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. 2016 Mar 9;11(3):e0151020.
doi: 10.1371/journal.pone.0151020. eCollection 2016.

Plasmalogen Augmentation Reverses Striatal Dopamine Loss in MPTP Mice

Edith Miville-Godbout  1   2 , Mélanie Bourque  1   2 , Marc Morissette  1 , Sara Al-Sweidi  1 , Tara Smith  3 , Asuka Mochizuki  3   4 , Vijitha Senanayake  3 , Dushmanthi Jayasinghe  3 , Li Wang  3 , Dayan Goodenowe  3 , Thérèse Di Paolo  1   2
Affiliations

Plasmalogen Augmentation Reverses Striatal Dopamine Loss in MPTP Mice

Edith Miville-Godbout et al. PLoS One. .

Abstract

Plasmalogens are a class of glycerophospholipids shown to play critical roles in membrane structure and function. Decreased plasmalogens are reported in the brain and blood of Parkinson's disease (PD) patients. The present study investigated the hypothesis that augmenting plasmalogens could protect striatal dopamine neurons that degenerate in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice, a PD model. First, in a pre-treatment experiment male mice were treated for 10 days with the docosahexaenoic acid (DHA)-plasmalogen precursor PPI-1011 (10, 50 and 200 mg/kg). On day 5 mice received MPTP and were killed on day 11. Next, in a post-treatment study, male mice were treated with MPTP and then received daily for 5 days PPI-1011 (5, 10 and 50 mg/kg). MPTP treatment reduced serum plasmalogen levels, striatal contents of dopamine (DA) and its metabolites, serotonin, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). Pre-treatment with PPI-1011 (10 and 50 mg/kg) prevented all MPTP-induced effects. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding. Post-treatment with PPI-1011 prevented all MPTP-induced effects at 50 mg/kg but not at lower doses. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding in the post-treatment experiment. PPI-1011 treatment (10 days at 5, 10 and 50 mg/kg) of intact mice left unchanged striatal biogenic amine contents. These data demonstrate that treatment with a plasmalogen precursor is capable of protecting striatal dopamine markers in an animal model of PD.

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Conflict of interest statement

