Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata

Abstract

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with 13 C 6-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient Pex7 hypo/null mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7 hypo/null mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted. This article has an associated First Person interview with the joint first authors of the paper.

Plasmalogens, platelet-activating factor and beyond – Ether lipids in signaling and neurodegeneration

“…In addition, the same substance as well as a related one (“PPI-1025”, containing a C18:0 alkyl group at sn -1 and oleic acid at sn -2) reportedly has positive effects on markers of dopaminergic neurons in MPTP-treated mice ( Miville-Godbout et al, 2016 ; Miville-Godbout et al, 2017 ). Remarkably, also the hyperactive behavior of an ether lipid-deficient mouse model was just recently demonstrated to be reversed by a novel plasmalogen-like compound ( Fallatah et al, 2020 ).…”

Prospects for the diagnosis and treatment of plasmalogen deficiency

“…Предшественник плазмалогенов 1-0-алкилглицерин (рис. 3) помогает восстановить уровни плазмалогенов у пациентов с пероксисомными заболеваниями спектра Целльвегера и у моделей животных с точечной ризомелической хондродисплазией [42,43]. P.L.…”

Sulfoquinovosylglyceryl ether, a new group of ether lipids from lake ball‐forming green alga Aegagropilopsis moravica (family Pithophoraceae)

“…[7,26,[28][29][30][31][32] Two synthetic plasmalogen precursors PPI-1011 and PPI-1040 (Figure 1) are under development for the treatment of AD, [33] PD, [34] or RCDP. [35] In contrast to the abundance of ether lipids in animals and microorganisms, those from plants are quite limited in number. Betaine lipids (BL), membrane lipids in time of phosphorus limitation [36] or low temperature, [37] are widely distributed in algae, bryophytes, and pteridophytes.…”

“…Shark liver oil, rich in diacylglyceryl ether, was used as a folk medicine or dietary supplement in Norway, [25] Sweden, [25] Japan, [26] and Cuba, [27] and supplementation of shark liver oil or ether lipids resulted in reduction of radiation‐induced sicknesses, tumor suppression, immune stimulation, better vaccination efficiency, increased sperm fertility, improved cognitive functions of patients with AD, and partial alleviation of some clinical symptoms by PD [7,26,28–32] . Two synthetic plasmalogen precursors PPI‐1011 and PPI‐1040 (Figure 1) are under development for the treatment of AD, [33] PD, [34] or RCDP [35] …”