Reinforced lipids

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Polyunsaturated fatty acids (PUFA), normal and deuterated, for the synthesis of reinforced lipids. Hydrogen atoms (H) are explicitly shown where they are replaced with deuterium (D), at oxidation-prone bis-allylic (between double bonds) positions. "R" stands for "radical", for example, hydrogen or ester.

Reinforced lipids are lipid molecules in which some of the fatty acids contain deuterium next to the double bonds. They can be used for the protection of living cells by slowing the chain reaction due to isotope effect on lipid peroxidation.[1] The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, use of reinforced lipids that stop the chain reaction of lipid peroxidation has preventive and therapeutic potential.

There are a number of polyunsaturated fatty acids that can be reinforced by deuteration.[2] They include (the names of the reinforced deuterated versions are separated by a slash):

Mechanism of action

Hydrogen is a chemical element with atomic number 1. It has just one proton and one electron. Deuterium is the heavier naturally occurring, stable isotope of hydrogen. Deuterium contains one proton, one electron, and a neutron, doubling the mass without changing its properties significantly. Substituting deuterium for hydrogen yields deuterated compounds that are similar in size and shape to normal hydrogen compounds.

One of the most pernicious and irreparable types of oxidative damage inflicted by reactive oxygen species (ROS) upon biomolecules involves the carbon-hydrogen bond cleavage (hydrogen abstraction). In theory, replacing hydrogen with deuterium "reinforces" the bond due to the kinetic isotope effect, and such reinforced biomolecules taken up by the body will be more resistant to ROS.[3]

The deuterium-reinforced lipids resists the non-enzymatic lipid peroxidation (LPO) through isotope effect — a non-antioxidant based mechanism that protects mitochondrial, neuronal and other lipid membranes, thereby greatly reducing the levels of numerous LPO-derived toxic products such as reactive carbonyls.[4][5]

Treating cells with deuterium-containing PUFAs (D-PUFAs) can prevent of ferroptosis. This treatment stops the autoxidation process through the kinetic isotope effect (KIE), as shown in Table 1 [66]. The efficacy of D-PUFAs in preventing ferroptosis has been demonstrated in models induced by erastin and RSL3, and has shown promising results in various disease models, especially those related to neurodegenerative disorders.[6]

Laboratory and animal research

The concept of using reinforced lipids to inhibit lipid peroxidation has been tested in numerous cell and animal models, including:

Clinical research

Further reading

References

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