• E Aizenman, M C McCord, R A Saadi, K A Hartnett, and K He.
• Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. redox@pitt.edu
• Neuroscience. 2010 Nov 24; 171 (1): 313931-9.

AbstractMethamphetamine 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.Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

40 keywords...

hide…