Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte

Abstract

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...

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

“…Therefore, protection in C. elegans by skn-1 activation may primarily result from the upregulation of other effectors of this pathway, particularly the numerous antioxidant genes that have been identified by gene expression analysis (Park et al 2009b). Supporting this model, Nrf2 activation is protective in PD models that do not involve accumulation of a toxic protein: MPTP treatment in mice (Chen et al 2009) and parkin loss-of-function in flies (Trinh et al 2008). It may be possible to identify additional protective processes induced by coffee exposure by RNAi knockdown of individual skn-1-modulated genes.…”

“…For example, Nrf2 activation has been reported to be protective in a mouse MPTP model of PD (Chen et al 2009), as well as a transgenic mouse model of familial amyotrophic lateral sclerosis (ALS) (Vargas et al 2008). Similarly, chemical or genetic activation of the Nrf2 pathway is protective in multiple Drosophila models of PD (Trinh et al 2008).…”

“…Indeed, a neuropeptide-like hormone, NLP-7, has been recently shown to act downstream of skn-1 to promote life-span extension by dietary restriction (Park et al 2010). It is also interesting to note that astrocyte activation of Nrf2 is sufficient to convey neuronal protection in mouse models of PD and ALS (Vargas et al 2008;Chen et al 2009), demonstrating that Nrf2-dependent neuroprotection in mammals can also be non-cell autonomous. The genetic tools available in C. elegans should allow us to determine to what degree cell autonomous activation of skn-1 contributes to protection against Ab 42 toxicity.…”

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

“…1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an inhibitor of complex I, is able to induce the clinical and pathological hallmarks of PD, and for this reason, is used as a model of the disease. Nrf2 activators have been found to be neuroprotective in the MPTP model of PD (Burton et al, 2006;Chen et al, 2009;Jazwa et al, 2011). The authors found that the deficiency in Nrf2 increased the sensitivity to the complex I inhibitor, while its activation in astrocytes was able to protect against MPTP-mediated toxicity.…”

The molecular basis of neurodegeneration in multiple sclerosis

“…As such the Nrf2 pathway represents an interesting therapeutic target since further activation of this protective system via specific Nrf2 activators might counteract oxidative stress and injury under pathological conditions. Importantly, recent studies demonstrate the efficacy and beneficial effects of Nrf2 activation by counteracting ROS-mediated injury and cytotoxicity in vitro and in EAE animals [17,18,52,50,67]. Moreover, clinical trials with BG12, an oral formulation of dimethyl fumarate, which is known to enhance Nrf2 activation, reported promising results [53].…”