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Electrophilic Cyclopentenone Isoprostanes in Neurodegeneration

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Abstract

Although oxidative stress has been implicated in the pathogenesis of numerous neurodegenerative conditions, the precise mechanisms by which reactive oxygen species (ROS) induce neuronal death are still being explored. The generation of reactive lipid peroxidation products is thought to contribute to ROS neurotoxicity. Isoprostanes (IsoPs), prostaglandin-like molecules formed in vivo via the ROS-mediated oxidation of arachidonic acid, have been previously demonstrated to be formed in increased amounts in the brains of patients with various neurodegenerative diseases. Recently, we have identified a new class of IsoPs, known as A2- and J2-IsoPs or cyclopentenone IsoPs, which are highly reactive electrophiles and form adducts with thiol-containing molecules, including cysteine residues in proteins and glutathione. Cyclopentenone IsoPs are favored products of the IsoP pathway in the brain and are formed abundantly after oxidant injury. These compounds also potently induce neuronal apoptosis by a mechanism which involves glutathione depletion, ROS generation, and activation of several redox-sensitive pathways that overlap with those involved in other forms of oxidative neurodegeneration. Cyclopentenone IsoPs also enhance neurodegeneration caused by other insults at biologically relevant concentrations. These data are reviewed, whereas new data demonstrating the neurotoxicity of J-ring IsoPs and a discussion of the possible role of cyclopentenone IsoPs as contributors to neurodegeneration are presented.

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Abbreviations

12/15-LOX:

12/15-lipoxygenase

AA:

arachidonic acid

AAPH:

2,2′-azobis(2-amidinopropane)hydrochloride

AD:

Alzheimer’s disease

ERK:

extracellular signal-regulated kinase

GSH:

glutathione

GST:

glutathione transferase

IsoP:

isoprostane

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

nM:

nanomolar

PG:

prostanglandin

μM:

micromolar

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Acknowledgements

This work was supported by NIH grants DK48831, GM15431, CA77839, RR00095, ES13125, HD15052, and NS050396. ESM was supported by a grant from the PhRMA Foundation.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, 526 RRB, 23rd and Pierce Aves, Nashville, TN, 37232-6602, USA

    Erik S. Musiek & Jason D. Morrow

  2. Departments of Neurology and Pharmacology, Vanderbilt University School of Medicine, MRB III Room 8110, 465 21st Avenue South, Nashville, TN, 37232-8548, USA

    BethAnn McLaughlin

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  1. Erik S. Musiek
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  2. BethAnn McLaughlin
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  3. Jason D. Morrow
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Correspondence to Jason D. Morrow.

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Musiek, E.S., McLaughlin, B. & Morrow, J.D. Electrophilic Cyclopentenone Isoprostanes in Neurodegeneration. J Mol Neurosci 33, 80–86 (2007). https://doi.org/10.1007/s12031-007-0042-3

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