Oral bioavailability of the ether lipid plasmalogen precursor, PPI-1011, in the rabbit: a new therapeutic strategy for Alzheimers diseaseReport as inadecuate




Oral bioavailability of the ether lipid plasmalogen precursor, PPI-1011, in the rabbit: a new therapeutic strategy for Alzheimers disease - Download this document for free, or read online. Document in PDF available to download.

Lipids in Health and Disease

, 10:227

First Online: 05 December 2011Received: 27 October 2011Accepted: 05 December 2011

Abstract

IntroductionDocosahexaenoic acid DHA and DHA-containing ethanolamine plasmalogens PlsEtn are decreased in the brain, liver and the circulation in Alzheimer-s disease. Decreased supply of plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing ether lipid precursor of plasmalogens. PPI-1011 is an alkyl-diacyl plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines PtdEtn.

MethodsRabbits were dosed orally with PPI-1011 in hard gelatin capsules for time-course and dose response studies. Incorporation into PlsEtn and PtdEtn was monitored by LC-MS-MS. Metabolism of released lipoic acid was monitored by GC-MS. To monitor the metabolic fate of different components of PPI-1011, we labeled the sn-1 palmitic acid, sn-2 DHA and glycerol backbone withC and monitored their metabolic fates by LC-MS-MS.

ResultsPPI-1011 was not detected in plasma suggesting rapid release of sn-3 lipoic acid via gut lipases. This conclusion was supported by peak levels of lipoic acid metabolites in the plasma 3 hours after dosing. While PPI-1011 did not gain access to the plasma, it increased circulating levels of DHA-containing PlsEtn and PtdEtn. Labeling experiments demonstrated that the PtdEtn increases resulted from increased availability of DHA released via remodeling at sn-2 of phospholipids derived from PPI-1011. This release of DHA peaked at 6 hrs while increases in phospholipids peaked at 12 hr. Increases in circulating PlsEtn were more complex. Labeling experiments demonstrated that increases in the target PlsEtn, 16:0-22:6, consisted of 2 pools. In one pool, the intact precursor received a sn-3 phosphoethanolamine group and desaturation at sn-1 to generate the target plasmalogen. The second pool, like the PtdEtn, resulted from increased availability of DHA released during remodeling of sn-2. In the case of sn-1 18:0 and 18:1 plasmalogens with C3DHA at sn-2, labeling was the result of increased availability of C3DHA from lipid remodeling. Isotope and repeated dosing 2 weeks experiments also demonstrated that plasmalogens and-or plasmalogen precursors derived from PPI-1011 are able to cross both the blood-retinal and blood-brain barriers.

ConclusionsOur data demonstrate that PPI-1011, an ether lipid precursor of plasmalogens is orally bioavailable in the rabbit, augmenting the circulating levels of unesterified DHA and DHA-containing PlsEtn and PtdEtn. Other ethanolamine plasmalogens were generated from the precursor via lipid remodeling de-acylation-re-acylation reactions at sn-2 and phosphatidylethanolamines were generated via de-alkylation-re-acylation reactions at sn-1. Repeated oral dosing for 2 weeks with PPI-1011 resulted in dose-dependent increases in circulating DHA and DHA-containing plasmalogens. These products and-or precursors were also able to cross the blood-retinal and blood-brain barriers.

List of abbreviations160: palmitic acid

180: stearic acid

181: oleic acid

182: linoleic acid

204: arachidonic acid

226: docosahexaeoic acid DHA

PtdEtnphosphatidylethanolamines

PlsEtnplasmalogen.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-511X-10-227 contains supplementary material, which is available to authorized users.

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Author: Paul L Wood - Tara Smith - Nina Lane - M Amin Khan - Greg Ehrmantraut - Dayan B Goodenowe

Source: https://link.springer.com/







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