Article

Intracellular zinc release and ERK phosphorylation are required upstream of 12-lipoxygenase activation in peroxynitrite toxicity to mature rat oligodendrocytes

Harvard University, Cambridge, Massachusetts, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 05/2006; 281(14):9460-70. DOI: 10.1074/jbc.M510650200
Source: PubMed

ABSTRACT Peroxynitrite toxicity has been implicated in the pathogenesis of white matter injury. The mechanisms of peroxynitrite toxicity to oligodendrocytes (OLs), the major cell type of the white matter, are unknown. Using primary cultures of mature OLs that express myelin basic protein, we found that 3-morpholinosydnonimine, a peroxynitrite generator, caused toxicity to OLs. N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine, a zinc chelator, completely blocked peroxynitrite-induced toxicity. Use of FluoZin-3, a specific fluorescence zinc indicator, demonstrated the liberation of zinc from intracellular stores by peroxynitrite. Peroxynitrite caused the sequential activation of extracellular signal-regulated kinase 42/44 (ERK42/44), 12-lipoxygenase, and generation of reactive oxygen species, which were all dependent upon the intracellular release of zinc. The same cell death pathway was also activated when exogenous zinc was used. These results suggest that in addition to preventing the formation of peroxynitrite, useful strategies in preventing disease progression in pathologies in which peroxynitrite toxicity plays a critical role might include maintaining intracellular zinc homeostasis, blocking phosphorylation of ERK42/44, inhibiting activation of 12-lipoxygenase, and eliminating the accumulation of reactive oxygen species.

Download full-text

Full-text

Available from: Jianrong Li, Jul 27, 2015
0 Followers
 · 
68 Views
  • Source
    • "We previously reported that glutamate receptor overactivation in oligodendrocytes induces rapid activation of ERK1/2 signaling and increased Dusp6 phosphatase expression, and that levels of phosphorylated ERK1 and 2 (pERK1/2)—which are controlled by Dusp6 phosphatase levels—are pivotal in determining cell death or survival (Domercq et al., 2011). ERK activation could be induced by a cytosolic Zn 21 increase (Zhang et al., 2006) since AMPA/kainate receptors are also permeable to Zn 21 (Sensi et al., 2009). ERK1/2 activation acts as a pro-survival signal in oligodendrocytes through its actions at different steps of the mitochondrial apoptotic pathway and by controlling AMPA receptor permeability (Domercq et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Much of the cell death following episodes of anoxia and ischemia in the mammalian central nervous system has been attributed to extracellular accumulation of glutamate and ATP, which causes a rise in [Ca(2+) ](i) , loss of mitochondrial potential, and cell death. However, restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury (the oxygen paradox). Herein we describe a novel signaling pathway that is activated during ischemia-like conditions (oxygen and glucose deprivation; OGD) and contributes to ischemia-induced oligodendroglial cell death. OGD induced a retarded and sustained increase in extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation after restoring glucose and O(2) (reperfusion-like conditions). Blocking the ERK1/2 pathway with the MEK inhibitor UO126 largely protected oligodendrocytes against ischemic insults. ERK1/2 activation was blocked by the high-affinity Zn(2+) chelator TPEN, but not by antagonists of AMPA/kainate or P2X7 receptors that were previously shown to be involved in ischemic oligodendroglial cell death. Using a high-affinity Zn(2+) probe, we showed that ischemia induced an intracellular Zn(2+) rise in oligodendrocytes, and that incubation with TPEN prevented mitochondrial depolarization and ROS generation after ischemia. Accordingly, exposure to TPEN and the antioxidant Trolox reduced ischemia-induced oligodendrocyte death. Moreover, UO126 blocked the ischemia-induced increase in poly-[ADP]-ribosylation of proteins, and the poly[ADP]-ribose polymerase 1 (PARP-1) inhibitor DPQ significantly inhibited ischemia-induced oligodendroglial cell death-demonstrating that PARP-1 was required downstream in the Zn(2+) -ERK oligodendrocyte cell death pathway. Chelation of cytosolic Zn(2+) , blocking ERK signaling, and antioxidants may be beneficial for treating CNS white matter ischemia-reperfusion injury. Importantly, all the inhibitors of this pathway protected oligodendrocytes when applied after the ischemic insult. © 2012 Wiley Periodicals, Inc.
    Glia 03/2013; 61(3). DOI:10.1002/glia.22441 · 6.03 Impact Factor
  • Source
    • "(Zhang et al., 2006 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Zinc ion elevation contributes to acute excitotoxic brain injury and correlates with the severity of dementia in chronic neurodegenerative diseases. Downstream control of zinc-triggered signals is believed to be an efficient countermeasure. In the current study, we examined whether the flavonoid luteolin (Lu) could protect human neuroblastoma SH-SY5Y cells against zinc toxicity. We found that Lu suppressed overproduction of reactive oxygen species and protected against apoptotic cell death induced by zinc. By using specific inhibitors, we found that zinc strongly triggered Akt and ERK1/2 activation via a PI3K-Akt-NF-κB-ERK1/2-dependent pathway. Furthermore, Lu completely blocked this activation. Our study strongly supports the hypothesis that Lu might protect SH-SY5Y cells against ROS-mediated apoptotic cell death induced by zinc in part by inhibiting the PI3K-Akt-NF-κB-ERKs pathway.
    Journal of Neuroscience Research 11/2011; 89(11):1859-68. DOI:10.1002/jnr.22714 · 2.73 Impact Factor
  • Source
    • "Therefore, the inhibitory action of nitric oxide on 12-LOX may be, at least partially, due to its attenuation of ERK phosphorylation. We have previously shown that peroxynitrite toxicity to mature OLs is mediated by intracellular zinc release (Zhang et al., 2006). Although the exact sources of labile zinc is unclear, metallothioneins, the low molecular weight and cysteine-rich metal binding proteins, may be one of the major sources from which zinc is released typically in response to thiol oxidization (Maret, 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide has been implicated in the pathogenesis of multiple sclerosis. However, it is still unclear whether nitric oxide plays a protective role or is deleterious. We have previously shown that peroxynitrite, a reaction product of nitric oxide and superoxide, is toxic to mature oligodendrocytes (OLs). The toxicity is mediated by intracellular zinc release, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), activation of 12-lipoxygenase (12-LOX) and the formation of reactive oxygen species (ROS). In this study, we found that the donors of nitric oxide, dipropylenetriamine NONOate (DPT NONOate) and diethylenetriamine NONOate (DETA NONOate), protected OLs from peroxynitrite or zinc-induced toxicity. The protective mechanisms appear to be attributable to their inhibition of peroxynitrite- or zinc-induced ERK1/2 phosphorylation and 12-LOX activation. In cultures of mature OLs exposed to lipopolysaccharide (LPS), induction of inducible nitric oxide synthase (iNOS) generated nitric oxide and rendered OLs resistant to peroxynitrite-induced toxicity. The protection was eliminated when 1400W, a specific inhibitor of iNOS, was co-applied with LPS. Using MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we found that nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was increased in the spinal cord white matter, which correlated with the loss of mature OLs. Targeted gene deletion of the NADPH oxidase component gp91phox reduced clinical scores, the formation of nitrotyrosine and the loss of mature OLs. These results suggest that blocking the formation specifically of peroxynitrite, rather than nitric oxide, may be a protective strategy against oxidative stress induced toxicity to OLs.
    Neuroscience 06/2011; 184:107-19. DOI:10.1016/j.neuroscience.2011.04.007 · 3.33 Impact Factor
Show more