title: Norepinephrine provides short-term neuroprotection against Aβ1-42 by reducing oxidative stress independent of Nrf2 activation.
abstract: Pathophysiological evidence correlating locus ceruleus neuron loss with increased Alzheimer's disease pathology suggests that norepinephrine (NE) is neuroprotective. Here, we evaluated the effects of NE on amyloid-β (Aβ)1-42-induced neurotoxicity and determined how NE exerts its actions in human SK-N-SH neurons. NE protected SK-N-SH cells against Aβ1-42-induced neurotoxicity only after a 4-hour treatment. The ability of NE to reduce Aβ1-42-induced neurotoxicity was independent of the adrenoceptor signaling pathway. Notably, NE downregulated Aβ1-42-mediated increases in intracellular reactive oxygen species (ROS) production. However, NE did not affect Aβ1-42-induced activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) redox signaling pathway, known to be involved in oxidative stress. Among the antioxidants tested, N-acetyl cysteine and glutathione, which are not only ROS scavengers but also thiol-reducing agents, mimicked the protective effects of NE. Consistently, Kelch-like ECH-associating protein 1 inhibitors, which activated the Nrf2 pathway, failed to decrease Aβ1-42-induced ROS generation and elicited no protection against Aβ1-42. Taken together, these findings suggest that NE could exert neuroprotective function against Aβ1-42 via redox cycling and reduction of intracellular oxidative stress regardless of downstream activation of the Nrf2 pathway.
authors: Department of Microbiology, Ewha Medical Research Institute, School of Medicine, Division of Molecular Biology and Neuroscience, Ewha Womans University, Seoul, Republic of Korea.
authors: Kyoung A
authors: KA
authors: Jhang
authors: Department of Microbiology, Ewha Medical Research Institute, School of Medicine, Division of Molecular Biology and Neuroscience, Ewha Womans University, Seoul, Republic of Korea.
authors: Eun Ok
authors: EO
authors: Lee
authors: Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Hye-Sun
authors: HS
authors: Kim
authors: Department of Microbiology, Ewha Medical Research Institute, School of Medicine, Division of Molecular Biology and Neuroscience, Ewha Womans University, Seoul, Republic of Korea. Electronic address: younghae@ewha.ac.kr.
authors: Young Hae
authors: YH
authors: Chong
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000975:Antioxidants; D002478:Cells, Cultured; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents; D009638:Norepinephrine / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D009638:Norepinephrine
keywords: Alzheimer's disease; Aβ1–42; Norepinephrine; Nrf2 pathway; Oxidative stress; Redox cycling