Isolation of a diterpenoid substance with potent neuroprotective activity from fetal calf serum

Toshiaki Kume, Naoki Asai, Hiroyuki Nishikawa, Nariyasu Mano, Taro Terauchi, Ryota Taguchi, Hisashi Shirakawa, Fumitaka Osakada, Hiroki Mori, Naoki Asakawa, Masahiro Yonaga, Yukio Nishizawa, Hachiro Sugimoto, Shun Shimohama, Hiroshi Katsuki, Shuji Kaneko, Akinori Akaike

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Abstract

Excess activation of glutamate receptors and production of free radicals including nitric oxide may result in severe and irreversible damage to the mammalian central nervous system (CNS), but endogenous defense systems that protect neurons from these insults are poorly understood. Here, we purified and isolated a neuroprotective substance, which has been named "serofendic acid," from a lipophilic fraction of FCS based on the ability to protect rat primary cortical neurons against nitric oxide cytotoxicity. Mass spectrometry and NMR spectroscopy revealed the chemical structure of serofendic acid (15-hydroxy-17- methylsulfinylatisan-19-oic acid) as a sulfur-containing atisane-type diterpenoid, which is unique among known endogenous substances. Synthetic serofendic acid exhibited potent protective actions on cortical neurons against cytotoxicity of a nitric oxide donor as well as of glutamate, although it did not show appreciable influences on glutamate receptor-mediated responses in these neurons. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on nitric oxide radicals but was capable of inhibiting the generation of hydroxyl radical, a presumed "executor" radical in the nitric oxide-mediated neurotoxic cascade. These findings suggest that serofendic acid is a low-molecular-weight bioactive factor that promotes survival of CNS neurons, probably through the attenuation of free radical-mediated insults.

Original languageEnglish
Pages (from-to)3288-3293
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number5
DOIs
Publication statusPublished - 2002 Mar 5

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    Kume, T., Asai, N., Nishikawa, H., Mano, N., Terauchi, T., Taguchi, R., Shirakawa, H., Osakada, F., Mori, H., Asakawa, N., Yonaga, M., Nishizawa, Y., Sugimoto, H., Shimohama, S., Katsuki, H., Kaneko, S., & Akaike, A. (2002). Isolation of a diterpenoid substance with potent neuroprotective activity from fetal calf serum. Proceedings of the National Academy of Sciences of the United States of America, 99(5), 3288-3293. https://doi.org/10.1073/pnas.052693999