.P., K.J.L.).
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rong
authors.initials: R
authors.lastname: Pan
authors.forename: Sen
authors.initials: S
authors.lastname: Li
authors.forename: Yumin
authors.initials: Y
authors.lastname: Luo
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Qi
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002614:Chelating Agents / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D005029:Ethylenediamines / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D005029:Ethylenediamines; D018696:Neuroprotective Agents; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: brain ischemia; infarction, middle cerebral artery; poly(ADP-ribose) polymerases; zinc