title: Neuroprotective effects of a novel single compound 1-methoxyoctadecan-1-ol isolated from Uncaria sinensis in primary cortical neurons and a photothrombotic ischemia model.
abstract: We identified a novel neuroprotective compound, 1-methoxyoctadecan-1-ol, from Uncaria sinensis (Oliv.) Havil and investigated its effects and mechanisms in primary cortical neurons and in a photothrombotic ischemic model. In primary rat cortical neurons against glutamate-induced neurotoxicity, pretreatment with 1-methoxyoctadecan-1-ol resulted in significantly reduced neuronal death in a dose-dependent manner. In addition, treatment with 1-methoxyoctadecan-1-ol resulted in decreased neuronal apoptotic death, as assessed by nuclear morphological approaches. To clarify the neuroprotective mechanism of 1-methoxyoctadecan-1-ol, we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation. Treatment with glutamate leads to early activation of NMDAR, which in turn leads to calpain-mediated cleavage of striatal-enriched protein tyrosine phosphatase (STEP) and subsequent activation of p38 mitogen activated protein kinase (MAPK). However, pretreatment with 1-methoxyoctadecan-1-ol resulted in significantly attenuated activation of GluN2B-NMDAR and a decrease in calpain-mediated STEP cleavage, leading to subsequent attenuation of p38 MAPK activation. We confirmed the critical role of p38 MAPK in neuroprotective effects of 1-methoxyoctadecan-1-ol using specific inhibitor SB203580. In the photothrombotic ischemic injury in mice, treatment with 1-methoxyoctadecan-1-ol resulted in significantly reduced infarct volume, edema size, and improved neurological function. 1-methoxyoctadecan-1-ol effectively prevents cerebral ischemic damage through down-regulation of calpain-mediated STEP cleavage and activation of p38 MAPK. These results suggest that 1-methoxyoctadecan-1-ol showed neuroprotective effects through down-regulation of calpain-mediated STEP cleavage with activation of GluN2B-NMDAR, and subsequent alleviation of p38 MAPK activation. In addition, 1-methoxyoctadecan-1-ol might be a useful therapeutic agent for brain disorder such as ischemic stroke.
authors.affiliation: Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Jang
authors.affiliation: Department of Horticultural Bioscience, College of Natural Resource and Life Science, Pusan National University, Miryang, Gyeongnam, Republic of Korea.
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Choi
authors.affiliation: Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Ha Neui
authors.initials: HN
authors.lastname: Kim
authors.affiliation: Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Yu Ri
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Division of Clinical Medicine 1, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Hong
authors.affiliation: Central Instrument Facility, Biomaterial Analytical Lab., Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Dong Won
authors.initials: DW
authors.lastname: Bae
authors.affiliation: Department of Horticultural Bioscience, College of Natural Resource and Life Science, Pusan National University, Miryang, Gyeongnam, Republic of Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.affiliation: Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea ; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Byung Tae
authors.initials: BT
authors.lastname: Choi
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005233:Fatty Alcohols / Q000302:isolation & purification / Q000494:pharmacology*; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000494:pharmacology*; D055668:Photochemical Processes; D061251:Primary Cell Culture; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013927:Thrombosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D032070:Uncaria / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C000591151:1-methoxyoctadecan-1-ol; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D007093:Imidazoles; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C489931:Ptpn5 protein, rat; D002154:Calpain; C093642:SB 203580