Plasmalogens have been reported to possess antioxidant activity; a paradoxical finding given that plasmalogens often comprise highly oxidizable polyunsaturated fatty acids esterified to the central position of the glycerol backbone. However a reasonable mechanism accounting for plasmenyl lipid activity has yet to be advanced, despite the fact that other monounsaturated lipids including cholesterol and oleate have been extensively studied. Plasmenylcholine was synthesized de novo to resolve its antioxidant activity as well as to carry out mechanistic studies to understand its basis. Autoxidation of a vinyl ether model substrate yielded a kp of 6 M-1 s-1, which affirmed it was as slower than cholesterol. However, corresponding experiments with a deuterated substrate yielded a value of 89 M-1 s-1, questioning the reliability of these studies. Our studies of plasmenyl lipid peroxidation inspired us to look into the mechanism of autoxidation of the monounsaturated lipid, oleate (using LC-MS/MS with APCI+), which was reported to proceed exclusively via H-atom transfer (HAT). Herein we have shown for the first time that oleate epoxides are formed in the autoxidation of the monounsaturated lipid.

Thesis advisor: Daniel A. Kirschner / Reactive oxygen species (ROS) are implicated in a range of degenerative conditions, including aging, neurodegenerative diseases, and neurological disorders such as multiple sclerosis. Myelin is a lipid-rich multilamellar assembly that facilitates rapid nerve conduction in higher animals, and may be intrinsically vulnerable to oxidative damage given the high energetic demands and low antioxidant capacity of myelinating cells. To determine whether ROS can cause structural damage to internodal myelin, whole mouse sciatic and optic nerves were incubated ex vivo with a previously-characterized copper (Cu)/hydrogen peroxide (HP)/o-phenanthroline (OP)-based hydroxyl radical-generating system followed by quantitative determination of myelin packing by x-ray diffraction. Exposure to Cu/OP/HP-mediated ROS caused irreversible myelin decompaction in both sciatic and optic nerves. The addition of the hydroxyl radical scavenger, sodium formate, to the ROS-producing incubation solution significantly prevented sciatic nerve myelin decompaction, implicating hydroxyl radical species in causing the damage. Furthermore, Cu/OP/HP-mediated decompaction could be prevented by the addition of EDTA, which can compete with OP for Cu binding and sequester the metal within the bulk solution. These findings suggest that Cu/OP/HP-dependent myelin decompaction is caused by OP-mediated membrane-targeted hydroxyl radical production. Myelin membranes are particularly enriched in plasmalogen phospholipids, which have been linked to antioxidant activity; this enrichment may constitute an endogenous ROS-defense mechanism that protects ROS-vulnerable myelin tissue from damage. Intriguingly, it was found that sciatic nerve myelin from plasmalogen deficient (Pex7 KO) mice was significantly more susceptible to ROS-mediated decompaction than that from WT mice, supporting the role of plasmalogens as endogenous antioxidants. / Thesis (MS) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

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