Neuroprotective mechanisms of dieckol against glutamate toxicity through reactive oxygen species scavenging and nuclear factor-like 2/heme oxygenase-1 pathway
Yanji Cui1,4, Khulan Amarsanaa1, Ji Hyung Lee1, Jong-Kook Rhim2,8, Jung Mi Kwon3,8, Seong-Ho Kim5, Joo Min Park6,7, Sung-Cherl Jung1,8, and Su-Yong Eun1,8,*
1Department of Physiology, 2Department of Neurosurgery, 3Division of Hematology-Oncology, Department of Internal Medicine, Jeju National University School of Medicine, Jeju 63243, Korea, 4Neurology 1, The Second Affiliated Hospital of Xinxiang Medical University, Henan 453002, China, 5BotaMedi Inc., Jeju 63309, 6Center for Cognition and Sociality, Institute for Basic Science (IBS), KAIST, Daejeon 34126, 7University of Science and Technology, Daejeon 34113, 8Institute of Medical Science, Jeju National University, Jeju 63243, Korea
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Glutamate toxicity-mediated mitochondrial dysfunction and neuronal cell death are involved in the pathogenesis of several neurodegenerative diseases as well as acute brain ischemia/stroke. In this study, we investigated the neuroprotective mechanism of dieckol (DEK), one of the phlorotannins isolated from the marine brown alga Ecklonia cava, against glutamate toxicity. Primary cortical neurons (100 µM, 24 h) and HT22 neurons (5 mM, 12 h) were stimulated with glutamate to induce glutamate toxic condition. The results demonstrated that DEK treatment significantly increased cell viability in a dose-dependent manner (1–50 µM) and recovered morphological deterioration in glutamate-stimulated neurons. In addition, DEK strongly attenuated intracellular reactive oxygen species (ROS) levels, mitochondrial overload of Ca2+ and ROS, mitochondrial membrane potential (∆Ѱm) disruption, adenine triphosphate depletion. DEK showed free radical scavenging activity in the cell-free system. Furthermore, DEK enhanced protein expression of heme oxygenase-1 (HO-1), an important anti-oxidant enzyme, via the nuclear translocation of nuclear factor-like 2 (Nrf2). Taken together, we conclude that DEK exerts neuroprotective activities against glutamate toxicity through its direct free radical scavenging property and the Nrf-2/HO-1 pathway activation.