Zinc translocation accelerates infarction after mild transient focal ischemia

Neuroscience. 2002;115(3):871-8. doi: 10.1016/s0306-4522(02)00513-4.

Abstract

Excess release of chelatable zinc (Zn(2+)) from central synaptic vesicles may contribute to the pathogenesis of selective neuronal cell death following transient forebrain ischemia, but a role in neurodegeneration after focal ischemia has not been defined. Adult male Long-Evans rats subjected to middle cerebral artery occlusion (MCAO) for 30 min followed by reperfusion developed delayed cerebral infarction reaching completion 3 days after the insult. One day after the insult, many degenerating cerebral neurons exhibited increased intracellular Zn(2+), and some labeled with the antibody against activated caspase-3. I.c.v. administration of the Zn(2+) chelator, EDTA saturated with equimolar Ca(2+) (CaEDTA), 15 min prior to ischemia attenuated subsequent Zn(2+) translocation into cortical neurons, and reduced infarct volume measured 3 days after ischemia. Although the protective effect of CaEDTA at this endpoint was substantial (about 70% infarct reduction), it was lost when insult severity was increased (from 30 to 60 min MCAO), or when infarct volume was measured at a much later time point (14 days instead of 3 days after ischemia). These data suggest that toxic Zn(2+) translocation, from presynaptic terminals to post-synaptic cell bodies, may accelerate the development of cerebral infarction following mild transient focal ischemia.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminoquinolines
  • Animals
  • Caspase 3
  • Caspases / metabolism
  • Cerebral Infarction / metabolism*
  • Cerebral Infarction / pathology
  • Cerebral Infarction / physiopathology
  • Chelating Agents / pharmacology
  • Fluorescent Dyes
  • Immunohistochemistry
  • Ischemic Attack, Transient / metabolism*
  • Ischemic Attack, Transient / pathology
  • Ischemic Attack, Transient / physiopathology
  • Male
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Neurons / metabolism*
  • Neurons / pathology
  • Presynaptic Terminals / metabolism
  • Rats
  • Rats, Long-Evans
  • Synaptic Transmission / physiology
  • Telencephalon / metabolism*
  • Telencephalon / pathology
  • Telencephalon / physiopathology
  • Tosyl Compounds
  • Zinc / metabolism*

Substances

  • Aminoquinolines
  • Chelating Agents
  • Fluorescent Dyes
  • Tosyl Compounds
  • N-(6-methoxy-8-quinolyl)-4-toluenesulfonamide
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Zinc