Lipid Peroxidation and Antioxidant Supplementation in Neurodegenerative Diseases: A Review of Human Studies

Abstract

Being characterized by progressive and severe damage in neuronal cells, neurodegenerative diseases (NDDs) are the major cause of disability and morbidity in the elderly, imposing a significant economic and social burden. As major components of the central nervous system, lipids play important roles in neural health and pathology. Disturbed lipid metabolism, particularly lipid peroxidation (LPO), is associated with the development of many NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), all of which show elevated levels of LPO products and LPO-modified proteins. Thus, the inhibition of neuronal oxidation might slow the progression and reduce the severity of NDD; natural antioxidants, such as polyphenols and antioxidant vitamins, seem to be the most promising agents. Here, we summarize current literature data that were derived from human studies on the effect of natural polyphenols and vitamins A, C, and E supplementation in patients with AD, PD, and ALS. Although these compounds may reduce the severity and slow the progression of NDD, research gaps remain in antioxidants supplementation in AD, PD, and ALS patients, which indicates that further human studies applying antioxidant supplementation in different forms of NDDs are urgently needed.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; antioxidant supplementation; lipid peroxidation; neurodegenerative diseases.

Figure 1

Pathophysiological mechanisms of Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) development and progression. Reactive oxygen species (ROS) produced by mitochondrial Cyt p-450, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and lipoxygenase (LOX) attacks brain lipids, proteins, and DNA, further increasing oxidative stress. Oxidative damage of lipids results in the formation of lipid peroxidation (LPO) products, which further attack lipids, proteins, and DNA, impairing brain function. LPO can affect different types of neurons: in hippocampal neurons, LPO products bind to amyloid β peptide and form misfolded amyloid β peptide and amyloid β senile plaque, which disturbs nerve signaling and structure and induces AD; in dopaminergic neurons, LPO products induce generation and accumulation of misfolded α-synuclein, resulting in insufficient dopamine production and development of PD; in motor neurons, mutation of the superoxide dismutase 1 (SOD1) gene leads to the formation of misfolded SOD1 enzymes and abnormal production of ROS and LPO products, causing necrosis and death of the affected neurons in ALS; LPO-modified proteins are also associated with neural disruption in ALS. AD, Alzheimer’s disease; PD, Parkinson’s disease; ALS, amyotrophic lateral sclerosis; ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; LOX, lipoxygenase; LPO, Lipid peroxidation; SOD1, superoxide dismutase 1.

Figure 2

Some of oxidation products from linoleic acid (LA). HPODE, hydroperoxyoctadecadienoic acid; HODE, hydroxyoctadecadienoic acid; LOX, lipoxygenase.

Figure 3

Three types of oxidation products of arachidonic acid (AA): isofurans (IsoFs), isoprostanes (IsoP), hydroperoxyeicosatetraenoic acid (HPETE), hydroxyeicosatetraenoic acid (HETE), ROS, and LOX.

Figure 4

Oxidation products from docosahecsaenoic acid (DHA): neurofurans (NFs) and neuroprostanes (NPs).

Figure 5

Short-chain aldehydes: acrolein, 4-hydroxy-2-hexenal (HNE), and malondialdehyde (MDA).