Competing Interests: EMG, MB, MM, SAS and TDP have no conflicts of interest. TS, VS, AM, DJ, LW and DG are employees of Phenomenome Discoveries. The authors confirm that this does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. PPI-1011 pre-treatment neuroprotection of striatal dopamine and its metabolites.
Effect of MPTP and PPI-1011 treatment on striatal A) dopamine (DA) contents (F4,46 = 5.91, p = 0.0006) and its metabolites B) 3,4-dihydroxyphenylacetic acid (DOPAC) (F4,46 = 6.17, p = 0.0005), C) 3-methoxytyramine (3-MT) (F4,46 = 3.90, p = 0.008), and D) homovanillic acid (HVA) (F4,46 = 9.32, p < 0.0001), as well as E) DOPAC/DA (F4,46 = 1.16, p = 0.34), and F) 3-MT/DA (F4,46 = 3.03, p = 0.03) and G) HVA/DA (F4,46 = 3.08, p = 0.02) ratios. Values shown are the means (ng/mg of proteins) ± S.E.M. of 9–12 mice per group. * p < 0.05, ** p < 0.01 and *** p < 0.001 vs control; † p < 0.05, †† p < 0.01, ††† p < 0.001 and †††† p < 0.0001 vs MPTP.
Fig 2
Fig 2. PPI-1011 pre-treatment neuroprotection of striatal serotonin and its metabolite.
Effect of MPTP and PPI-1011 treatment on striatal A) serotonin (F4,46 = 4.04, p = 0.007) contents and its metabolite B) 5-hydroxyindoleacetic acid (5-HIAA) (F4,46 = 19.83, p < 0.0001), as well as C) 5-HIAA/serotonin (F4,46 = 7.04, p = 0.0002) ratio. Values shown are the means (ng/mg of proteins) ± S.E.M. of 9–12 mice per group. * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001 vs control; † p < 0.05, †† p < 0.01 ††† p < 0.001 and †††† p < 0.0001 vs MPTP.
Fig 3
Fig 3. PPI-1011 pre-treatment neuroprotection of nigrostriatal dopamine transporters.
Examples A) and effect of MPTP and PPI-1011 treatment in mice on DAT ([125I]-RTI) specific binding in B) striatum (F4,44 = 5.51, p = 0.001) and C) substantia nigra (F4,44 = 1.15, p = 0.35) as well as VMAT2 ([3H]-TBZ-OH) specific binding in D) striatum (F4,44 = 4.05, p = 0.007) and E) substantia nigra (F4,44 = 0.24, p = 0.91). Values shown are the means (fmol/mg of tissue) ± S.E.M. of 9–12 mice per group. ** p < 0.01 and *** p < 0.001 vs control; † p < 0.05 vs MPTP.
Fig 4
Fig 4. Correlation of striatal dopamine markers in PPI-1011 pre-treatment neuroprotection.
Correlations between dopamine (DA) contents and A) DAT and B) VMAT2 specific binding, as well as C) between DAT and VMAT2 specific binding in mice treated with MPTP and PPI-1011.
Fig 5
Fig 5. PPI-1011 pre-treatment neuroprotection of serum and brain plasmalogen levels.
Effect of MPTP and PPI-1011 treatment in mice on total serum levels of A) 16:0 plasmalogens (F4,46 = 5.29, p = 0.001) and B) 18:0 plasmalogens (F4,46 = 4.15, p = 0.006) as well as in brain tissue of C) 16:0 plasmalogens (F4,53 = 0.78, p = 0.78) and D) 18:0 plasmalogens (F4,53 = 0.40, p = 0.89). Values shown are the means (relative to controls) ± S.E.M. of 9–12 mice per group. * p < 0.05 and ** p < 0.01 vs control; † p < 0.05, †† p < 0.01and ††† p < 0.001 vs MPTP.
Fig 6
Fig 6. Correlation of striatal dopamine concentrations and plasmalogen levels in PPI-1011 pre-treatment neuroprotection.
Correlations between the levels of serum plasmalogens A) 16:0/22:6, B) 18:0/18:1 and C) 18:0/20:4 and striatal dopamine (DA) concentrations as well as D) correlation between total serum plasmalogen levels and DA content.
Fig 7
Fig 7. PPI-1011 post-treatment neuroprotection of striatal dopamine and its metabolites.
Effect of MPTP and PPI-1011 treatment on striatal A) DA contents (F4,49 = 15.76, p < 0.0001) and its metabolites B) DOPAC (F4,49 = 10.53, p < 0.0001), C) 3-MT (F4,49 = 5.59, p = 0.0009) and D) HVA (F4,49 = 6.20, p = 0.0004), as well as E) DOPAC/DA (F4,49 = 4.87, p = 0.002), F) 3-MT/DA (F4,49 = 3.92, p = 0.008) and G) HVA/DA (F4,49 = 8.60, p < 0.0001) ratios. Values shown are the means (ng/mg of proteins) ± S.E.M. of 9–14 mice per group. * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001 vs control; † p < 0.05 vs MPTP.
Fig 8
Fig 8. PPI-1011 post-treatment neuroprotection of striatal serotonin and its metabolite.
Effect of MPTP and PPI-1011 treatment on striatal A) serotonin (F4,49 = 2.66, p = 0.04) contents and its metabolite B) 5-hydroxyindoleacetic acid (5-HIAA) (F4,49 = 3.52, p = 0.01), as well as C) 5-HIAA/serotonin (F4,49 = 7.05, p = 0.0001) ratio. Values shown are the means (ng/mg of proteins) ± S.E.M. of 9–14 mice per group. * p < 0.05, ** p < 0.01 and *** p < 0.001 vs control.
Fig 9
Fig 9. PPI-1011 post-treatment neuroprotection of nigrostriatal dopamine transporters.
Examples A) and effect of MPTP and PPI-1011 treatment in mice on DAT ([125I]-RTI) specific binding in B) striatum (F4,46 = 15.17, p <0.0001) and C) substantia nigra (F4,49 = 1.55, p = 0.20) as well as VMAT2 ([3H]-TBZ-OH) specific binding in D) striatum (F4,48 = 16.44, p < 0.0001) and E) substantia nigra (F4,47 = 0.27, p = 0.90). Values shown are the means (fmol/mg of tissue) ± S.E.M. of 8–14 mice per group. ** p < 0.01, *** p < 0.001 and **** p < 0.0001 vs control; †† p < 0.01 vs MPTP.
Fig 10
Fig 10. Correlation of striatal dopamine markers and plasmalogen in PPI-1011 post-treatment neuroprotection.
Correlations between dopamine (DA) contents and A) DAT and B) VMAT2 specific binding, C) between DAT and VMAT2 specific binding in mice treated with MPTP and PPI-1011 as well as correlation D) between the serum level of plasmalogen 16:0/22:6 in serum and striatal DA contents.
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