Neuroprotective Effect of Antioxidants in the Brain

Abstract

The brain is vulnerable to excessive oxidative insults because of its abundant lipid content, high energy requirements, and weak antioxidant capacity. Reactive oxygen species (ROS) increase susceptibility to neuronal damage and functional deficits, via oxidative changes in the brain in neurodegenerative diseases. Overabundance and abnormal levels of ROS and/or overload of metals are regulated by cellular defense mechanisms, intracellular signaling, and physiological functions of antioxidants in the brain. Single and/or complex antioxidant compounds targeting oxidative stress, redox metals, and neuronal cell death have been evaluated in multiple preclinical and clinical trials as a complementary therapeutic strategy for combating oxidative stress associated with neurodegenerative diseases. Herein, we present a general analysis and overview of various antioxidants and suggest potential courses of antioxidant treatments for the neuroprotection of the brain from oxidative injury. This review focuses on enzymatic and non-enzymatic antioxidant mechanisms in the brain and examines the relative advantages and methodological concerns when assessing antioxidant compounds for the treatment of neurodegenerative disorders.

Keywords: antioxidant; brain; neurodegenerative disease; neuroprotection; oxidative stress.

Figure 1

Development of various diseases by the pathophysiology of oxidative stress in the brain. Balance and imbalance between pro-oxidants and antioxidants against reactive oxygen species production induce oxidative stress and are consequently involved in neuronal damage resulting in the neurodegenerative diseases.

Figure 2

Enzymatic antioxidant defense system against the production of reactive oxygen species (ROS). Various pathways of cell death caused by ROS and its transformation are observed in brain injury. NADPH oxidase and mitochondrial respiratory transport chain are known as major cellular sources of the superoxide radical anion (O₂⁻). The superoxide radical anion reacts with nitric oxide (NO) to form the peroxynitrite anion (ONOO⁻) which mediates oxidative modification of protein residues via an interaction with NO. The superoxide radical is dismuted by the superoxide dismutase enzyme (SOD) to form hydrogen peroxide. In addition, manganese containing superoxide dismutase (Mn-SOD) reduces the superoxide radical anion generated during the electron transport chain in the mitochondrial matrix. Catalase (CAT) and/or glutathione peroxidase (GPx) decomposes hydrogen peroxide to water and oxygen by enzymatic reactions. Hydrogen peroxide is decomposed into reactive hydroxyl radicals by reaction with catalytically active redox metals such as (copper and iron). Hydroxyl radicals can react with oxygen to form peroxyl or alkoxyl radicals which can lead to lipid peroxidation and react with DNA and primarily cause damage to DNA. Peroxiredoxins (Prx) and thioredoxin (Trx) act as redox-regulated proteins to additional redox relay bases.

Figure 3

Schematic representation of vitamin uptake and protective mechanisms by exogenous vitamins as antioxidants. Vitamin C: During uptake in the CNS, ascorbate passes through the BBB to enter directly through the SVCT-2 and/or possibly DHA through GLUT1s. Moreover, the neuronal uptake of ascorbate occurs through SVCT-2 and DHA via the GLUT1s. In the neuron, DHA can be reduced to ascorbate or released back into the extracellular space by GLUT1. Ascorbate free radicals convert to form DHA and ascorbate. Ascorbate recycles both the ascorbate free radical and DHA by cellular metabolism. Astrocytes contain ascorbate from recycling of DHA which is taken up through GLUT1s. Neurons directly acquire ascorbate via SVCT-2. Vitamin E: With respect to vitamin E uptake, HDL particles can pass through SRB1 receptors expressed on endothelial cells. Astrocytes that exist adjacent to the BBB take up vitamin E into the inner cell membrane. Synthesized ApoE lipoproteins take up vitamin E that is left out of an ABC transporter, for transport into neurons through LRP1 requiring vitamin E for maintenance or during conditions of oxidative stress. Vitamin A: In cellular retinoid signaling pathways, retinol is metabolized to all-trans-retinoic acid (ATRA). Vitamin A (retinol, ROL) binds to plasma retinol binding protein (RBP4) and circulates; RBP4 protein binds to the membrane receptor STAR6 to promote cellular absorption of retinol from the cells. A chylomicron remnant (CMRE), as a form of circulating vitamin A, can serve as a source of vitamin A for the cells and retinol is esterified and stored by lecithin: retinol acyltransferase (LRAT) and is reversibly oxidized to retinaldehyde (RAL) by retinol dehydrogenase (RDH/ADH). In addition, retinol is further oxidized to RA in an irreversible manner by retinaldehyde dehydrogenase (RALDH). ATRA regulates gene transcription through retinoic acid receptors (RAR) and/or retinoid X receptors (RXRs) which are bound to retinoic acid response elements (RARE) in the nucleus. These representative schematics are modified from [130,154,161]. Abbreviations: VC, vitamin C; VE, vitamin E; VA, vitamin A; ASC, ascorbate; ASF, ascorbate free radical; DHA, dehydroascorbic acid; GLUT1, glucose transports; SVTC-2, sodium-dependent transporters; LRP, lipoprotein receptor-related protein; GSH, glutathione; ApoE, apolipoprotein E; HDL, density lipoprotein; CMRE, chylomicron remnant; CRABP, cellular retinoic acid-binding protein; LRAT, lethicin: retinol acyltransferase; RBP, retinol binding protein; RAL, retinaldehyde; RDH/ADH, retinol dehydrogenase; RALDH, retinaldehyde dehydrogenase; RXR, retinoid X receptors; RAR, retinoic acid receptors; ATRA, all-trans-retinoic acid; BBB, blood–brain barrier.

Figure 4

Neuroprotective effect of vitamin E. (A): Representative propidium iodide (PI) images. When hippocampal slices were exposed to 5 μM KA for 15 h, PI uptake in the CA3 region was significantly higher than the CA1 region. Co-treatment using ATPH (100 μM) or ATTN (100 μM) with KA significantly reduced PI uptake in the CA3 region compared with KA treatment alone. (B): Quantification of PI intensity. * p < 0.05, # p < 0.05; one-way ANOVA followed by Dunnett’s post hoc comparison (* p < 0.05 vs. normal, # p < 0.05 vs. KA-treated cultures). This present data is a part of our previous research showing neuronal rescue after oxidative stress by alpha-tocopherol and tocotrienol treatment [166]. Abbreviations: ATPH, alpha-tocopherol; ATTN, alpha-tocotrienol; OHSC, organotypic hippocampal slice culture; KA, kainic acid; PI, propidium iodide; DCF, dichlorofluorescein.