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. 2011 Dec;52(12):2287-2297.
doi: 10.1194/jlr.P017798. Epub 2011 Sep 13.

F2-dihomo-isoprostanes as potential early biomarkers of lipid oxidative damage in Rett syndrome

Claudio De Felice  1 , Cinzia Signorini  2 , Thierry Durand  3 , Camille Oger  3 , Alexandre Guy  3 , Valérie Bultel-Poncé  3 , Jean-Marie Galano  3 , Lucia Ciccoli  2 , Silvia Leoncini  2 , Maurizio D'Esposito  4 , Stefania Filosa  4 , Alessandra Pecorelli  2 , Giuseppe Valacchi  5 , Joussef Hayek  6
Affiliations

F2-dihomo-isoprostanes as potential early biomarkers of lipid oxidative damage in Rett syndrome

Claudio De Felice et al. J Lipid Res. 2011 Dec.

Abstract

Oxidative damage has been reported in Rett syndrome (RTT), a pervasive developmental disorder caused in up to 95% of cases by mutations in the X-linked methyl-CpG binding protein 2 gene. Herein, we have synthesized F(2)-dihomo-isoprostanes (F(2)-dihomo-IsoPs), peroxidation products from adrenic acid (22:4 n-6), a known component of myelin, and tested the potential value of F(2)-dihomo-IsoPs as a novel disease marker and its relationship with clinical presentation and disease progression. F(2)-dihomo-IsoPs were determined by gas chromatography/negative-ion chemical ionization tandem mass spectrometry. Newly synthesized F(2)-dihomo-IsoP isomers [ent-7(RS)-F(2t)-dihomo-IsoP and 17-F(2t)-dihomo-IsoP] were used as reference standards. The measured ions were the product ions at m/z 327 derived from the [M-181](-) precursor ions (m/z 597) produced from both the derivatized ent-7(RS)-F(2t)-dihomo-IsoP and 17-F(2t)-dihomo-IsoP. Average plasma F(2)-dihomo-IsoP levels in RTT were about one order of magnitude higher than those in healthy controls, being higher in typical RTT as compared with RTT variants, with a remarkable increase of about two orders of magnitude in patients at the earliest stage of the disease followed by a steady decrease during the natural clinical progression. hese data indicate for the first time that quantification of F(2)-dihomo-IsoPs in plasma represents an early marker of the disease and may provide a better understanding of the pathogenic mechanisms behind the neurological regression in patients with RTT.

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Figures

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Fig. 1.
Fig. 1.
One-dimensional 1H- and 13C-NMR of the ent-7(RS)-F2t-dihomo-IsoP 2 and the 17-F2t-dihomo-IsoP 3.
Fig. 2.
Fig. 2.
Reconstructed ion chromatograms obtained under GC/NICI-MS/MS conditions by selecting the species [M–181]− (m/z 597) of F2-dihomo-IsoP as precursor ion. The detection of product ions was carried out by μscan in the m/z range 326.5–327.5. A: Ion chromatogram and product ion (327 m/z, precursor ion m/z 597 for F2-dihomo-IsoPs and 303 m/z, precursor ion m/z 573 for the internal standard PGF2α-d4) of a stage I RTT patient. B: Ion chromatogram and product ion (327 m/z, precursor ion m/z 597) of ent-7(RS)-F2t-dihomo-IsoP and 17-F2t-dihomo-IsoP (retention time, 17.20 and 17.45 min) and commercial 1a,1b-dihomo prostaglandin F2α (retention time 18.70 min). Ion chromatogram and product ion (303 m/z, precursor ion m/z 73) of the internal standard PGF2α-d4 (retention time, 13.21 min) are also reported. Retention times are indicated. The collision energy was 1.3 eV.
Fig. 2.
Fig. 2.
Reconstructed ion chromatograms obtained under GC/NICI-MS/MS conditions by selecting the species [M–181]− (m/z 597) of F2-dihomo-IsoP as precursor ion. The detection of product ions was carried out by μscan in the m/z range 326.5–327.5. A: Ion chromatogram and product ion (327 m/z, precursor ion m/z 597 for F2-dihomo-IsoPs and 303 m/z, precursor ion m/z 573 for the internal standard PGF2α-d4) of a stage I RTT patient. B: Ion chromatogram and product ion (327 m/z, precursor ion m/z 597) of ent-7(RS)-F2t-dihomo-IsoP and 17-F2t-dihomo-IsoP (retention time, 17.20 and 17.45 min) and commercial 1a,1b-dihomo prostaglandin F2α (retention time 18.70 min). Ion chromatogram and product ion (303 m/z, precursor ion m/z 73) of the internal standard PGF2α-d4 (retention time, 13.21 min) are also reported. Retention times are indicated. The collision energy was 1.3 eV.
Fig. 3.
Fig. 3.
GC/NICI-MS/MS product ion mass spectra of F2-dihomo-IsoPs obtained by selecting ions [M–181]− (m/z 597) as precursor ion. The collision energy was 1.3 eV (C). Ent-7(RS)-F2t-dihomo-IsoP and 17-F2t-dihomo-IsoP derivatives (A, B, respectively) are also shown.
Fig. 4.
Fig. 4.
Plasma F2-dihomo-IsoPs are related to disease stage for RTT patients with the classical form of the disease. Plasma F2-dihomo-IsoPs were increased by about two orders of magnitude in RTT patients in stage I of the disease, whereas these values decreased by about 2- to 3-fold more than in controls in later stages of the natural progression of the disease. It is clear that control subjects cannot have stages, but they have been matched for gender (all females) and age with patients at stages I (control subjects, n = 10; mean age 1.5 years), II (control subjects, n = 15; mean age 5 years), III (control subjects, n = 20; mean age 12 years), and IV (control subjects, n = 25; mean age 16 years). Plasma F2-dihomo-IsoP values (mean ± SE) are presented in logarithmic scale. Asterisks indicate significant differences (P < 0.001) for RTT values versus those of controls.
Fig. 5.
Fig. 5.
Formation of the 7-, 10-, 14-, and 17-series F2-dihomo-IsoPs.
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