Oxidative stress has been implicated in the etiology of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. It is known that under conditions of oxidative stress, the transcription factor NF-E2-related factor (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. To investigate the role of Nrf2 in the process of MPTP-induced toxicity, mice expressing the human placental alkaline phosphatase (hPAP) gene driven by a promoter containing a core ARE sequence (ARE-hPAP) were used. ARE-hPAP mice were injected (30 mg/kg) once per day for 5 days and killed 7 days after the last MPTP injection. In response to this design, ARE-dependent gene expression was decreased in striatum whereas it was increased in substantia nigra. The same MPTP protocol was applied in Nrf2 ؉/؉ and Nrf2 ؊/؊ mice; Nrf2 deficiency increases MPTP sensitivity. Furthermore, we evaluated the potential for astrocytic Nrf2 overexpression to protect from MPTP toxicity. Transgenic mice with Nrf2 under control of the astrocyte-specific promoter for the glial fribillary acidic protein (GFAP-Nrf2) on both a Nrf2 ؉/؉ and Nrf2 ؊/؊ background were administered MPTP. In the latter case, only the astrocytes expressed Nrf2. Independent of background, MPTP-mediated toxicity was abolished in GFAP-Nrf2 mice. These striking results indicate that Nrf2 expression restricted to astrocytes is sufficient to protect against MPTP and astrocytic modulation of the Nrf2-ARE pathway is a promising target for therapeutics aimed at reducing or preventing neuronal death in PD.antioxidant response element ͉ human placental alkaline phosphatase M PTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a mitochondrial complex I inhibitor that is known to damage the nigrostriatal dopaminergic pathway as seen in Parkinson's disease (PD) (1, 2). PD is a progressive neurodegenerative disease characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta. Dopaminergic neuron loss results in reduced striatal dopamine (DA) and the hallmark clinical features of PD (3). Most cases of PD are considered sporadic with unknown cause, and the etiology of sporadic PD is not fully understood. Increasing evidence suggests that mitochondrial dysfunction, oxidative damage, excitotoxicity, and inflammation are contributing factors (4-7).Evidence for the existence of oxidative stress in PD is derived from post mortem analysis of brain tissue of PD patients that demonstrates increased levels of oxidized proteins, lipids, and nucleic acids (8-13). One mechanism by which cells may combat oxidative insult is through increased transcription of genes containing the antioxidant response element (ARE). The ARE is a cis-acting enhancer sequence that regulates many cytoprotective genes via the transcription factor NF-E2-related factor (Nrf2) (Nrf2 regulation is reviewed in ref. 14). ARE-regulated genes include heme oxygenase-1 (HO-1) (15), NAD(P)H:quinone oxidoreductase-1 (NQO...

Activation of the transcription factor Nrf2 in astrocytes coordinates the upregulation of antioxidant defenses and confers protection to neighboring neurons. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. Non-neuronal cells, including astrocytes, shape motor neuron survival in ALS and are a potential target to prevent motor neuron degeneration. The protective effect of Nrf2 activation in astrocytes has never been examined in a chronic model of neurodegeneration. We generated transgenic mice over-expressing Nrf2 selectively in astrocytes using the glial fibrillary acidic protein (GFAP) promoter. The toxicity of astrocytes expressing ALS-linked mutant hSOD1 to cocultured motor neurons was reversed by Nrf2 over-expression. Motor neuron protection depended on increased glutathione secretion from astrocytes. This protective effect was also observed by crossing the GFAP-Nrf2 mice with two ALS-mouse models. Overexpression of Nrf2 in astrocytes significantly delayed onset and extended survival. These findings demonstrate that Nrf2 activation in astrocytes is a viable therapeutic target to prevent chronic neurodegeneration.

