Astrocytes are more resistant than neurons to the cytotoxic effects of increased [Zn(2+)](i).
Increased intracellular free Zn(2+) ([Zn(2+)](i)) is toxic to neurons. Glia are more resistant to Zn(2+)-mediated toxicity; however, it is not known if this is because glia are less permeable to Zn(2+) or if glia possess intrinsic mechanisms that serve to buffer or extrude excess [Zn(2+)](i). We used the Zn(2+)-selective ionophore pyrithione to directly increase [Zn(2+)](i) in both neurons and astrocytes. In neurons, a 5-min exposure to 1 microM extracellular Zn(2+) in combination with pyrithione produced widespread toxicity, whereas extensive astrocyte injury was not observed until extracellular Zn(2+) was increased to 10 microM. Measurements with magfura-2 demonstrated that pyrithione increased [Zn(2+)](i) to similar levels in both cell types. We also measured how increased [Zn(2+)](i) affects mitochondrial membrane potential (Deltapsi(m)). In astrocytes, but not in neurons, toxic [Zn(2+)](i) resulted in an acute loss of Deltapsi(m), suggesting that mitochondrial dysregulation may be an early event in [Zn(2+)](i)-induced astrocyte but not neuronal death.
Dineley
K E
KE
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261, USA.
Scanlon
J M
JM
Kress
G J
GJ
Stout
A K
AK
Reynolds
I J
IJ
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D016257:Fura-2 / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D007425:Intracellular Membranes / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D016548:Prosencephalon; D051381:Rats; D015032:Zinc / Q000633:toxicity*
D005456:Fluorescent Dyes; C058776:2-(2-(5-carboxy)oxazole)-5-hydroxy-6-aminobenzofuran-N,N,O-triacetic acid; D015032:Zinc; D016257:Fura-2