Role of oxidative stress in neurodegenerative disorders: a review of reactive oxygen species and prevention by antioxidants

Abstract

Neurological disorders include a variety of conditions, including Alzheimer's disease, motor neuron disease and Parkinson's disease, affecting longevity and quality of life, and their pathogenesis is associated with oxidative stress. Several of the chronic neurodegenerative pathologies of the CNS share some common features, such as oxidative stress, inflammation, synapse dysfunctions, protein misfolding and defective autophagia. Neuroinflammation can involve the activation of mast cells, contributing to oxidative stress, in addition to other sources of reactive oxygen species. Antioxidants can powerfully neutralize reactive oxygen species and free radicals, decreasing oxidative damage. Antioxidant genes, like the manganese superoxide dismutase enzyme, can undergo epigenetic changes that reduce their expression, thus increasing oxidative stress in tissue. Alternatively, DNA can be altered by free radical damage. The epigenetic landscape of these genes can change antioxidant function and may result in neurodegenerative disease. This imbalance of free radical production and antioxidant function increases the reactive oxygen species that cause cell damage in neurons and is often observed as an age-related event. Increased antioxidant expression in mice is protective against reactive oxygen species in neurons as is the exogenous supplementation of antioxidants. Manganese superoxide dismutase requires manganese for its enzymic function. Antioxidant therapy is considered for age-related neurodegenerative diseases, and a new mimetic of a manganese superoxide dismutase, avasopasem manganese, is described and suggested as a putative treatment to reduce the oxidative stress that causes neurodegenerative disease. The aim of this narrative review is to explore the evidence that oxidative stress causes neurodegenerative damage and the role of antioxidant genes in inhibiting reactive oxygen species damage. Can the neuronal environment of oxidative stress, causing neuroinflammation and neurodegeneration, be reduced or reversed?

Keywords: Alzheimer’s disease; avasopasem manganese; neurodegeneration; reactive oxygen species; superoxide dismutase.

Graphical Abstract

Figure 1

ROS. Examples of ROS as by-products of normal oxygen metabolism including peroxide, superoxide anion, hydroxyl radical and hydroxyl ion. All these species have an unpaired electron (except for the hydroxyl ion) making them highly unstable resulting in OS that can cause damage to cell structures and DNA. However, some low levels of ROS can have roles in intracellular signalling. Figure based on information from Phaniendra et al.

Figure 2

OS and NDG. ROS are generated by endogenous and exogenous sources. ROS cause OS that can cause DNA and tissue damage, resulting in disease processes. Antioxidant genes, such as SOD2, can reduce OS, enabling cell repair to occur and reduce pathogenesis of disease caused by OS. OS can damage the CNS and brain cells causing NDG-related diseases such as Alzheimer’s disease, Parkinson’s disease and motor neuron disease—these are indicated on the brain figures by the blue and purple areas of the brains, respectively. It is postulated that reducing OS may inhibit the pathogenesis of NDG. Figure based on information from Islam.

Figure 3

SOD genes. A comparison of the different SOD genes and the enzymes that they encode, showing the catalytic domains that bind Cu/Zn in SOD1 and SOD3 and Mn in SOD2. Homology is shown between intracellular SOD1 and extracellular SOD3. There is no significant amino acid homology between SOD2 and SOD1 and SOD3. Figure adapted from Sah et al.

Figure 4

Antioxidant mechanism of SOD2. Proposed mechanism for Mn SOD (SOD2) chemical reaction in neutralizing superoxide ROS. Figure adapted from Azadmanesh and Borgstahl and Azadmanesh et al.