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to induce expression of a variety of cytoprotective and detoxification genes. Several of the genes commonly regulated by Nrf2 have been implicated in protection from neurodegenerative conditions. Work from several laboratories has uncovered the potential for Nrf2-mediated transcription to protect from neurodegeneration resulting from mechanisms involving oxidative stress. For this reason, Nrf2 may be considered a therapeutic target for conditions that are known to involve free radical damage. Because common mechanisms of neurodegeneration, such as mitochondrial dysfunction and build-up of reactive oxygen species, are currently being uncovered, targeting Nrf2 may be valuable in combating conditions with variable causes and etiologies. Most effectively to target this protein in neurodegenerative conditions, a description of the involvement of Nrf2 and potential for neuroprotection must come from laboratory models. Herein, we review the current literature that suggests that Nrf2 may be a valuable therapeutic target for neurodegenerative disease, as well as experiments that illustrate potential mechanisms of protection. Antioxid. Redox Signal. 11,[497][498][499][500][501][502][503][504][505][506][507][508]

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Astrocytes may modulate the survival of motor neurons in amyotrophic lateral sclerosis (ALS). We have previously shown that fibroblast growth factor-1 (FGF-1) activates astrocytes to increase secretion of nerve growth factor (NGF). NGF in turn induces apoptosis in co-cultured motor neurons expressing the p75 neurotrophin receptor (p75 NTR ) by a mechanism involving nitric oxide (NO) and peroxynitrite formation. We show here that FGF-1 increased the expression of inducible nitric oxide synthase and NO production in astrocytes, making adjacent motor neurons vulnerable to NGF-induced apoptosis. Spinal cord astrocytes isolated from transgenic SOD1 G93A rats displayed increased NO production and spontaneously induced apoptosis of co-cultured motor neurons. FGF-1 also activates the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in astrocytes. Because Nrf2 increases glutathione (GSH) biosynthesis, we investigated the role of GSH production by astrocytes on p75 NTR -dependent motor neuron apoptosis. The combined treatment of astrocytes with FGF-1 and t-butylhydroquinone (tBHQ) increased GSH production and secretion, preventing motor neuron apoptosis. Moreover, Nrf2 activation in SOD1 G93A astrocytes abolished their apoptotic activity. The protection exerted by increased Nrf2 activity was overcome by adding the NO donor DETANONOate to the co-cultures or by inhibiting GSH synthesis and release from astrocytes. These results suggest that activation of Nrf2 in astrocytes can reduce NO-dependent toxicity to motor neurons by increasing GSH biosynthesis. Keywords: amyotrophic lateral sclerosis, astrocytes, glutathione, motor neurons, nuclear factor erythroid 2-related factor 2, p75 neurotrophin receptor. Degenerating neurons can trigger the activation of surrounding astrocytes through the secretion of several proinflammatory mediators. In turn, reactive astrocytes may either promote neuronal survival by providing trophic, metabolic and antioxidant support or stimulate apoptosis by diffusible factors that activate death receptors . Recent evidence showed that mobilization of fibroblast growth factor-1 (FGF-1) can follow motor neuron damage and cause astrocyte activation in an amyotrophic lateral sclerosis (ALS) animal model . Treatment of astrocytes with FGF-1 up-regulates the expression of nerve growth factor (NGF) (Yoshida and Gage 1991), which induces apoptosis of co-cultured motor neurons through activation of the p75 neurotrophin receptor (p75 NTR ) . Although p75NTR is not present in mature motor neurons, the receptor can be re-expressed in pathological conditions, including axotomy (Ernfors et al. 1989;Koliatsos et al. 1991;Rende et al. 1995;Wu 1996;Ferri et al. 1998) Abbreviations used: ALS, amyotrophic lateral sclerosis; ARE, antioxidant response element; BSO, buthionine sulfoximine; DTNB, 5,5¢-dithiobis(2-nitrobenzoic acid); FGF-1, fibroblast growth factor-1; GFAP, glial fibrillary acidic protein; GSH, reduced glutathione; GSSG, oxidized glutathione; HO-1, heme oxygena...