Blocking Mitochondrial Zn2+ Accumulation after Ischemia Reduces Mitochondrial Dysfunction and Neuronal Injury.

Zn²⁺ is an important contributor to ischemic brain injury, and recent studies support the hypothesis that mitochondria are key sites of its injurious effects. In murine hippocampal slices (both sexes) subjected to oxygen glucose deprivation (OGD), we found that Zn²⁺ accumulation and its entry into mitochondria precedes and contributes to the induction of acute neuronal death. In addition, if the ischemic episode is short (and sublethal), there is ongoing Zn²⁺ accumulation in CA1 mitochondria after OGD that may contribute to their delayed dysfunction. Using this slice model of sublethal OGD, we have examined Zn²⁺ contributions to the progression of changes evoked by OGD and occurring over 4-5 h. We detected progressive mitochondrial depolarization occurring from ~2 h after ischemia, a large increase in spontaneous synaptic activity between 2 and 3 h, and mitochondrial swelling and fragmentation at 4 h. Blockade of the primary route for Zn²⁺ entry, the mitochondrial Ca²⁺ uniporter (with ruthenium red [RR]) or Zn²⁺ chelation shortly after OGD withdrawal substantially attenuated the mitochondrial depolarization and the changes in synaptic activity. RR also largely reversed the mitochondrial swelling. Finally, using an in vivo rat (male) asphyxial cardiac arrest model of transient global ischemia, we found that ~8 min asphyxia induces considerable injury of CA1 neurons 4 h later that is associated with strong Zn²⁺ accumulation within many damaged mitochondria. These effects were substantially attenuated by infusion of RR on reperfusion. Our findings highlight mitochondrial Zn²⁺ accumulation after ischemia as a possible target for neuroprotective therapy. [ABSTRACT FROM AUTHOR]