Review ArticleNrf2-induced antioxidant protection: A promising target to counteract ROS-mediated damage in neurodegenerative disease?
Introduction
Reactive oxygen species (ROS), such as superoxide, hydrogen peroxide, and hydroxyl radicals, are continuously produced in aerobic organisms. Under physiological conditions the level of ROS formation is in equilibrium with the antioxidant capacity; however, when the production of ROS overwhelms the cellular antioxidant capacity, oxidative stress and subsequent damage occur [1]. The central nervous system (CNS) is particularly sensitive to oxidative stress, owing to a high oxygen consumption and enrichment in polyunsaturated fatty acids, making it particularly vulnerable to lipid peroxidation. Oxidative stress and injury have been implicated in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11].
Neurodegenerative diseases share several common pathological features, including abnormal protein deposition associated with microglial activation and alterations in tissue redox balance [4], [12], [13], [14], [15]. Although oxidative stress has been implicated in the pathogenesis of several neurodegenerative diseases, therapies based on exogenous antioxidants have been disappointing [16]. High amounts of antioxidants are needed to achieve protective effects in the CNS, as most exogenous antioxidants do not efficiently cross the blood–brain barrier owing to their hydrophilic nature. Furthermore, administration of antioxidants is limited owing to their toxicity at high doses, resulting in a small therapeutic window of these agents [16]. This emphasizes the need for alternative strategies to therapeutically counteract the detrimental effects of ROS and restore the cellular redox balance. A promising candidate to limit ROS-mediated damage is the activation of endogenous antioxidant enzymes present in the CNS, such as catalase, superoxide dismutases, and peroxiredoxins [1], [17]. Transcription of these cytoprotective proteins is under control of the nuclear transcription factor NF-E2-related factor 2 (Nrf2), which plays a central role in the regulation of the cellular redox status [18], [19], [20]. Under normal homeostatic conditions, Nrf2 transcription is repressed by its negative regulator Kelch-like ECH-associated protein 1 (Keap1) [18]. However, upon exposure to ROS, Nrf2 dissociates from cytosolic Keap1 and translocates to the nucleus, where it binds to the antioxidant response element (ARE) in the promoter region of genes encoding antioxidant enzymes, thereby inducing the production of endogenous antioxidant enzymes [19]. Likewise, various xenobiotics, including tert-butylhydroquinone (tBHQ), 1,2-dithiole-3-thione, dimethylfumarate, sulforaphane, and 3-hydroxycoumarin, mimic a transient oxidative insult, thereby promoting transcription of Nrf2-driven antioxidant enzymes [19], [21]. In this paper, we review the involvement of oxidative stress and ROS-induced injury in AD, PD, and HD pathology and discuss the putative protective effects of Nrf2-induced antioxidant protection.
Section snippets
Reactive oxygen species and oxidative stress
ROS are small biological molecules, which are constantly produced in aerobic organisms as a natural by-product of oxygen metabolism. ROS play an important physiological role in cell signaling [22], although long-term exposure of cells to enhanced levels of ROS will lead to profound toxic effects, such as necrotic or apoptotic cell death. Several enzymatic systems contribute to intracellular ROS production, including NA(D)PH oxidase [23], cytochrome P450-dependent oxygenases [24], and xanthine
Keap1-Nrf2-ARE pathway
To maintain a physiological redox balance, cells are equipped with a wide variety of endogenous antioxidant enzymes. Production of these cytoprotective enzymes is induced upon exposure to ROS via a mechanism regulated at the transcriptional level [33]. Genes that code for proteins involved in ROS detoxification share a common promoter element, called the antioxidant response element. ARE-mediated gene activation is coordinated by Nrf2, which, upon exposure to electrophiles or ROS, translocates
The involvement of ROS and Nrf2 in neurodegenerative diseases
Oxidative stress and the production of ROS are involved in the pathogenesis of a wide variety of chronic neurodegenerative diseases such as AD, PD, and HD. The facts that age is a risk factor for these neurodegenerative disorders and that ROS in the brain increase with age support the involvement of ROS in neurodegeneration [31]. The free radical theory of aging hypothesizes that the aging process is associated with (i) an increase in the production of ROS together with (ii) a concurrent
Conclusion
Although initial experiments using knockout mice demonstrated that Nrf2 protein is not essential for normal development [185], recent data inevitably show that mice with a targeted disruption of the Nrf2 gene are prone to developing autoimmune-mediated lesions and increased oxidative lesions in various tissues [186]. In addition, it has been reported that mice lacking Nrf2 develop vacuolar leukoencephalopathy with concomitant widespread astrogliosis due to oxidative damaging of myelin [187].
Acknowledgment
This work was supported by grants from Stichting Vrienden MS Research, The Netherlands, Project Nos. MS 05-567 and MS 05-358c (J. van Horssen).
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