PMID- 23608463 OWN - NLM STAT- MEDLINE DCOM- 20150821 LR - 20211021 IS - 1873-4596 (Electronic) IS - 0891-5849 (Print) IS - 0891-5849 (Linking) VI - 61 DP - 2013 Aug TI - S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis. PG - 438-52 LID - S0891-5849(13)00158-5 [pii] LID - 10.1016/j.freeradbiomed.2013.04.018 [doi] AB - 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. CI - Copyright (c) 2013 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Mead, Richard J AU - Mead RJ AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Higginbottom, Adrian AU - Higginbottom A AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Allen, Scott P AU - Allen SP AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Kirby, Janine AU - Kirby J AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Bennett, Ellen AU - Bennett E AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Barber, Sian C AU - Barber SC AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Heath, Paul R AU - Heath PR AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Coluccia, Antonio AU - Coluccia A AD - Welsh School of Pharmacy, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK. FAU - Patel, Neelam AU - Patel N AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Gardner, Iain AU - Gardner I AD - SimCyp, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK. FAU - Brancale, Andrea AU - Brancale A AD - Welsh School of Pharmacy, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK. FAU - Grierson, Andrew J AU - Grierson AJ AD - Sheffield Institute for Translational Neuroscience, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK. FAU - Shaw, Pamela J AU - Shaw PJ AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130419 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Diterpenes) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Nfe2l2 protein, mouse) RN - 410105JHGR (andrographolide) RN - N21FAR7B4S (Apomorphine) SB - IM MH - Amyotrophic Lateral Sclerosis/*metabolism MH - Animals MH - Antioxidant Response Elements/*physiology MH - Apomorphine/*pharmacology MH - Brain/*metabolism MH - Cells, Cultured MH - Diterpenes/pharmacology MH - Fibroblasts/metabolism MH - Humans MH - Mice MH - NF-E2-Related Factor 2/*physiology MH - Oxidative Stress MH - Signal Transduction/*physiology PMC - PMC3684770 OTO - NOTNLM OT - Amyotrophic lateral sclerosis OT - Nrf2 OT - motor neurone disease OT - neurodegeneration OT - preclinical pharmacology EDAT- 2013/04/24 06:00 MHDA- 2015/08/22 06:00 PMCR- 2013/08/01 CRDT- 2013/04/24 06:00 PHST- 2012/07/17 00:00 [received] PHST- 2013/03/22 00:00 [revised] PHST- 2013/04/12 00:00 [accepted] PHST- 2013/04/24 06:00 [entrez] PHST- 2013/04/24 06:00 [pubmed] PHST- 2015/08/22 06:00 [medline] PHST- 2013/08/01 00:00 [pmc-release] AID - S0891-5849(13)00158-5 [pii] AID - 10.1016/j.freeradbiomed.2013.04.018 [doi] PST - ppublish SO - Free Radic Biol Med. 2013 Aug;61:438-52. doi: 10.1016/j.freeradbiomed.2013.04.018. Epub 2013 Apr 19.