Over the past decades, several exogenous compounds have been suggested as anti-oxidative treatment approaches, many with ambiguous clinical success. In the recent years, the characterization of endogenous cellular anti-oxidative responses entered the focus of interest, e.g., signaling pathways involving nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Nrf2 is a redox-sensitive basic leucine zipper transcription factor which possesses a domain for interaction with the cytoplasmatic protein kelch like ECH associated protein (Keap-1) [4
]. Upon disruption of the keap1 gene, constitutive activation of Nrf2 and its targeted genes causes juvenile lethality due to hyperkeratotic lesions in the esophagus and rodent fore- stomach. In vivo
evidence of a functional interaction between Nrf2 and Keap1 has been demonstrated in a setting where the lethality of keap1 deficiency is reversed by the parallel knockout of the nrf2 gene [5
]. Under basal conditions, Nrf2 remains in the cytoplasm, associated with the actin cytoskeleton through Keap1 [4
]. In the status of homeostasis, Nrf2 is rapidly degraded and displays a half-life between 10 and 40 min [6
]. In the presence of oxidative stress or electrophilic compounds, the Nrf2-Keap1 interaction is abolished via disruption of distinct cysteine residues in Keap1. Subsequently, Nrf2 translocates into the nucleus, where it dimerizes with small Maf proteins (musculoaponeurotic fibrosarcoma oncogene homologues) to increase the transcription rate of antioxidative response element (ARE)-driven genes (). Thus, Nrf2 activation can inhibit or diminish cellular damage in different tissues and organs [8
]. Nrf2 associated protective effects depend on the coordinated expression of genes with detoxifying, anti-oxidant capabilities. Here, two enzymatic systems are particularly important for the prevention of oxidative damage in cells of the nervous system: the heme oxygenase system and a group of enzymes involved in glutathione synthesis and utilization.
Scheme depicting the activation of the anti-oxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) including selected target genes presumably involved in anti-oxidant responses.
First, HO is a microsomal enzyme with two isoforms: a constitutive isoform HO-2 and an inducible enzyme HO-1 [9
]. In the CNS of rodents, HO-2 is nearly ubiquitously expressed. In contrast, in the normal brain, basal HO-1 expression is confined to small groups of scattered neurons and glial cells [11
]. The induction of HO-1 is considered to counteract oxidative damage and confer cytoprotection, as suggested by studies with either deficiency in, or overexpression, of HO-1 [12
]. In the nervous system, HO-1 can be activated in glial cells by its substrate heme, via Nrf2 activation, and by a plethora of pro-oxidant and inflammatory stimuli [15
Second, superoxide dismutase (SOD) activity plays a major role in the process of radical detoxification by converting superoxide to hydrogen peroxide. The efficacy of the SOD system relies on the subsequent decomposition of hydrogen peroxide by catalase or glutathione peroxidase to inhibit the conversion of hydrogen peroxide to the hydroxyl radical. Here, the peroxisomal catalase quickly metabolizes peroxide into water and molecular oxygen. Yet, the specific activity of catalase in the brain is much lower than in peripheral tissues [18
]. Thus, glutathione peroxidase has a major role in the disposition of hydrogen peroxide and organic hydroperoxides in CNS tissue. Here, astrocytes harbor a more efficient detoxification and anti-oxidative potential than neurons. On a cellular level, catalase is not expressed in mitochondria. In this organelle, glutathione is mainly responsible for detoxification during physiological or pathological conditions.
Well in line with a pivotal role of Nrf2 for ROS detoxification, Nrf2 deficient cells are more sensitive to peroxides, NO, mitochondrial toxins, endoplasmatic reticulum stress and glucose deprivation [8
]. Although Nrf2 knock-out mice apparently develop normally, aged mice are prone to autoimmune diseases: Female Nrf2 deficient mice older than 60 weeks of age develop a lupus-like severe nephritis, characterized by cellular proliferation, lobar formation, and massive granular deposits of IgG, IgM and C3 along the capillary walls. In this context, Nrf2 and consequently the oxidative cellular response may constitute one of the factors which influences the susceptibility towards autoimmune diseases [20
]. Moreover, Nrf2 is also a regulator of innate immune responses. Disruption of the nrf2 gene leads to dramatically increased mortality rates in response to pro-inflammatory challenges as mediated e.g., by LPS as well as TNF-α [21
]. Consequently, Nrf2 deficient mice are more sensitive to pulmonary inflammatory diseases, chemical hepatotoxicity and carcinogenesis [22
]. On a molecular level, Nrf2 dependent glutathione levels regulate the sensitivity of cells to Fas and TNF-α induced apoptosis [23
]. There is an inverse correlation between glutathione content and the ability to initiate apoptotic downstream signaling pathways, suggesting that glutathione levels regulate the susceptibility of the cell towards death receptor signals. Accordingly, increased glutathione levels mediated by Nrf2 completely prevent p75 neurotrophin receptor and Fas mediated motor neuron apoptosis [25