Plasmalogen Augmentation Reverses Striatal Dopamine Loss in MPTP Mice

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.

Peroxisomal Dysfunction in Age-Related Diseases

“…Plasmalogen levels are significantly reduced in postmortem human frontal cortex lipid rafts with PD [61]. Supplementation of plasmalogens in a mouse model of PD, using the orally bioavailable ethanolamine plasmalogen precursor PPI-1011, reverses striatal dopamine loss [62]. The mechanism through which this occurs is unknown.…”

“…In this study, PPI-1011 significantly increased plasmalogen levels in serum but not in brain tissue, which the authors conjectured could have been due to challenges in assaying small quantities of brain tissue for plasmalogen species. Another possibility is that neuroprotection was provided through increases in docosahexaenoic acid or lipoic acid levels, which are also increased by PPI-1011 [62]. Peroxisomal dysfunction may contribute to the accumulation of αS in the brain.…”

Improvement of Blood Plasmalogens and Clinical Symptoms in Parkinson’s Disease by Oral Administration of Ether Phospholipids: A Preliminary Report

“…Effectiveness of plasmalogens to symptoms of PD was suggested by animal models of PD. It has been reported that plasmalogen precursor analog treatment reduced levodopainduced dyskinesia in parkinsonian monkeys [43], and the same group also reported that plasmalogen augmentation with a plasmalogen precursor reversed striatal dopamine loss in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP-) treated mice [44].…”

Plasmalogen deficiency and neuropathology in Alzheimer's disease: Causation or coincidence?

“…In another study, pretreatment with a plasmalogen precursor (10, 50, and 200 mg/kg or with vehicle daily for 10 days) followed by MPTP administration on day 5 prevented MPTP‐induced striatal dopamine loss in precursor‐treated (10 and 50 mg/kg doses) MPTP mice [53]. MPTP treatment reduced Dopamine Transporter and vesicular monoamine transporter 2 ligand binding.…”