TY - JOUR
T1 - The lipophilic zinc chelator DP-b99 prevents zinc induced neuronal death
AU - BarKalifa, Ronit
AU - Hershfinkel, Michal
AU - Friedman, Jonathan E.
AU - Kozak, Alex
AU - Sekler, Israel
N1 - Funding Information:
This work was partially supported by the Israel Science Foundation (grant #985/07 Dorot Foundation to IS). JEF and AK acknowledge support from the EU FP6 NeuroNE Network of Excellence for D-Pharm.
PY - 2009/9/15
Y1 - 2009/9/15
N2 - Zinc plays a key pathophysiological role in major neurological disorders as well as diabetes, while being essential for the activity of numerous zinc binding proteins. A major challenge in chelation based therapy must take into consideration these apparently conflicting effects of zinc. One approach is to limit the activity of the chelator to regions and levels of zinc pathology, making normal zinc-dependent processes invisible to the chelator. Combining fluorescent zinc imaging with cytotoxicity assays we studied the zinc chelation efficacy and neuroprotective effect of the lipophilic divalent transition metal chelator DP-b99 (1,2-Bis(2-amino-phenoxy)ethane-N,N,N′,N′-tetraacetic acid-N-N′-di[2-(octyloxy)ethyl ester],-N,N′-disodium salt). The affinity of DP-b99 to Zn2+ and Ca2+ ions is moderate in water and enhanced significantly in the lipid milieu. Application of DP-b99 to MIN6 β-cells that were preloaded with zinc was followed by a decrease in fluorescence of the intracellular Zn2+ sensitive dye, ZnAF-2DA, to resting levels. Preloading of MIN6 cells with DP-b99 was also effective in attenuating subsequent cellular zinc rise. Concentration-dependence analysis of zinc accumulation indicated that DP-b99 acts as a zinc chelator with moderate affinity. DP-b99 preapplication attenuated both Zn2+ and Ca2+ rise in neuronal cultures and also Zn2+ rise in brain slices. Finally, DP-b99 attenuated Zn2+-induced neuronal death. Our results indicate that DP-b99 is effective in attenuating Zn2+ and Ca2+ surges and protecting neurons against a toxic Zn2+-rise. This may underlie the efficacy of DP-b99 in stroke treatment.
AB - Zinc plays a key pathophysiological role in major neurological disorders as well as diabetes, while being essential for the activity of numerous zinc binding proteins. A major challenge in chelation based therapy must take into consideration these apparently conflicting effects of zinc. One approach is to limit the activity of the chelator to regions and levels of zinc pathology, making normal zinc-dependent processes invisible to the chelator. Combining fluorescent zinc imaging with cytotoxicity assays we studied the zinc chelation efficacy and neuroprotective effect of the lipophilic divalent transition metal chelator DP-b99 (1,2-Bis(2-amino-phenoxy)ethane-N,N,N′,N′-tetraacetic acid-N-N′-di[2-(octyloxy)ethyl ester],-N,N′-disodium salt). The affinity of DP-b99 to Zn2+ and Ca2+ ions is moderate in water and enhanced significantly in the lipid milieu. Application of DP-b99 to MIN6 β-cells that were preloaded with zinc was followed by a decrease in fluorescence of the intracellular Zn2+ sensitive dye, ZnAF-2DA, to resting levels. Preloading of MIN6 cells with DP-b99 was also effective in attenuating subsequent cellular zinc rise. Concentration-dependence analysis of zinc accumulation indicated that DP-b99 acts as a zinc chelator with moderate affinity. DP-b99 preapplication attenuated both Zn2+ and Ca2+ rise in neuronal cultures and also Zn2+ rise in brain slices. Finally, DP-b99 attenuated Zn2+-induced neuronal death. Our results indicate that DP-b99 is effective in attenuating Zn2+ and Ca2+ surges and protecting neurons against a toxic Zn2+-rise. This may underlie the efficacy of DP-b99 in stroke treatment.
KW - Heavy metal toxicity
KW - Lipophilic chelator
KW - Stroke
KW - Zinc and neuronal cell death
KW - Zinc chelation
KW - Zinc homeostasis
UR - http://www.scopus.com/inward/record.url?scp=69249208456&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2009.07.019
DO - 10.1016/j.ejphar.2009.07.019
M3 - Article
AN - SCOPUS:69249208456
SN - 0014-2999
VL - 618
SP - 15
EP - 21
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -
