Electrophilic Cyclopentenone Isoprostanes in Neurodegeneration

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 A(2)- and J(2)-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.

A dielectrophoresis and image processing based system for loading single-neurons per micro-well in planar microelectrode arrays

“…Similar observations have been made by [14] and [19]. In addition, there is evidence that the solvent cyclopentenone used in the SU8 2015 formulation enhances neuro-degeneration and may cause apoptosis [20]. Control samples that had neurons cultured on SU-8 2015 without the use of DEP were used to verify the aforementioned and exclude the effect of the DEP field on the cells as a possible culprit for the lack of neural process outgrowth.…”

Action potential recording from dielectrophoretically positioned neurons inside micro-wells of a planar microelectrode array

“…For instance, Merz and Fromherz (2005) and Zhang et al, (2006) used the original SU-8 formulation, while the work described here and the experiments by Vernekar et al, (2008) utilised the SU-8 2000 formulation. The first SU-8 formulation uses gamma-butyrolacetone as the solvent, while the solvent in SU-8 2000 is cyclopentenone, which has been recently found to induce neuronal apoptosis and enhance neuro-degeneration (Musiek et al, 2007). Unless an effective method for solving the toxicity problem of the photoresists is found, other materials with better biocompatibility have to be investigated.…”

The isoprostanes—25 years later

“…A 2 /J 2 -IsoPs, dehydration products of D 2 /E 2 -IsoPs, are reactive electro-philes that readily form Michael adducts with cellular thiols due to the presence of an α,β-unsaturated cyclopentenone ring structure. Current knowledge regarding the biological actions of these molecules has been reviewed elsewhere [70,87,234–238]. The biological activity of isothromboxanes and isofurans has not been studied.…”