Dibenzocyclooctadiene Lignans From Schisandra chinensis Protect Primary Cultures of Rat Cortical Cells From Glutamate- Induced Toxicity So Ra Kim, 1 Mi Kyeong Lee, 1 Kyung Ah Koo, 1 Seung Hyun Kim, 1 Sang Hyun Sung, 1 Na Gyong Lee, 3 George J. Markelonis, 4 Tae H. Oh, 4 Jae Ho Yang, 2 and Young Choong Kim 1 * 1 College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul, Korea 2 College of Dentistry, Seoul National University, Seoul, Korea 3 Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea 4 Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland A methanolic extract of dried Schisandra fruit (Schisandra chinensis Baill.; Schisandraceae) significantly attenuated the neurotoxicity induced by L-glutamate in primary cul- tures of rat cortical cells. Five dibenzocyclooctadiene lig- nans (deoxyschisandrin, gomisin N, gomisin A, schisandrin, and wuweizisu C) were isolated from the methanolic ex- tract; their protective effects against glutamate-induced neurotoxicity were then evaluated. Among the five lignans, deoxyschisandrin, gomisin N, and wuweizisu C significantly attenuated glutamate-induced neurotoxicity as measured by 1) an inhibition in the increase of intracellular [Ca 2+ ]; 2) an improvement in the glutathione defense system, the level of glutathione, and the activity of glutathione peroxi- dase; and 3) an inhibition in the formation of cellular perox- ide. These results suggest that dibenzocyclooctadiene lig- nans from Schisandra chinensis may possess therapeutic potential against oxidative neuronal damage induced by excitotoxin. © 2004 Wiley-Liss, Inc. Key words: dibenzocyclooctadiene lignans; excitotoxic cell damage; glutathione defense system; neuroprotec- tive activity; Schisandra chinensis L-glutamate is a major amino acid associated with central excitatory neurotransmission as occurs in neuronal survival, synaptogenesis, neuronal plasticity, learning, and memory processes in the brain (Albright et al., 2000). However, glutamate also causes neuronal cell loss (Choi, 1988; Coyle and Puttfarcken, 1993) by two distinct forms of response, acute and delayed (Choi, 1985, 1987). Glutamate-induced neuronal cell death may be involved in neurological disorders such as seizures (Lipton and Rosenberg, 1994), ischemia, and spinal cord trauma (Heintz and Zoghbi, 2000) and neurodegenerative disor- ders such as Alzheimer’s disease (Michaelis, 2003) and Parkinson’s disease (Mattson et al., 1999). Thus, neuro- protection against glutamate-induced neurotoxicity has been a therapeutic strategy for preventing and/or treating both acute and chronic forms of neurodegeneration (Muir and Lees, 1995; Trist, 2000). In Oriental countries, natural products have been used for the treatment of certain neurological illnesses. Therefore, we have examined several natural products for an ability to protect rat cortical cell cultures from the deleterious effects of the neurotoxicant glutamate as a primary screening method. In the course of screening extracts of natural products, we found that the total extract of ripe Schisandra fruits (Schisandra chinensis Baill.; Schisan- draceae) could protect neuronal cells against glutamate- induced neurotoxicity. In Oriental societies, ripe Schisan- dra fruits have been used as a tonic (Liu, 1985). The fruit of S. chinensis was known to be enriched in lignans; more than 30 lignans have been isolated from this fruit (Naka- jima et al., 1983). Several lignans, including wuweizisu C and gomisin A, have been reported to protect the liver from hepatotoxicity induced by carbon tetrachloride, galactosamine, and acetaminophen (Hikino et al., 1984; Kiso et al., 1985; Yamada et al., 1993; Ko et al., 1995). Pharmacological studies of lignans have also revealed an- tiinflammatory (Wang et al., 1994), anticancer (Yasukawa et al., 1992), and anti-HIV effects (Fujihashi et al., 1995). To date, however, there are no reports concerning their specific neuroprotective activity. Therefore, we attempted to isolate the neuroprotective constituents of the methan- Contract grant sponsor: National Center for Complementary and Alternative Medicine at the National Institutes of Health; Contract grant number: RO1- AT00106-05; Contract grant sponsor: Brain Korea 21 project in 2003. *Correspondence to: Young Choong Kim, PhD, College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, Korea. E-mail: youngkim@plaza.snu.ac.kr Received 10 October 2003; Revised 26 January 2004; Accepted 28 January 2004 Published online 19 March 2004 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.20089 Journal of Neuroscience Research 76:397– 405 (2004) © 2004 Wiley-Liss, Inc.