Free Radical Chain Reactions and Polyunsaturated Fatty Acids in Brain Lipids

Abstract

Polyunsaturated fatty acyl chains (PUFAs) concentrate in the brain and give rise to numerous oxidative chemical degradation products. It is widely assumed that these products are the result of free radical chain reactions, and reactions of this type have been demonstrated in preparations where a single PUFA substrate species predominates. However, it is unclear whether such reactions can occur in the biologically complex milieu of lipid membranes where PUFA substrates are a minority species, and where diverse free radical scavengers or other quenching mechanisms are present. It is of particular interest to know whether they occur in brain, where PUFAs are concentrated and where PUFA oxidation products have been implicated in the pathogenesis of neurodegenerative disorders. To ascertain whether free radical chain reactions can occur in a complex brain lipid mixture, mouse brain lipids were extracted, formed into vesicles, and treated with a fixed number of hydroxyl radicals under conditions wherein the concentrations and types of PUFA-containing phospholipids were varied. Specific phospholipid species in the mixture were assayed by tandem mass spectrometry to quantify the oxidative losses of endogenous PUFA-containing phospholipids. Results reveal crosstalk between the oxidative degradation of ω3 and ω6 PUFAs that can only be explained by the occurrence of free radical chain reactions. These results demonstrate that PUFAs in a complex brain lipid mixture can participate in free radical chain reactions wherein the extent of oxidative degradation is not limited by the number of reactive oxygen species available to initiate such reactions. These reactions may help explain otherwise puzzling in vivo interactions between ω3 and ω6 PUFAs in mouse brain.

The Chemical Reactivity of Membrane Lipids

“…316,363 Evidence for this step being rate-limiting in membranes arises from observations that deuteration of the allylic positions of the PUFAs in cell models significantly reduces the overall rates of peroxidation in response to oxidative challenge by Fe(III), 364 Cu(II), 365 and hydroxyl radicals generated from Cu(II)/ ascorbate. 366 The magnitude of the kinetic isotope effects in these examples also indicate that tunneling is involved in the hydrogen transfer process. 316 In the presence of ions such as Fe 3+ , hydroperoxide 21 can be converted back to the peroxyl radical 20, although this is a slow process.…”

“…Reaction of the allylic radical 19 with triplet oxygen forms a peroxyl radical ( 20 ). Abstraction of a hydrogen atom by the peroxyl radical from the diene ( 18 ) forms a hydroperoxide ( 21 ), plus a further equivalent of 19 , and is usually the rate limiting step in autoxidation. , Evidence for this step being rate-limiting in membranes arises from observations that deuteration of the allylic positions of the PUFAs in cell models significantly reduces the overall rates of peroxidation in response to oxidative challenge by Fe­(III), Cu­(II), and hydroxyl radicals generated from Cu­(II)/ascorbate . The magnitude of the kinetic isotope effects in these examples also indicate that tunneling is involved in the hydrogen transfer process .…”

Spatial Lipidomics Maps Brain Alterations Associated with Mild Traumatic Brain Injury

“…These secondary responses are reflected in lipid alterations since the brain is one of the most lipid rich organs (Piomelli et al 2007) and lipid metabolism is known to be disrupted after injury (Hogan et al 2018; Roux et al 2016). Brain lipid alterations associated with TBI and other neurodegenerative diseases have been shown to induce neuroinflammation and high abundance of polyunsaturated fatty acid (PUFA)-containing lipids make the brain more vulnerable to oxidative stress (Ng et al 2022).…”

Neuronal deletion of MnSOD in mice leads to demyelination, inflammation and progressive paralysis that mimics phenotypes associated with progressive multiple sclerosis

“…Oxidative stress is implicated in the initiation and progression of a number of neurodegenerative diseases including Alzheimer's disease (AD) [ 1 ] Parkinson's disease (PD) [ 2 ] and multiple sclerosis (MS), an inflammatory, demyelinating disease of the central nervous system [ 3 , 4 ]. Neurons are particularly sensitive to changes in oxidative stress, likely because they are postmitotic, have critical energy demands and high concentrations of polyunsaturated fatty acids in their membranes that can be easily altered by oxidation [ 5 ].…”