Nrf2--mediated protection against 6-hydroxydopamine

Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, WI 53705, USA.
Brain Research (Impact Factor: 2.83). 06/2007; 1144:192-201. DOI: 10.1016/j.brainres.2007.01.131
Source: PubMed

ABSTRACT 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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    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 · 4.99 Impact Factor
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    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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    ABSTRACT: Exposure to cigarette smoke has been associated with an increased risk of neurological diseases such as stroke, Alzheimer's disease and multiple sclerosis. In these studies, serum and brain sections from Lewis rats or those exposed to cigarette smoke and control rats were examined for evidence of increased inflammation and oxidative stress. Immunocytochemical staining of brain sections from CS-exposed rats showed increased expression of class II MHC and, in ELISA, levels of IFN-gamma and TNF-α were higher than for non-exposed rats. In polymerase chain reaction assays there was increased interferon-gamma, TNF-α, IL-1α, IL-1β, IL-23, IL-6, IL-23, IL-17, IL-10, TGF-β, T-bet and FoxP3 gene expression with CS exposure. There was also markedly elevated MIP-1α/CCL3, less prominent MCP-1/CCL2 and no elevation of SDF-1α gene expression. Analysis of samples from CS-exposed and control rats for anti-oxidant expression showed no significant difference in serum levels of glutathione and, in brain, similar levels of superoxide dismutase and decreased thioredoxin gene expression. In contrast, there was increased brain gene expression for the pro-oxidants iNOS and the NADPH components NOX4, dual oxidase 1 and p22(phox). Nrf2 expression, which is typically triggered as a secondary response to oxidative stress, was also increased in brains from CS-exposed rats with nuclear translocation of this protein from cytoplasm demonstrated in astrocytes in association with increased expression of the aryl hydrocarbon receptor gene, an Nrf2 target. These studies, therefore, demonstrate that CS exposure in these animals can trigger multiple immune and oxidative responses that may have important roles in the pathogenesis of CNS inflammatory neurological diseases.
    Journal of neuroimmunology 09/2012; 254(1-2). DOI:10.1016/j.jneuroim.2012.09.006 · 2.79 Impact Factor


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