title: S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis.
abstract: Compelling evidence indicates that oxidative stress contributes to motor neuron injury in amyotrophic lateral sclerosis (ALS), but antioxidant therapies have not yet achieved therapeutic benefit in the clinic. The nuclear erythroid 2-related-factor 2 (Nrf2) transcription factor is a key regulator of an important neuroprotective response by driving the expression of multiple cytoprotective genes via its interaction with the antioxidant response element (ARE). Dysregulation of the Nrf2-ARE system has been identified in ALS models and human disease. Taking the Nrf2-ARE pathway as an attractive therapeutic target for neuroprotection in ALS, we aimed to identify CNS penetrating, small molecule activators of Nrf2-mediated transcription in a library of 2000 drugs and natural products. Compounds were screened extensively for Nrf2 activation, and antioxidant and neuroprotective properties in vitro. S[+]-Apomorphine, a receptor-inactive enantiomer of the clinically approved dopamine-receptor agonist (R[-]-apomorphine), was identified as a nontoxic Nrf2 activating molecule. In vivo S[+]-apomorphine demonstrated CNS penetrance, Nrf2 induction, and significant attenuation of motor dysfunction in the SOD1(G93A) transgenic mouse model of ALS. S[+]-apomorphine also reduced pathological oxidative stress and improved survival following an oxidative insult in fibroblasts from ALS patients. This molecule emerges as a promising candidate for evaluation as a potential neuroprotective agent in ALS patients in the clinic.
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Mead
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Higginbottom
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Allen
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Ellen
authors.initials: E
authors.lastname: Bennett
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Siân C
authors.initials: SC
authors.lastname: Barber
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.affiliation: Welsh School of Pharmacy, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Neelam
authors.initials: N
authors.lastname: Patel
authors.affiliation: SimCyp, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.affiliation: Welsh School of Pharmacy, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grierson
authors.affiliation: Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. Electronic address: pamela.shaw@sheffield.ac.uk.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D061745:Antioxidant Response Elements / Q000502:physiology*; D001058:Apomorphine / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004224:Diterpenes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; C030419:andrographolide; D001058:Apomorphine
keywords: Amyotrophic lateral sclerosis; Nrf2; motor neurone disease; neurodegeneration; preclinical pharmacology