Nrf2--mediated protection against 6-hydroxydopamine

Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, WI 53705, USA.
Brain Research (Impact Factor: 2.84). 06/2007; 1144(1):192-201. DOI: 10.1016/j.brainres.2007.01.131
Source: PubMed


Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by cell loss in the substantia nigra resulting in striatal dopamine depletion. Although the cause of sporadic PD is unknown, oxidative stress is thought to contribute to disease pathogenesis. One mechanism by which cells defend themselves against oxidative stress is through the transcriptional upregulation of cytoprotective genes. Under oxidative stress conditions, the transcription factor NF-E2-related factor (Nrf2) binds to the antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. Here we show that loss of Nrf2-mediated transcription exacerbates vulnerability to the neurotoxin 6-hydroxydopamine (6-OHDA) both in vitro and in vivo. We further demonstrate that activation of the Nrf2-ARE pathway by the known chemical inducer tert-butylhydroquinone can protect against 6-OHDA in vitro. Induction of this pathway by transplantation of astrocytes overexpressing Nrf2 can protect against 6-OHDA-induced damage in the living mouse. This suggests that the Nrf2-ARE pathway is a promising target for therapeutics aimed at reducing or preventing cell death in PD.

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    • "models of AD , induction of the Nrf2 – ARE transcrip - tional pathway has been demonstrated to improve spatial learning ( Kanninen et al . , 2009 ) and attenuate inflammation ( Thimmulappa et al . , 2006 ) and oxidative stress . In PD , several inducers of Nrf2 have been shown to have the ability to protect cells and ameliorate symptoms in vitro ( Jakel et al . , 2007 ) and in vivo ( Chen et al . , 2009 ) . There is also evidence of the therapeutic potential of the Nrf2 – ARE pathway in Hun - tington disease ( Calkins et al . , 2005 ; Ellrichmann et al . , 2011 ) , amyotrophic lateral sclerosis ( Vargas et al . , 2008 ) and brain ischaemic damage . Sulforaphane , a potent Nrf2 inducer iso - lated fro"
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    ABSTRACT: Background and purposeNeurodegenerative diseases are a major problem afflicting aging populations; however, there are no effective treatments to stop their progression. Oxidative stress and neuroinflammation are common factors in their pathogenesis. Nrf2 is the master regulator to control oxidative stress and melatonin is an endogenous hormone with antioxidative properties that reduces its levels with aging. We have designed a new compound that combines melatonin with Nrf2 induction properties with the idea of achieving improved neuroprotective properties.Experimental approachCompound ITH12674 is a hybrid of melatonin and sulforaphane designed to exert a dual drug-prodrug mechanism of action. We have obtained the proposed hybrid in a single step; to test its neuroprotective properties we have used different in vitro models of oxidative stress related to neurodegenerative diseases and brain ischemia.Key resultsITH12674 shows an interesting neuroprotective profile, improving that of melatonin and sulforaphane; ITH12674 exhibits (i) concentration-dependent protection in cortical neurons subjected to oxidative stress; (ii) decreased ROS production; (iii) augmentation of glutathione concentrations in cortical neurons; (iv) induction of the Nrf2-ARE transcriptional response in transfected HEK293T cells; (v) protection of organotypic cultures of hippocampal slices subjected to oxygen and glucose deprivation and reoxygenation via induction of HO-1 and free radical reduction.Conclusion The melatonin-sulforaphane hybrid ITH12674 combines the signaling pathways of the parent compounds to improve its neuroprotective properties; this open a new line of research for such hybrid compounds to treat neurodegenerative diseases.
    British Journal of Pharmacology 11/2014; 172(7). DOI:10.1111/bph.13025 · 4.84 Impact Factor
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    • "Alterations in Nrf2 signaling were linked to abnormal redox homeostasis. Loss of Nrf2-mediated transcription exacerbated the vulnerability of dopaminergic neurons to oxidative stresses [10]. Nrf2 knockout mice showed a greater loss of dopaminergic neurons compared with wild type mice when exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [11]. "
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    ABSTRACT: Background Mounting evidence shows that urate may become a biomarker of Parkinson's disease (PD) diagnosis and prognosis and a neuroprotectant candidate for PD therapy. However, the cellular and molecular mechanisms underlying its neuroprotective actions remain poorly understood. Results In this study, we showed that urate pretreatment protected dopaminergic cell line (SH-SY5Y and MES23.5) against 6-hydroxydopamine (6-OHDA)- and hydrogen peroxide- induced cell damage. Urate was found to be accumulated into SH-SY5Y cells after 30 min treatment. Moreover, urate induced NF-E2-related factor 2 (Nrf2) accumulation by inhibiting its ubiquitinationa and degradation, and also promoted its nuclear translocation; however, it did not modulate Nrf2 mRNA level or Kelch-like ECH-associated protein 1 (Keap1) expression. In addition, urate markedly up-regulated the transcription and protein expression of γ-glutamate-cysteine ligase catalytic subunit (γ-GCLC) and heme oxygenase-1 (HO-1), both of which are controlled by Nrf2 activity. Furthermore, Nrf2 knockdown by siRNA abolished the intracellular glutathione augmentation and the protection exerted by urate pretreatment. Conclusion Our findings demonstrated that urate treatment may result in Nrf2-targeted anti-oxidant genes transcription and expression by reducing Nrf2 ubiquitination and degradation and promoting its nuclear translocation, and thus offer neuroprotection on dopaminergic cells against oxidative stresses.
    PLoS ONE 06/2014; 9(6):e100286. DOI:10.1371/journal.pone.0100286 · 3.23 Impact Factor
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    • "In vivo and in vitro studies showed that the activation of the transcription factor Nrf2 and expression of antioxidant response element (ARE)containing genes protected neurons from PD-related neurotoxins such as paraquat, 6-hydroxydopamine (6-OHDA), MPTP, and rotenone (Lee et al. 2003, Jakel et al. 2007, MacKenzie et al. 2008, Chen et al. 2009b, Satoh et al. 2009, Niso-Santano et al. 2010). Nrf2 knockout mice presented increased vulnerability to 6-OHDA, and the induction of the Nrf2/ARE pathway by transplantation of astrocytes overexpressing Nrf2 protected the brain against 6-OHDA-induced injury (Jakel et al. 2007). Among the target genes of Nrf2/ARE pathway are several pivotal enzymes involved in the homeostasis of glutathione, a major cellular antioxidant (Lee and Johnson 2004). "

    Role of Oxidative Stress in Chronic Diseases, Edited by Isaias Dichi, José Wander Breganó, Andréa Name Colado Simão, Rubens Cecchini, 01/2014: chapter 5.3: pages 521-548; CRC Press.
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