Elevated intracellular free Zn2+ concentrations ([Zn2+]i) have been implicated in the neuronal death caused by stroke. Therefore, a therapy that restores low [Zn2+]i has the potential to improve the outcome of stroke. The goal of proposed research is to design such a therapy. Preliminary studies on hippocampal neurons indicate that an intracellular acidification similar to that taking place during stroke causes [Zn2+]i elevations due to Zn2+ release from intracellular stores. We will determine the role of low affinity Zn2+ ligands, such as adenine nucleotides, in these [Zn2+]i elevations and establish whether neuronal viability can be improved by a specific chelation of acid-induced [Zn2+]i elevations. In particular, we will design a method of Zn2+ chelation that specifically targets these acid-induced [Zn2+]i elevations. The research will be conducted on primary hippocampal neurons from mice.
Aim 1 will clarify which low affinity intracellular Zn2+ ligands release this ion when the pH drops into a stroke-characteristic range.
In Aim 2, a method will be developed to specifically chelate acid-induced [Zn2+]i elevations.
Aim 3 will determine whether this method of Zn2+ chelation improves the viability of neurons exposed to oxygen and glucose-deprivation. If it does, our method will provide a framework for the development of therapy that counteracts excessive [Zn2+]i elevations during stroke.

Public Health Relevance

The acidification taking place during stroke compromises neuronal viability via mechanisms that are as yet unclear. The proposed research addresses these mechanisms and tests a novel approach to develop therapies to counteract acidification-induced neuronal death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082786-01A1
Application #
8638191
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2013-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$184,500
Indirect Cost
$59,500
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Kiedrowski, Lech (2014) Proton-dependent zinc release from intracellular ligands. J Neurochem 130:87-96