Complex role of zinc in methamphetamine toxicity in vitro.
Methamphetamine is a drug of abuse that can induce oxidative stress and neurotoxicity to dopaminergic neurons. We have previously reported that oxidative stress promotes the liberation of intracellular Zn(2+) from metal-binding proteins, which, in turn, can initiate neuronal injurious signaling processes. Here, we report that methamphetamine mobilizes Zn(2+) in catecholaminergic rat pheochromocytoma (PC12) cells, as measured by an increase in Zn(2+)-regulated gene expression driven by the metal response element transcription factor-1. Moreover, methamphetamine-liberated Zn(2+) was responsible for a pronounced enhancement in voltage-dependent K(+) currents in these cells, a process that normally accompanies Zn(2+)-dependent cell injury. Overnight exposure to methamphetamine induced PC12 cell death. This toxicity could be prevented by the cell-permeant zinc chelator N,N,N', N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), and by over-expression of the Zn(2+)-binding protein metallothionein 3 (MT3), but not by tricine, an extracellular Zn(2+) chelator. The toxicity of methamphetamine to PC12 cells was enhanced by the presence of co-cultured microglia. Remarkably, under these conditions, TPEN no longer protected but, in fact, dramatically exacerbated methamphetamine toxicity, tricine again being without effect. Over-expression of MT3 in PC12 cells did not mimic these toxicity-enhancing actions of TPEN, suggesting that the chelator affected microglial function. Interestingly, P2X receptor antagonists reversed the toxicity-enhancing effect of TPEN. As such, endogenous levels of intracellular Zn(2+) may normally interfere with the activation of P2X channels in microglia. We conclude that Zn(2+) plays a significant but complex role in modulating the cellular response of PC12 cells to methamphetamine exposure in both the absence and presence of microglia.
Aizenman
E
E
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. redox@pitt.edu
McCord
M C
MC
Saadi
R A
RA
Hartnett
K A
KA
He
K
K
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005029:Ethylenediamines / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D000090023:Metallothionein 3; D008694:Methamphetamine / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016716:PC12 Cells; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D014131:Trace Elements / Q000494:pharmacology*; D014162:Transfection; D015032:Zinc / Q000378:metabolism*
D000697:Central Nervous System Stimulants; D002800:Cholinesterase Inhibitors; D005029:Ethylenediamines; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D014131:Trace Elements; D049452:Green Fluorescent Proteins; D008694:Methamphetamine; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D005998:Glycine; C100184:tricine
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