Plasmalogen Supplementation Prevents Demyelination (C104)

Animals pretreated with plasmalogen supplements are protected against the neurotoxin cuprizone. Cuprizone selectively targets oligodendrocytes and creates symptoms and neuropathology similar to multiple sclerosis.

To access the FREE seminars with full presentations and videos please visit Dr. Goodenowe’s resource site here. This is the article for seminar C104, Supplements (Series C).

Multiple sclerosis (MS) is a neurodegenerative disease that affects a specific type of brain cell called an oligodendrocyte. The brain uses oligodendrocytes to make the protective myelin coating that surrounds neurons. Cuprizone is a neurotoxin that selectively targets and kills these oligodendrocytes and creates MS-like symptoms. This type of neurodegeneration is called demyelination. This seminar describes the biochemical mechanism of cuprizone and how plasmalogen precursor treatment protects oligodendrocytes from neurodegeneration and prevents the demyelination of neurons.  

The most common white matter neurological diseases are MS, vascular dementia, and stroke. Non-neuronal brain cells can be roughly divided into three parts: astrocytes, microglia, and oligodendrocytes (white matter). As described in greater detail in other seminars, the astrocytes can be viewed as having a multi-functional liver-like metabolic support purpose, the microglia have an active immune-like reactionary purpose, and the oligodendrocytes have a precise and specialized structural purpose. The role of oligodendrocytes is to make and maintain the myelin sheath that surrounds and protects the neuron axon. Oligodendrocytes and neurons are the most specialized cell types in the brain.  

Breakdowns in the myelin have direct neurological consequences. Typically, white matter disease is an oligodendrocyte disease. Denervation is the process whereby neuron to neuron connectivity is lost. Renervation involves the re-connection of neurons. A neuron’s function is defined by its connections. In contrast, demyelination is the process of breaking down the protective myelin sheath surrounding the neuron. Remyelination is the rebuilding and restoration of the myelin sheath. Unless there is a precise genetic defect in the myelin-producing biochemistry of the oligodendrocyte, all demyelination is caused by inflammation. Inflammation in the brain is a process where astrocytes and microglia are activated to behave like immune cells and clean up damaged cells and cellular debris so that new cells can come in and restore the cellular infrastructure to a healthy state. This inflammation stage is supposed to be, and normally is, a temporary phenomenon. However, in certain diseases, such as autism and multiple sclerosis, the inflammation phase becomes chronic. Regardless, the healthy maintenance of myelin depends on the ability of the oligodendrocyte to make myelin. The major component of myelin is plasmalogen. Elegant genetic mutation experiments that specifically targeted oligodendrocyte peroxisomes (the organelle responsible for making plasmalogens) were shown to cause demyelination similar to MS. This study was essential because it revealed that in-brain plasmalogen biosynthesis is a critical requirement for myelin maintenance. 

Cuprizone is a copper chelating compound that does not cross the blood-brain barrier. In the 1960s, it was discovered that animals that were fed cuprizone exhibited brain demyelination. Since then, this model has been extensively studied. The key feature of the cuprizone model is that mice fed 0.2 to 0.3% cuprizone in their diet exhibit a specific cascade of events. Microglial and astrocyte activation occurs within the first few days. However, it takes about two weeks before measurable demyelination is observed (even though oligodendrocyte loss begins within days). Maximum demyelination is observed in five to six weeks. Copper is an essential metal ion used by many enzymes of the human body to manipulate molecular oxygen. It needs to be tightly controlled, or it will create excess free radical oxygen species. The biochemistry of copper is fascinating but complex. One particular part of copper biochemistry is relevant to this discussion: the role of a particular copper chaperone and copper-dependent enzyme, Cu/Zn-Superoxide dismutase (SOD). This copper chaperone is not only critical for transferring Cu/Zn-SOD from the cytosol to peroxisomes, but it is also the protein that activates SOD. Therefore, copper depletion by cuprizone reduces the ability of all cells in the CNS to deactivate superoxide radicals (which are common byproducts of several metabolic reactions). This is likely the cause of the neuroinflammation observed with cuprizone. However, oligodendrocytes have a special need for Cu/Zn-SOD above and beyond what is needed by other brain cells. Oligodendrocytes need to make lots of plasmalogens, and they cannot do this if they do not have Cu/Zn-SOD in their peroxisomes because this enzyme is critical for peroxisomal β-oxidation, which is critical for plasmalogen biosynthesis. This is the most likely reason that cuprizone selectively damages oligodendrocytes.  

For these reasons, the cuprizone model of demyelination is an ideal model to investigate the ability of alkyl-diacylglycerol (ADG) plasmalogen precursors to directly deliver plasmalogen precursors to oligodendrocytes and restore and maintain brain myelin. To test these hypotheses, I performed two experiments: 

  1. Mice were treated with 0.3% cuprizone for seven weeks. After five weeks (the time that near-maximal demyelination has occurred), half of the mice were treated with 100 mg/kg of DHA-ADG. 
  1. Five groups of mice were evaluated for six weeks. Four groups received 0.2% cuprizone, and one group received a normal diet. Of the four cuprizone-treated groups, one group received no plasmalogen supplement, and the other three groups received either 25, 50, or 100 mg/kg of a cocktail of three different ADG plasmalogen precursors in a 1:1:1 mixture. Two of the precursors contained oleic acid (18:1), and one contained DHA (22:6) at the sn-2 position. 

The purpose of the first experiment was to see if plasmalogen precursor supplementation could induce remyelination in the presence of cuprizone. At the completion of the study, mice treated with only the cuprizone had decreased levels of cholesterol, myoinositol, myelin basic protein, and CNP (2’,3’-cyclic-nucleotide 3’phosphodiesterase) versus controls. All four of these myelin biomarkers were restored to normal in the plasmalogen precursor treated group. These data clearly indicate that ADG plasmalogen precursors can stop demyelination and induce remyelination, even during continuous cuprizone stress and inflammation. 

The purpose of the second experiment was to see if plasmalogen precursors provided at the same time as cuprizone to the mice could allow them to maintain myelin integrity in the presence of the cuprizone stress. At the completion of the study, the mice treated with the plasmalogen precursors exhibited no detectible demyelination. Inflammation biomarkers were also decreased. 

Overall, these two cuprizone myelin degeneration studies show that ADG plasmalogen precursor supplementation can create a reserve capacity for oligodendrocytes that enables them to maintain myelin under extreme demyelinating conditions. They also show that even after demyelination has started, and the demyelinating stress continues to be present, plasmalogen precursor supplementation enables the oligodendrocytes to begin remyelinating the neurons. 

Dr. Goodenowe explains the relevant research and literature regarding plasmalogen precursors and the prevention of demyelination using Multiple Sclerosis as an example in seminar C104 – Plasmalogen Supplementation Prevents of Demyelination. 

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