Plasmalogen Replacement Therapy
Bozelli JC and Epand RM. (2021) Plasmalogen Replacement Therapy. Membranes, 11 (838)
Plasmalogens are a class of phospholipids that contain a vinyl-ether bond at the sn-1 position, which gives these lipids their unique qualities. This double bond causes plasmalogens to have a more compact structure, allowing these lipids to influence membrane fluidity and structure. Plasmalogens are also able to protect against oxidative stress since each vinyl-ether bond can scavenge two reactive oxygen species. Plasmalogens have been found to have roles in cholesterol transport, vesicular fusion, and are a major component in lipid rafts. Since plasmalogens are required for many fundamental cellular processes, it is unsurprising that their absence is associated with aging, metabolic disorders, and neurological disorders. Plasmalogens have been shown to gradually increase in humans until the age of forty when levels begin to plateau, then degrease with age. A 40% decrease in plasmalogen levels has been observed in individuals older than 70 years of age. A number of peroxisomal deficiency diseases are caused by an inability to synthesize plasmalogens and result in rare inherited diseases including Zellweger’s syndrome (ZS) and rhizomelic chondrodysplasia punctata (RCDP). Since the brain is the region with the highest plasmalogen content, a reduction has also been associated with Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Bozelli and Epand discuss the consequences of reduced plasmalogen levels and the potential of plasmalogen replacement therapy (PRT) in recovering their levels and improving health outcomes in their review.
PRT is a pharmacological intervention with the goal of restoring plasmalogen levels in the body and reduce pathological symptoms. A plasmalogen treatment has advantages since it can be orally administered, the components used for PRT exhibit no toxicity at any dose level, and have been found to be safe in humans. Plasmalogens and plasmalogen precursors are found in high levels in marine animals including krill, mussels, sea squirt, and scallops as well as in land animals such as pork, beef, and chicken. Bozelli and Epand suggest the potential of a therapy through dietary intervention, but state that although these foods do provide some plasmalogens, the decreased bioavailability and immense volume of raw meat that would need to be consumed makes this route unreasonable. An example they provide is that scallops have 7.5 μg of plasmalogens/gram of muscle therefore to deliver a daily dose of 50 mg/kg to a human with an average weight of 70 kg, they would need to consume 460 kg of scallops every day. Consuming dietary plasmalogens cannot feasibly deliver a high enough dose therefore, purified or synthetic plasmalogens would be better options.
Both purified and synthetic plasmalogens or plasmalogen precursors have been shown to be effective in animal studies where plasmalogen levels are increased and disease pathology reduced. 1-O-octadecyl-sn-glycerol (OG), a plasmalogen precursor, was found to increase ethanolamine plasmalogen levels in two models of RCDP (Gnpat knock-out and Pex7 knock-out, two of the enzymes in the plasmalogen biosynthetic pathway). This treatment was also able to normalize cardiac impulse and nerve conduction. PPI-1040, a synthetic plasmalogen treatment, was also effective at increasing levels in the Pex7 knockout mouse model. Studies focusing on neurological diseases have found success with PRT treatments. Purified ethanolamine plasmalogens have been able to reduce microglia activation, accumulation of beta-amyloid, and neuronal apoptosis, causing a reduction in neurotoxicity and neuroinflammation, which are commonly seen in AD. Plasmalogens were also found to be increased in these animals along with improvements in reference memory and working memory. Purified plasmalogens administered to hamsters and mouse models of atherosclerosis showed improved atherosclerosis lesions, total cholesterol, and low-density lipoprotein cholesterol in serum. In mouse and monkey models treated with PPI-1011, a synthetic plasmalogen precursor, plasmalogen levels were increased in the serum and the animals demonstrated neuroprotective and anti-inflammatory properties in addition to recovered dopamine and serotonin loss.
Although plasmalogens can be found in every-day foods, the levels are not nearly high enough for a change in diet to be capable of acting as a PRT. Thankfully, studies looking at purified plasmalogens have shown success in a range of animal models of peroxisomal and neurodegenerative disorders. Purified plasmalogens demonstrate success, but a similar challenge will arise if we were to try to treat every disease by extracting plasmalogens from certain marine animals. With 747 000 people with AD (1), 100 000 with PD (2), 77 000 with MS (3) just in Canada, extracting plasmalogens from natural sources would not be feasible, therefore synthetic plasmalogens and plasmalogen precursors are a more viable option. Bozelli and Epand list a few of the challenges with bringing PRTs to the clinic including having the treatment cross the blood-brain barrier, developing PRTs that target specific plasmalogen species, and whether PRTs and antioxidants should be administered together so that radical oxygen species in aqueous environments, which are inaccessible to plasmalogens, would still be eradicated. Further work into developing synthetic plasmalogens and plasmalogen precursors could provide effective therapies for treating a range of diseases without an additional dietary or environmental burden.
1. Alzheimer's & Dementia Help | Canada | Alzheimer's Association