Neuroprotective Compound from an Endophytic Fungus, Colletotrichum sp. JS-0367 Ji Hoon Song, †,# Changyeol Lee, ‡,# Dahae Lee, §,# Soonok Kim, ⊥ Sunghee Bang, ‡ Myoung-Sook Shin, § Jun Lee, ∥,▽ Ki Sung Kang,* ,§ and Sang Hee Shim* ,‡ † Department of Medicine, University of Ulsan College of Medicine, Seoul 05505, South Korea ‡ College of Pharmacy, Duksung Women’s University, Seoul 01369, South Korea § College of Korean Medicine, Gachon University, Seongnam 13120, South Korea ⊥ National Institute of Biological Resources, Incheon 22689, South Korea ∥ Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea ▽ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, South Korea * S Supporting Information ABSTRACT: Colletotrichum sp. JS-0367 was isolated from Morus alba (mulberry), identified, and cultured on a large scale for chemical investigation. One new anthraquinone (1) and three known anthraquinones (2−4) were isolated and identified using spectroscopic methods including 1D/2D-NMR and HRESIMS. Although the neuroprotective effects of some anthraquinones have been reported, the biological activities of the four anthraquinones isolated in this study have not been reported. Therefore, the neuroprotective effects of these compounds were determined against murine hippocampal HT22 cell death induced by glu- tamate. Compound 4, evariquinone, showed strong protective effects against HT22 cell death induced by glutamate by the inhibition of intracellular ROS accumulation and Ca 2+ influx triggered by glutamate. Immunoblot analysis revealed that com- pound 4 reduced the phosphorylation of MAPKs (JNK, ERK1/2, and p38) induced by glutamate. Furthermore, compound 4 strongly attenuated glutamate-mediated apoptotic cell death. T he extracts of root barks, leaves, and fruits of Morus alba L. (mulberry) have been used to improve health for a long time in oriental medicine. 1 The leaves of mulberry trees have been valued as a primary food for silkworms for centuries. Pre- vious studies have reported on the anti-inflammatory and hypo- glycemic activities of the bark extract and the antidiabetic, anti- atherosclerotic, antiobesity, and hepatoprotective activities of the leaf extract. 2,3 Endophytic fungi, which live within the tissues of the plant, have notable mutualistic symbiotic relationships with their host plant. 4 Endophytes have been considered as poten- tial sources for various bioactive metabolites with intriguing structures, which could be useful drug candidates. 4 Among the endophytes, Colletotrichum sp., a filamentous fungus, is dis- tributed worldwide and is genetically diverse; 5 its extracts and secondary metabolites have shown antimicrobial activities against bacteria and fungi. 6 Oxidative stress is known to be a major cause of neuronal cytotoxicity in the central nervous system (CNS). The brain is highly vulnerable to oxidative stress because of its relatively high demand for oxygen and unsaturated fat content. 7 Although glu- tamate is a well-known CNS excitatory neurotransmitter, an excess concentration can trigger neuronal cell death by excitotoxicity and oxidative stress and contributes to neurological diseases, including Alzheimer’s diseases, Parkinson’s disease, ischemic brain injuries, traumatic brain injuries, amyotrophic lateral sclerosis, and epilepsy. 8−11 Glutamate-mediated oxidative stress is mainly Received: January 10, 2018 Article pubs.acs.org/jnp Cite This: J. Nat. Prod. XXXX, XXX, XXX-XXX © XXXX American Chemical Society and American Society of Pharmacognosy A DOI: 10.1021/acs.jnatprod.8b00033 J. Nat. Prod. XXXX, XXX, XXX−XXX