Yongmei Zhao1, Rong Pan, Sen Li, Yumin Luo, Feng Yan, Jie Yin, Zhifeng Qi, Ying Yan, Xunming Ji, Ke Jian Liu. 1. 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.).
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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 occlusionrats, 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: Miguel Mendivil-Perez; Carlos Velez-Pardo; Gloria E David-Yepes; Javier E Fox; Marlene Jimenez-Del-Rio Journal: Biometals Date: 2020-10-24 Impact factor: 2.949
Authors: Rong Pan; Song Yu; Haikun Zhang; Graham S Timmins; John Weaver; Yirong Yang; Xixi Zhou; Ke Jian Liu Journal: J Cereb Blood Flow Metab Date: 2021-06-29 Impact factor: 6.960